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Author(s): Daniel J. Clauw, M.D., 2009
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Professor of Anesthesiology and Medicine (Rheumatology)
Associate Dean for Clinical and Translational Research
The University of Michigan
Fall 2008
M2 Musculoskeletal Mechanistic Characterization of Pain Peripheral (nociceptive) Primarily due to inflammation or mechanical damage in periphery
NSAID, opioid responsive
Responds to procedures
Behavioral factors minor
Examples
Osteoarthritis
Rheumatoid arthritis
Cancer pain Neuropathic Damage or entrapment of peripheral nerves
Responds to both peripheral and central pharmacological therapy Central (non-nociceptive) Primarily due to a central disturbance in pain processing
Tricyclic, neuroactive compounds most effective
Behavioral factors more prominent
Examples
Fibromyalgia
Irritable bowel syndrome
Tension headache
Idiopathic low back pain D. Clauw Paradigm Shift in Fibromyalgia Anterior Posterior Discrete illness
Focal areas of tenderness
Psychologic and behavioral factors nearly always present and negative
Chronic widespread pain
Tenderness in ≥11 of 18 tender points American College of Rheumatology (ACR) Criteria Final common pathway
Part of a larger continuum
Many somatic symptoms, diffuse tenderness
Psychologic and behavioral factors play roles in some individuals Source Undetermined Source Undetermined Fibromyalgia
2%-4% of population
Defined by widespread pain and tenderness Chronic Fatigue Syndrome (CFS)
1% of population
Fatigue and 4 of 8 “minor criteria” Somatoform Disorders
4% of population
multiple unexplained symptoms — no “organic” findings Regional Pain Syndromes
eg, irritable bowel [IBS]
Painful bladder / interstitial cystitis [PBS/IC]
TMD
Tension HA
Vulvodynia Overlap Between Fibromyalgia and Related Syndromes LBP = low back pain; TMD = temporomandibular disorders.
Clauw and Chrousos. Neuroimmunomodulation. 1997;4:134-53. Pain and/or
sensory
amplification
Psychiatric Disorders
Major depression
OCD
Bipolar
PTSD
GAD
Panic attack D. Clauw Shared features Characterized by multiple somatic symptoms and high rates of comorbidities with other related syndromes
1.5 – 2X more common in females
Strong familial/genetic underpinnings
Triggered or exacerbated by “stressors”
Pain and/or sensory amplification most reproducible pathophysiological feature
Dysautonomia, neuroendocrine dysfunction, and neurogenic inflammation also commonly noted, but of unclear physiological significance “Stressors” Capable of Triggering These Illnesses (Supported by Case-Control Studies1,2) Early life stressors3
Children born in 1958 who had experienced a motor traffic accident or who were institutionalized were 1.5 – 2X more likely to have CWP 42 years later
Peripheral pain syndromes (e.g. RA, SLE, osteoarthritis)4
Physical trauma (automobile accidents)5
Certain catastrophic events (war but not natural disasters)6
Infections
Psychological stress/distress Sources: 1. Clauw and Chrousos. Neuroimmunomodulation. 1997;4:134-53. 2. McLean and Clauw. Med Hypotheses. 2004;63:653-8.
