1. FibromyalgiaWRAP Principles and Practice Strategies for Fibromyalgia

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

3. Primary Care and Functional Illnesses Account for 30-50% of office visitsAccount for 30-50% of office visits Medical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headachesMedical classification: FM, IBS, irritable bladder, vulvodynia, non-cardiac chest pain, TMJ, multiple chemical sensitivity, tension headaches Psychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSDPsychiatric classification: Somatization disorder, hypochondriasis, conversion disorder, PTSD Commonest primary care problemCommonest primary care problem Specialty referral based on most distressing syndromeSpecialty referral based on most distressing syndrome

4. Chronic Pain/Suffering Syndromes FM is the prototype for a fundamentally different type of pain syndrome where pain is FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes 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 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 There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted ownership of these patients No medical specialty has accepted ownership of these patients FM is the prototype for a fundamentally different type of pain syndrome where pain is FM is the prototype for a fundamentally different type of pain syndrome where pain is Not due to damage or inflammation of peripheral tissues Not due to damage or inflammation of peripheral tissues Frequently accompanied by a variety of other somatic symptoms and syndromes 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 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 There is no agreed upon, all encompassing term to describe this entire spectrum of illness No medical specialty has accepted ownership of these patients No medical specialty has accepted ownership of these patients

5. American College of Rheumatology (ACR) Diagnostic Criteria for FM ACR diagnostic criteria ACR diagnostic criteria History of chronic widespread pain 3 months History of chronic widespread pain 3 months Patients must exhibit 11 of 18 tender points Patients must exhibit 11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%) ACR diagnostic criteria ACR diagnostic criteria History of chronic widespread pain 3 months History of chronic widespread pain 3 months Patients must exhibit 11 of 18 tender points Patients must exhibit 11 of 18 tender points FM can be identified from among other rheumatologic conditions with use of ACR criteria with FM can be identified from among other rheumatologic conditions with use of ACR criteria with good sensitivity (88.4%) and specificity (81.1%)

6. FM Diagnosis is Very Physician Dependent Modified from Goldenberg JAMA 2004 4646 4Rule out other conditions that may present with chronic widespread pain (Operator dependent) 4History of chronic, widespread pain for 3 months 4Confirm presence of tender points 4(Fibromyalgia may be present, even if <11 of 18) 4General physical exam, neurologic exam, selected laboratory testing (ESR, thyroid tests; avoid screening serologic tests) 4Confirm 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

7. Problems in Defining Fibromyalgia Real if no clear pathophysiologic basis? Real if no clear pathophysiologic basis? Gold standard is expert opinion Gold standard is expert opinion Tender points, symptoms are subjective Tender points, symptoms are subjective Fewer than 11 tender points? Fewer than 11 tender points? Symptoms are not dichotomous Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Real if no clear pathophysiologic basis? Real if no clear pathophysiologic basis? Gold standard is expert opinion Gold standard is expert opinion Tender points, symptoms are subjective Tender points, symptoms are subjective Fewer than 11 tender points? Fewer than 11 tender points? Symptoms are not dichotomous Symptoms are not dichotomous Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS) Same diagnostic criteria and dilemma for any illness lacking objective biologic markers (depression, migraine, IBS, CFS)

8. Earlier Diagnosis of Fibromyalgia Long delay in diagnosis adversely affects outcome Long delay in diagnosis adversely affects outcome Characteristic symptoms speed diagnosis: Characteristic symptoms speed diagnosis: I hurt all over I hurt all over It feels like I always have the flu It feels like I always have the flu Fatigue, Sleep and Mood disturbances Fatigue, Sleep and Mood disturbances IBS, Irritable bladder, multiple other somatic complaints IBS, Irritable bladder, multiple other somatic complaints Exclusion of structural or systemic disease Not a fishing expedition Avoid screening rheumatology tests Early subspecialty referral

9. 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 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

10. Why Do A Tender Point Exam? Confirm Dx impressionConfirm Dx impression Proxy for pain sensitivityProxy for pain sensitivity Compare to joint tendernessCompare to joint tenderness Potential prognostic factorPotential prognostic factor

