Fibromyalgia PowerPoint Presentation

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology?

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%)

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS)

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper)

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion”

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress?

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes?

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153.

Slide 21 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008).

Slide 22 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907

Slide 23 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation

Slide 25 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212.

Slide 26 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate

Slide 27 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. .

Slide 28 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine ***

Slide 32 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran

Slide 33 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran

Slide 34 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran

Slide 35 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts

Slide 39 -

FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Fibromyalgia Controversies Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties Problems with “causation” Use headache or fatigue models

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Fibromyalgia Controversies Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties Problems with “causation” Use headache or fatigue models -5 0 5 -10 Years relative to index date 0 50 100 150 200 95% CI Case Control Rate per 100 person-years Hughes G, et al. Arthritis Rheum. 2006;54:177-183. Total Rate of Diagnostic Tests Performed on FM Cases and on Matched Controls (N=2,260) Positive Impact of Fibromyalgia Diagnosis in Clinical Practice The vertical line at 0 indicates the date of fibromyalgia diagnosis Decrease in diagnostic testing and visit rates following diagnosis

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Fibromyalgia Controversies Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties Problems with “causation” Use headache or fatigue models -5 0 5 -10 Years relative to index date 0 50 100 150 200 95% CI Case Control Rate per 100 person-years Hughes G, et al. Arthritis Rheum. 2006;54:177-183. Total Rate of Diagnostic Tests Performed on FM Cases and on Matched Controls (N=2,260) Positive Impact of Fibromyalgia Diagnosis in Clinical Practice The vertical line at 0 indicates the date of fibromyalgia diagnosis Decrease in diagnostic testing and visit rates following diagnosis As a first-line approach for patients with moderate to severe pain, trial with evidence-based medications for example: Trial with low-dose tricyclic antidepressants, SSRI, SNRI, antiseizure medication Initial Medication and Non-pharmacologic Treatment of Fibromyalgia Provide additional treatment for comorbid conditions Encourage exercise according to fitness level Stress management techniques Modified From Arnold LM. Arthritis Res Ther 2006;8:212.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Fibromyalgia Controversies Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties Problems with “causation” Use headache or fatigue models -5 0 5 -10 Years relative to index date 0 50 100 150 200 95% CI Case Control Rate per 100 person-years Hughes G, et al. Arthritis Rheum. 2006;54:177-183. Total Rate of Diagnostic Tests Performed on FM Cases and on Matched Controls (N=2,260) Positive Impact of Fibromyalgia Diagnosis in Clinical Practice The vertical line at 0 indicates the date of fibromyalgia diagnosis Decrease in diagnostic testing and visit rates following diagnosis As a first-line approach for patients with moderate to severe pain, trial with evidence-based medications for example: Trial with low-dose tricyclic antidepressants, SSRI, SNRI, antiseizure medication Initial Medication and Non-pharmacologic Treatment of Fibromyalgia Provide additional treatment for comorbid conditions Encourage exercise according to fitness level Stress management techniques Modified From Arnold LM. Arthritis Res Ther 2006;8:212. Polypharmacy; for example, trial of SSRI in AM and tricyclic in PM, SNRI in AM and anti-seizure drug in PM Further Medication and Non-pharmacologic Treatment of Fibromyalgia: Often with Specialists’ Input Trial of additional analgesics such as tramadol Comprehensive pain management program Structured rehabilitation program; Formal mental health program, such as CBT for patients with prominent psychosocial stressors, and/or difficulty coping, and/or difficulty functioning Modified from Arnold LM. Arthritis Res Ther 2006;8:212.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Fibromyalgia Controversies Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties Problems with “causation” Use headache or fatigue models -5 0 5 -10 Years relative to index date 0 50 100 150 200 95% CI Case Control Rate per 100 person-years Hughes G, et al. Arthritis Rheum. 2006;54:177-183. Total Rate of Diagnostic Tests Performed on FM Cases and on Matched Controls (N=2,260) Positive Impact of Fibromyalgia Diagnosis in Clinical Practice The vertical line at 0 indicates the date of fibromyalgia diagnosis Decrease in diagnostic testing and visit rates following diagnosis As a first-line approach for patients with moderate to severe pain, trial with evidence-based medications for example: Trial with low-dose tricyclic antidepressants, SSRI, SNRI, antiseizure medication Initial Medication and Non-pharmacologic Treatment of Fibromyalgia Provide additional treatment for comorbid conditions Encourage exercise according to fitness level Stress management techniques Modified From Arnold LM. Arthritis Res Ther 2006;8:212. Polypharmacy; for example, trial of SSRI in AM and tricyclic in PM, SNRI in AM and anti-seizure drug in PM Further Medication and Non-pharmacologic Treatment of Fibromyalgia: Often with Specialists’ Input Trial of additional analgesics such as tramadol Comprehensive pain management program Structured rehabilitation program; Formal mental health program, such as CBT for patients with prominent psychosocial stressors, and/or difficulty coping, and/or difficulty functioning Modified from Arnold LM. Arthritis Res Ther 2006;8:212. Explaining the Typical Outcome in Fibromyalgia FM does not herald the onset of a systemic disease There is no progressive, structural or organ damage Most patients in specialty practice have chronic, persistent symptoms Primary care patients more commonly report complete remission of symptoms Most patients continue to work, but 10-15% are disabled There is often adverse impact on work and leisure activities Most patients quality of life improves with medical management Granges G, Zilko P, Littlejohn GO.Fibromyalgia syndrome: assessment of the severity of the condition 2 years after diagnosis. J Rheumatol 21:523-529, 1994 Felson DT, Goldenberg DL. The natural history of fibromyalgia. Arthritis Rheum. 1986;29:1522-1526.