3. Jones et al. ACR Meeting. 2007. 4. Clauw et al. JCR. 1997.
5. McBeth. ACR Meeting. 2006. 6. Clauw et al. J Occup Environ Med. 2003;45:1040-8. Genetics of Fibromyalgia Familial predisposition1
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 disorder
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 Sources: 1. Arnold et al. Arthritis Rheum. 2004;50:944-52. 2. Bondy et al. Neurobiol Dis. 1999;6:433-9. 3. Offenbaecher et al. Arthritis Rheum. 1999;42:2482-8. 4. Buskila et al. Mol Psychiatry. 2004;9:730-1. 5. Gürsoy et al. Rheumatol Int. 2003;23:104-7. Conditions Characterized by Widespread Secondary Hyperalgesia / Allodynia Fibromyalgia
Temperomandibular disorder1,2
Headache (tension > migraine)3,4
Idiopathic low back pain5,6
Vulvodynia/vulvar vestibulitis7
Whiplash associated disorder8
IBS9,10 Sources: 1. Maixner et al. Pain. 1995;63:341-51. 2. Kashima et al. Cranio. 1999;17:241-246. 3. Langemark et al. Arch Neurol. 1993;50:1061-4. 4. Buchgreitz et al. Pain. 2006;123:19-27. 5. Giesecke et al. Arthritis Rheum. 2004;50:613-23. 6. Giesbrecht and Battie. Phys Ther. 2005;85:1085-92. 7. Giesecke et al. Obstet Gynecol. 2004;104:126-33. 8. Lemming et al. Clin J Pain. 2005;21:412-21. 9. Whitehead at al. Gastroenterology. 1990;98:336-40. 10. Mertz et al. Gastroenterology. 1995;109:40-52. Supraspinal Influences on Pain and Sensory Processing Substance P
Glutamate and EAA
Serotonin (5HT2a, 3a)
Nerve growth factor
CCK Descending anti-nociceptive pathways
Norepinephrine- serotonin (5HT1a,b), dopamine
Opioids
GABA
Cannabanoids
Adenosine Facilitation Inhibition Source Undetermined (All Images) D. Clauw Fibromyalgia Cerebrospinal Fluid Substance P 1. Vaeroy et al. Pain. 1988;32:21-6. 2. Russell et al. Arthritis Rheum. 1994;37:1593-601.
3. Liu et al. Peptides. 2000;21:853-60. 4. Bradley and Alarcon. Arthritis Rheum. 1999;42:2731-2. 1 2 3 4 Substance P (ng/ml) D. Clauw *P<0.003; **P<0.001. BDNF, brain-derived neurotrophic factor; EAA, excitatory amino acid; NGF, nerve growth factor.
N=20 patients with fibromyalgia and 20 control subjects.
Sarchielli et al. J Pain. 2007;8:737-45. Increased Spinal Fluid Levels Of Glutamate and Neurotrophins EAAs Neurotrophins CSF Neurotrophins, pg/mL ** ** * CSF Glutamate, µmol/L NGF BDNF FM NC FM NC D. Clauw *P=0.028; **P=0.057; ***P=0.005 vs nonfibromyalgia controls. 5-HIAA, 5-hydroxyindole acetic acid; HVA, homovanillic acid; MHPG, 3-methoxy-4-hydroxyphenethylene glycol.
N=17 patients with fibromyalgia, 5 patients with rheumatoid arthritis, and 7 control subjects.
Russell et al. Arthritis Rheum. 1992;35:550-6. Decreased Spinal Fluid Levels Of Biogenic Monoamines CSF Biogenic Amines, ng/mL * *** MHPG RA NC FM RA NC FM RA NC FM 5-HIAA HVA ** D. Clauw “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 prefrontal regions Source:
Melzack and Wall. Science. 1965;150:971-9.
Casey. Headache. 1969;8:141-53. fMRI of Evoked Pressure Pain in Fibromyalgia and Related Conditions Is there objective evidence of augmented pain processing in fibromyalgia?1
Role of depression in pain processing in FM2
Role of cognitive factors in pain processing in FM
Locus of control
Catastrophizing3
fMRI changes of augmented central processing of pain also seen in idiopathic low back pain4 Sources:
1. Gracely et al. Arthritis Rheum. 2002;46:1333-43. 2. Giesecke et al. Arthritis Rheum. 2003;48:2916-22.
3. Gracely et al. Brain. 2004;127:835-43. 4. Giesecke et al. Arthritis Rheum. 2004;50:613-23. Stimuli and Responses During Pain Scans IPL SII STG, Insula, Putamen Cerebellum SI SI (decrease) STG=superior temporal gyri; SI=primary somatosensory cortex; SII=secondary somatosensory cortex; IPL=inferior parietal lobule.
Gracely et al. Arthritis Rheum. 2002;46:1333-43. 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
Sources:
1. Geisser et al. J Pain. 2008;9:417-22. 2. Gracely et al. Arthritis Rheum. 2002;46:1333-43.
3. Giesecke et al. Arthritis Rheum. 2004;50:613-23. 4. Cook et al. J Rheumatol. 2004;31:364-78.
5. Harris et al. Arthritis Rheum. 2008;58:903-7. Reduction in Glu is Associated with Reduced Experimental Pressure Pain in FM Less Glu (post) Less Pain Sensitivity (post) r=-0.95; P<0.001. Change in Pressure (kg; pre-post) Change in Glu/Cr (post-pre) Harris et al. Arthritis Rheum. 2008;58:903-7. Specific Underlying Mechanisms in Fibromyalgia Decreased descending analgesic activity
Absent or attenuated DNIC in FM and IBS1-3
Brainstem activations with conditioning stimulus seen in controls but not in FM patients4 Source:
1. Kosek and Hansson. Pain. 1997;70:41-51. 2. Julien et al. Pain. 2005;114:295-302.
3. Wilder-Smith and Robert-Yap. World J. Gastroenterol. 2007;13:3699-704. 4. Gracely et al. Arthritis Rheum. 2006 (abstract). There is a Deficiency of Descending Analgesic Activity in FM:1,2 Which one? Opioids
Normal or high levels of CSF enkephalins3
Never been 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 FM4
Noradrenergic/Serotonergic
Low levels of biogenic monoamines in CSF in FM5
Nearly any class of drug that raises both serotonin and norepinephrine has demonstrated efficacy in FM Sources:
1. Kosek and Hansson. Pain. 1997;70:41-51. 2. Julien et al. Pain. 2005;114:295-302.
3. Baraniuk et al. BMC Musculoskelet Disord. 2004;5:48. 4. Harris et al. J Neurosci. 2007;27:10000-6.
5. Russell et al. Arthritis Rheum. 1992;35:550-6. FM Patients Have Reduced MOR Availability Z 4.12 4.21 3.39
P-Value* <0.05 < 0.05 <0.05
%D BP 33.1(7.1) 31.1(7.0) 21.5(6.4) *corrected L NAcc lAMY L dCC Harris et al. J Neurosci. 2007;27:10000-6. Is Chronic Pain a Neurodegenerative Disease? Apkarian1 was first to show that chronic pain may be a neurodegenerative disease, showing
Decreased gray matter density in DLPFC and thalamus
Related to length of pain
More recently seen in other pain states including
Headache (insula and ACC)2
IBS (insula and ACC)3
Fibromyalgia4 (multiple regions)
PTSD5 (insula) Sources:
1. Apkarian et al. J Neurosci. 2004;24:10410-5. 2. Schmidt-Wilcke et al. Pain. 2007;132 Suppl 1:S109-16.
3. Davis et al. Neurology. 2008;70:153-4. 4. Kuchinad et al. J Neurosci. 2007;27:4004-7.
5. Chen et al. Psychiatry Res. 2006;146:65-72. The Biopsychosocial Continuum Neurobiological
Abnormal sensory processing
Autonomic dysfunction
HPA dysfunction
Psychiatric disorders
? Peripheral nociceptive input Psychosocial factors
General “distress”
Psychiatric comorbidities
Cognitive factors
Maladaptive illness behaviors
Secondary gain issues Population Primary Care Tertiary Care Source: Aaron et al. Arthritis Rheum. 1996;39:436-45. FM: From Mechanism to Treatment This is a polygenic disorder There will be subgroups of FM needing different treatments Treatments aimed at the periphery (i.e., drugs, injections) are not very efficacious This is primarily a neural disease and “central” factors play a critical role There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters Drugs that raise norepinephrine and serotonin, or lower levels of excitatory neurotransmitters, will be efficacious in some Lack of sleep or exercise increase pain and other somatic sx, even in normals Exercise, “sleep hygiene,” and other behavioral interventions are effective therapies for biological reasons How FM patients think about their pain (cognitions) may directly influence pain levels Cognitive therapies are effective in FM and have a biological substrate So How Do I Really Diagnose Fibromyalgia? The History – I Pain