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FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia Fibromyalgia Controversies Is it real? What is the relationship with other functional somatic syndromes? Can it be reliably diagnosed? Is it physical or psychological? Is there any effective treatment? Is a diagnosis helpful or harmful? What is role of rheumatology? Primary Care and Functional Illnesses Account for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problem Specialty referral based on most distressing syndrome Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes There are many different “labels” that one can legitimately use for an individual with this type of pain (if one decides to use any label) There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted “ownership” of these patients American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria History of chronic widespread pain ≥3 months Patients must exhibit ≥11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) FM Diagnosis is Very “Physician Dependent” Modified from Goldenberg JAMA 2004 6 Rule out other conditions that may present with chronic widespread pain (“Operator dependent”) History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Rule out other conditions that may present with chronic widespread pain Depending on physician: Mental health evaluation, sleep evaluation History of chronic, widespread pain for ≥3 months Confirm presence of tender points (Fibromyalgia may be present, even if <11 of 18) General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) Confirm diagnosis of fibromyalgia Problems in Defining Fibromyalgia “Real” if no clear pathophysiologic basis? Gold standard is “expert opinion” Tender points, symptoms are subjective Fewer than 11 tender points? Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: “I hurt all over” “It feels like I always have the flu” Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a “fishing” expedition Avoid “screening” rheumatology tests Early subspecialty referral Structured Interview for Fibromyalgia A. Generalized, chronic pain (≥ 3 months) affecting the axial, plus upper and lower segments, plus left and right sides of the body C. At least 4 of the following symptoms 1. Generalized fatigue 2. Headaches 3. Sleep disturbance 4. Neuropsychiatric complaints 5. Numbness, tingling sensations 6. Irritable bowel symptoms Pope HG Jr, Hudson JI. Int J Psychiatry Med 1991;21(3):205-232 A. Widespread pain (axial + upper and lower + L and R sides) B. 11 of 18 reproducible tender points C. At least 4 of: generalized fatigue, headache, sleep disturbance, neuropsych complaints, numbness/tingling, IBS Explained by no other condition Fibromyalgia OR Why Do A Tender Point Exam? Confirm Dx impression Proxy for pain sensitivity Compare to joint tenderness Potential prognostic factor Who Gets Fibromyalgia? No concurrent medical illness Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies Concurrent medical illness (e.g., SLE, RA, OA, hypothyroidism, hepatitis). Important to consider in patients with rheumatic or chronic pain disorders Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Irritable bowel syndrome Muscle, migraine headaches Irritable bladder syndrome Mood disturbances Vulvodynia Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Symptoms rather than signs No reproducible laboratory findings Gold standard is “expert opinion” Is FM Physical or Psychological? Is it a psychiatric illness? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it somatization? What is the role of stress? FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. Increased prevalence of mood disorders is primarily in tertiary-referral patients. Increased lifetime and family history of mood disorders in FM vs RA (Odds = 2.0). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). Arnold LM et al. J Clin Psychiatry 2006;67:1219–1225, Arnold, et al. Arthritis Rheum 200; 50:944-952 Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms FM and Fragmented Sleep Some patients with FM have fragmented sleep, which is associated with involuntary sleep-related periodic disturbances during the night. These disturbances include Periodic limb movements (PLMs) Restless leg syndrome (RLS) Sleep apnea An underlying periodic arousal disturbance in the sleep EEG known as sleep related periodic K-alpha or frequent cyclic alternating EEG sleep pattern (CAP) Al-Alarvi A at al. J Clin Sleep Med. 2006;2:281-287. Jennum P et al. J Rheumatol. 1993;201756-1759. EEG, electroencephalogram. CAP, cyclic alternating pattern. Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Childhood abuse, stress Catastrophizing Imaging studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology FM Pathophysiologic Pathways Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first-degree relatives) No single candidate gene identified Central pain augmentation CSF substance P Neuroimaging studies Autonomic/neuroendocrine dysfunction Immune dysfunction? Structural changes? Genetics of Fibromyalgia Familial predisposition Most recent work by Arnold, et al suggests >8 odds ratio (OR) for first-degree relatives, and much less familial aggregation (OR 2) with major mood disorders, much stronger with bipolarity, obsessive compulsive disorder1 Genes that may be involved 5-HT2A receptor polymorphism T/T phenotype2 Serotonin transporter3 Dopamine D4 receptor exon III repeat polymorphism4 COMT (catecholamine o-methyl transferase)5 1. Arnold LM, et al. Arthritis Rheum. 2004;50:944-952. 2. Bondy B, et al. Neurobiol Dis. 1999;6:433-439. 3. Offenbaecher M, et al. Arthritis Rheum. 1999;42:2482-2488. 4. Buskila D, et al. Mol Psychiatry. 2004;9:730-731. 6. Gürsoy S, et al. Rheumatol Int. 2003;23:104-107. “Pain Matrix” – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Thalamus Posterior insula Affective – Emotional valence of pain Anterior cingulate cortex Anterior insula Amygdala Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones1 Insular hyper-reactivity consistently seen2-4 H-MRS studies of glutamate levels in posterior insula5 1. Geisser et. al. J. Pain (2008); 2. Gracely et. al. Arthritis Rheum. 46, 1333-1343 (2002); 3. Giesecke et. al. Arthritis Rheum. 50, 613-623 (2004); 4. Cook J Rheumatol. 31, 364-378 (2004); 5. Harris et. al. Arthritis Rheum. 58, 903-907 (2008). Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception In FM, levels of depression did not modulate the sensory aspects of pain but correlated with the magnitude of brain activation in the medial region of the brain. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Gracely et al. Arthritis Rheum. 2002;46:1333-1343. Giesecke, et al Arthritis Rheum 2005 52:1577 Harris, et al Arthritis Rheum 2008 58, 903-907 Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia CSF=cerebrospinal fluid; PET=positron emission tomography. 1. Baraniuk JN et al. BMC Musculoskelet Disord. 2004;5:48; 2. Harris JA et al. J Neurosci. 2007;27:7136-7140; 3. Russell IJ et al. Arthritis Rheum. 1992;35:550-556. Is There Any Effective Management of Fibromyalgia? All patients Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Most patients Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Physical rehabilitation Initial Treatment of Fibromyalgia May require referral to a specialist for full evaluation; for example: To psychiatry, sleep clinic Assess psychosocial stressors, level of fitness, and barriers to treatment Provide education about fibromyalgia Modified from Arnold LM. Arthritis Res Ther 2006;8:212. FM: From Mechanism to Treatment This is primarily a neural disease and “central” factors play a critical role This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Lack of sleep or exercise increases pain and other somatic sx, even in normals How FM patients think about their pain (cognitions) may directly influence pain levels Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Genetic predisposition 5-HT2A receptor polymorphism ↑ Pain severity in FM patients with T/T genotype ↑ Frequency of S/S genotype in FM patients compared with healthy controls ↑ Incidence of COMT polymorphism in FM patients Substance P increased in CSF 5-HT and NE serum levels decreased in some studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Russell IJ et al. Arthritis Rheum. 1992;35:550-556 Bondy B et al. Neurobiol Dis. 1999;6:433-439; Offenbaecher M et al. Arthritis Rheum. 1999;42:2482-2488. Arnold LM, et al. Arthritis Rheum. 2004;50:944-52. Moldofsky H. Adv Neuroimmunol. 1995;5:39-56. Buskila D, Sarzi-Puttini P. Arthritis Res Ther. 2006;8(5):218 Harris RE, et al. Arthritis Rheum. 2008;58:903-907. . Medications in FMS Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine No evidence: opioids, NSAIDS, benzodiazepene and nonbenzodiazepene hypnotics, melatonin, magnesium, DHEA, thyroid hormone, OTC including guaifenesin Modified from Goldenberg, et al: Management of fibromyalgia syndrome. JAMA 2004; 292:2388-95. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo-controlled trials Goldenberg,1985 Carette,1986 Carette,1994 Dose 25 – 50 mg Duration 6-26 weeks All showed modest efficacy CYCLOBENZAPRINE Four placebo-controlled trials Quimby, 1989 Carette, 1994 Reynolds,1991 Dose 10 – 40 mg Duration 4 – 12 weeks 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113. Pregabalin in Fibromyalgia Patient Global Impression of Change Treatment Group (mg/day) p < 0.01 vs PBO % Patients p < 0.01 vs PBO Crofford L, et al. Arth Rheum 2005; 52: 1264-1273 Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 -1 0 0 1 2 4 6 8 10 12 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 ***P≤.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine *** (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran Number – 1196 Parallel, PL controlled, double blind Randomized to M 100 or 200 mg or placebo for 3 months Completers – 810 (68%) Pain composite – VAS - 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 3 mnths 39,46% achieved Pain composite, v 25% PL (0.011, 0.015) 25,26% achieved FM composite, v 13% PL (0.025, 0.004) Generally well tolerated (discontinuations 34,35% v 28% PL) Common AEs – nausea M – 37%, PL -20% (both studies) headache M – 18%, PL -14% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran Milnacipran Phase III (6 months) Number – 888 Randomized to M 100 or 200 mg or placebo for 6 months Completers – 511 (58%) Pain composite - VAS, 30% + very much or much impr on PGIC FM composite – pain composite + 6 pt impr on PCS of SF36 Secondary – PGIC, SF36 (PCS and MCS) and FIQ total Baseline observation carried forward (BOCF) at 6 mnths 44,45% achieved Pain composite, v 28% PL (0.056, 0.032) 33,32% achieved FM composite, v 19% PL (0.028, 0.017) Milnacipran Nonpharmacologic Strategies: Evidence of Efficacy Strong Evidence Exercise Physical and psychological benefits May increase aerobic performance and tender point pain pressure threshold, and improve pain Efficacy not maintained if exercise stops Cognitive-behavioral therapy Improvements in pain, fatigue, mood, and physical function Improvement often sustained for months Patient education/self-management Improves pain, sleep, fatigue, and quality of life Combination (multidisciplinary therapy) Goldenberg DL, et al. JAMA. 2004;292:2388-2395; Williams DA, et al. J Rheumatol. 2002;29:1280-1286; Busch AJ, et al. Cochrane Database Syst Rev. 2002 FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better prognosis Longer-term studies with larger study populations are needed to define risk factors for prognosis and to determine outcome relative to those risk factors Modified from Horizon A and Weisman MH. In Fibromyalgia and Other Pain Related Syndromes. 2006, p. 401. Patient, Family Education Primary care or specialist setting. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Encourage patient participation. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) Other specialists should include mental health professionals, physiatrists and pain management experts Physical medicine/rehabilitation Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Stretching, strengthening OT, work rehab, ergonomics Mental health professional Psychopharmacology Counseling CBT Multidisciplinary FM Treatment Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Only one controlled study; it didn’t Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Fibromyalgia Controversies Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties Problems with “causation” Use headache or fatigue models -5 0 5 -10 Years relative to index date 0 50 100 150 200 95% CI Case Control Rate per 100 person-years Hughes G, et al. Arthritis Rheum. 2006;54:177-183. Total Rate of Diagnostic Tests Performed on FM Cases and on Matched Controls (N=2,260) Positive Impact of Fibromyalgia Diagnosis in Clinical Practice The vertical line at 0 indicates the date of fibromyalgia diagnosis Decrease in diagnostic testing and visit rates following diagnosis As a first-line approach for patients with moderate to severe pain, trial with evidence-based medications for example: Trial with low-dose tricyclic antidepressants, SSRI, SNRI, antiseizure medication Initial Medication and Non-pharmacologic Treatment of Fibromyalgia Provide additional treatment for comorbid conditions Encourage exercise according to fitness level Stress management techniques Modified From Arnold LM. Arthritis Res Ther 2006;8:212. Polypharmacy; for example, trial of SSRI in AM and tricyclic in PM, SNRI in AM and anti-seizure drug in PM Further Medication and Non-pharmacologic Treatment of Fibromyalgia: Often with Specialists’ Input Trial of additional analgesics such as tramadol Comprehensive pain management program Structured rehabilitation program; Formal mental health program, such as CBT for patients with prominent psychosocial stressors, and/or difficulty coping, and/or difficulty functioning Modified from Arnold LM. Arthritis Res Ther 2006;8:212. Explaining the Typical Outcome in Fibromyalgia FM does not herald the onset of a systemic disease There is no progressive, structural or organ damage Most patients in specialty practice have chronic, persistent symptoms Primary care patients more commonly report complete remission of symptoms Most patients continue to work, but 10-15% are disabled There is often adverse impact on work and leisure activities Most patients quality of life improves with medical management Granges G, Zilko P, Littlejohn GO.Fibromyalgia syndrome: assessment of the severity of the condition 2 years after diagnosis. J Rheumatol 21:523-529, 1994 Felson DT, Goldenberg DL. The natural history of fibromyalgia. Arthritis Rheum. 1986;29:1522-1526. Interdisciplinary Pain Management Integrated Coordinated Neurologist Social Worker Pain Specialist Physical Therapist Psychiatrist Anesthesiologist Physiatrist Psychologist Nurses Rheumatologist Occupational Therapist Pharmacist Physician Assistant Primary Clinician