Current and lifetime history of widespread pain
The more widespread, the more likely it is fibromyalgia
“I hurt all over”
Pain felt in any area of musculoskeletal and non-musculoskeletal regions
Often “unpredictable”, worsened by stress
Often accompanied by stiffness, non-dermatomal paresthesias So How Do I Really Diagnose Fibromyalgia? The History – II Other somatic symptoms
Fatigue
Not made better by rest or exercise
Memory difficulties
Difficulty with memory and concentration
Insomnia and sleep disturbances
Co-morbid syndromes
Irritable bowel
Interstitial cystitis
Headache
TMJ/TMD So How Do I Really Diagnose Fibromyalgia? Family History Family history of other pain syndromes Past Medical History Regional somatic and visceral pain syndromes
Psychiatric disorders Social History Symptoms often triggered or exacerbated by “stressors” Physical Exam Normal except for diffuse tenderness
Tenderness not just confined to the joints D. Clauw Diagnostic Work-up Intensity of evaluation depends largely on history
If symptoms acute or sub-acute extensive evaluation necessary
If symptoms have lasted for many years and history is classic virtually no work-up is necessary
Laboratory evaluation at some point in illness
ESR, CRP
CBC and chemistry profile
TSH, Vitamin D
Avoid serological studies e.g. ANA, RF Treatment of Fibromyalgia and Other Central Pain Syndromes Education Aerobic Exercise Pharmacological Therapy Cognitive Behavioral Therapy (CBT) D. Clauw Summary Increased
Neurotransmitters
Serotonin
Norepinephrine
Opioids
Exercise
Sleep
Decreased
Neurotransmitters
Glutamate
Substance P
Nerve growth factor
Cognitions
Catastrophizing
External locus of control
0 2 4 6 8 10 12 14 16 Pain Threshold D. Clauw Pharmacological Therapies Modified from Goldenberg et al. JAMA. 2004;292:2388-95. Strong Evidence Dual reuptake inhibitors such as
Tricyclic compounds (amitriptyline, cyclobenzaprine)
SNRIs and NSRIs (milnacipran, duloxetine, venlafaxine?)
Anticonvulsants (e.g., pregabalin, gabapentin) Modest Evidence Tramadol
Selective serotonin reuptake inhibitors (SSRIs)
Gamma hydroxybutyrate
Dopamine agonists Weak Evidence Growth hormone, 5-hydroxytryptamine, tropisetron, S-adenosyl-L-methionine (SAMe) No Evidence Opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and nonbenzodiazepine hypnotics, guanifenesin Supraspinal Influences on Pain Processing + Substance P
Glutamate and EAA
Serotonin (5HT2a, 3a)
Neurotensin
Nerve growth factor
CCK Descending anti-nociceptive pathways
Norepinephrine- serotonin (5HT1a,b), dopamine
Opioids
GABA
Cannabanoids
Adenosine Facilitation Inhibition Source Undetermined (All Images) D. Clauw Likely MOA of Dual-Reuptake Inhibitors + Substance P
Glutamate and EAA
Serotonin (5HT2a, 3a)
Neurotensin
Nerve growth factor
CCK Descending anti-nociceptive pathways
Norepinephrine- serotonin (5HT1a,b), dopamine
Opioids
GABA
Cannabanoids
Adenosine Facilitation Inhibition Source Undetermined (All Images) D. Clauw Possible MOA of Pregabalin/Gabapentin + Substance P
Decrease SP release in inflammatory states1
Glutamate and EAA
Inhibit SP-induced glutamate release2 Descending anti-nociceptive pathways
Norepinephrine- serotonin (5HT1a,b), dopamine
Opioids
GABA
Cannabanoids
Adenosine Facilitation Inhibition Sources: 1. Fehrenbacher et al. Pain. 2003;105:133-41. 2. Maneuf et al. Pain. 2001;93:191-6. Source Undetermined (All Images) D. Clauw There is a Deficiency of Descending Analgesic Activity in FM:1,2 Which one? Opioids
Normal or high levels of CSF enkephalins3
Never been 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 FM4
Noradrenergic/Serotonergic
Low levels of biogenic monoamines in CSF in FM5
Nearly any class of drug that raises both serotonin and norepinephrine has demonstrated efficacy in FM Sources:
1. Kosek and Hansson. Pain. 1997;70:41-51. 2. Julien et al. Pain. 2005;114:295-302.
3. Baraniuk et al. BMC Musculoskelet Disord. 2004;5:48. 4. Harris et al. J Neurosci. 2007;27:10000-6.
5. Russell et al. Arthritis Rheum. 1992;35:550-6. Relative Activity on Serotonin and Norepinephrine Reuptake Among Antidepressants Citalopram
Fluvoxamine
Sertraline
Paroxetine
Fluoxetine Venlafaxine
Duloxetine
Maprotiline
Desipramine
Nortriptyline
Reboxetine Amitriptyline
Milnacipran
Imipramine Antidepressant Fishbain et al. Pain Med. 2000;1:310-6. Serotonin Mixed Norepinephrine Analgesic/Antidepressant Nonpharmacological Therapies Goldenberg et al. JAMA. 2004;292:2388-95. Strong Evidence Education
Aerobic exercise
Cognitive behavior therapy Modest Evidence Strength training
Hypnotherapy, biofeedback, balneotherapy Weak Evidence Acupuncture, chiropractic, manual and massage therapy, electrotherapy, ultrasound No Evidence Tender (trigger) point injections, flexibility exercise Pharmacological therapies to improve symptoms Increased Distress
Decreased activity
Isolation
Poor sleep
Maladaptive illness behaviors Nociceptive processes (damage or inflammation of tissues)
Disordered sensory processing Clauw and Crofford. Best Pract Res Clin Rheumatol. 2003;17:685-701. Symptoms of Pain, Fatigue, etc. Functional Consequences of Symptoms Dually Focused Treatment Nonpharmacological therapies to address dysfunction Exercise Aerobic exercise nearly universally beneficial; tolerance, compliance, adherence are biggest issues
To maximize benefits
Begin several months after pharmacologic therapy
Begin with low-impact exercises; avoid strength training until late
Both physician and patient should consider this as a “drug”
Less evidence supporting strengthening, stretching Exercise for Treating Fibromyalgia: Cochrane Review Aerobic
training (17) Strength
training (3) Flexibility (2) ACSM Guidelines
2 days/week
40% to 85% HR reserve
55% to 90% maximum HR
20 minutes
6 weeks ACSM=American College of Sports Medicine; HR=heart rate. 20 RCTs Met ACSM Guidelines 34 RCTs
47 Interventions Aerobic only: 6 moderate to high-quality RCTs Strength only: 2 low-quality RCTs Busch AJ et al. Cochrane Database Syst Rev. 2007;(4):CD003786. Cognitive Behavioral Therapy A program designed to teach patients techniques to reduce their symptoms, to increase coping strategies, and to identify and eliminate maladaptive illness behaviors
Shown to be effective for nearly any chronic medical illness
Not all CBT is created equally; very dependent on content, therapist and program Improvements Noted in CBT vs Standard Care Over 12 Months (n=122) *Clinically significant. OR 2.9, P<.05. * Patients (%) Williams DA et al. J Rheumatol. 2002;29:1280-1286. Recommended Approach Education
Identify and treat “peripheral” pain generators
For patients who need or want medications, start with low doses of mixed tricyclic antidepressants (amitriptyline, cyclobenzaprine); start low, go slow
If patient has depression, memory problems, fatigue as most prominent symptoms
Add mixed reuptake inhibitor (eg, duloxetine, milnacipran, venlafaxine) or SSRI (may need high doses)
If patient has sleep disturbance as most prominent symptom
Use pregabalin or gabapentin first, give higher % of dose at night Source: Clauw and Crofford. Best Pract Res Clin Rheumatol. 2003;17:685-701. Recommended Approach - II If no response, consider use of dopamine agonist, sodium oxybate
For additional analgesic effect, add tramadol, tizanidine, opioids
For sleep, if patient doesn’t tolerate TCA, use zolpidem, zaleplon, trazodone
Aggressively introduce non-pharmacological therapies Source: Clauw and Crofford. Best Pract Res Clin Rheumatol. 2003;17:685-701. Conclusions Fibromyalgia has strong neurobiological underpinnings
This is a polygenic disorder characterized by pain and sensory amplification
There is evidence of increased levels of pro-nociceptive neurotransmitters (e.g. Subtance P, glutamate) and decreased levels of anti-nociceptive neurotransmittters (e.g. serotonin, norepinephrine)
The condition can be easily diagnosed in clinical practice based primarily on the patient history
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