11. Who Gets Fibromyalgia? No concurrent medical illness No concurrent medical illness Any age, but peak age 40-60 Any age, but peak age 40-60 60-90% female in clinic, although less gender difference in population-based studies 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 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) Prior medical illness (e.g., Lyme disease, viral illness) Medications (steroid taper) Medications (steroid taper)

12. Medically Unexplained Illnesses Concurrent With Fibromyalgia Chronic fatigue syndrome Chronic fatigue syndrome Irritable bowel syndrome Irritable bowel syndrome Muscle, migraine headaches Muscle, migraine headaches Irritable bladder syndrome Irritable bladder syndrome Mood disturbances Mood disturbances Vulvodynia Vulvodynia Temporomandibular joint (TMJ) disorder Temporomandibular joint (TMJ) disorder IN EACH OF THESE: Diagnosis dependent on:IN EACH OF THESE: Diagnosis dependent on: Exclusion of disease Exclusion of disease Symptoms rather than signsSymptoms rather than signs No reproducible laboratory findingsNo reproducible laboratory findings Gold standard is expert opinionGold standard is expert opinion

13. Is FM Physical or Psychological? Is it a psychiatric illness? Is it a psychiatric illness? What is the interaction with depression? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it a maladaptive psychosocial response? Is it somatization? Is it somatization? What is the role of stress? What is the role of stress? Is it a psychiatric illness? Is it a psychiatric illness? What is the interaction with depression? What is the interaction with depression? Is it a maladaptive psychosocial response? Is it a maladaptive psychosocial response? Is it somatization? Is it somatization? What is the role of stress? What is the role of stress?

14. FM and Mood Disorders At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. 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 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). 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). Fibromyalgia co-aggregates with major mood disorder in families (OR 1.8 [95% CI 1.1, 2.9), p=0.01). At the time of FM diagnosis, mood disorders are present in 30-50%, primarily depression. 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 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). 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). 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

15. Is Fibromyalgia a Medical or Psychiatric Illness? Harmful and unproductive argument Harmful and unproductive argument Fruitless quandary to work out what came first Fruitless quandary to work out what came first For all patients, symptoms are real and can be disabling For all patients, symptoms are real and can be disabling Need a dual treatment approach targeting both physical and psychological symptoms Need a dual treatment approach targeting both physical and psychological symptoms

16. 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 includeSome 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) Periodic limb movements (PLMs) Restless leg syndrome (RLS) Restless leg syndrome (RLS) Sleep apnea 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) 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.

17. Both have strong genetic predisposition and similar co-morbidity Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar sleep disturbances Similar cognitive disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Orthostatic features, ANS dysfunction Childhood abuse, stress Childhood abuse, stress Catastrophizing Catastrophizing Imaging studies Imaging studies Neuroendocrine studies Neuroendocrine studies Both have strong genetic predisposition and similar co-morbidity Both have strong genetic predisposition and similar co-morbidity Similar sleep disturbances Similar sleep disturbances Similar cognitive disturbances Similar cognitive disturbances Orthostatic features, ANS dysfunction Orthostatic features, ANS dysfunction Childhood abuse, stress Childhood abuse, stress Catastrophizing Catastrophizing Imaging studies Imaging studies Neuroendocrine studies Neuroendocrine studies Shared Features of FM and Depression: Clues to Pathophysiology

18. FM Pathophysiologic Pathways Genetic factors Genetic factors Fibromyalgia is strongly familial (the odds ratio is 8.5 for first- degree relatives) Fibromyalgia is strongly familial (the odds ratio is 8.5 for first- degree relatives) No single candidate gene identified No single candidate gene identified Central pain augmentation Central pain augmentation CSF substance P CSF substance P Neuroimaging studies Neuroimaging studies Autonomic/neuroendocrine dysfunction Autonomic/neuroendocrine dysfunction Immune dysfunction? Immune dysfunction? Structural changes? Structural changes?

19. Genetics of Fibromyalgia Familial predisposition 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 disorder 1 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 1 Genes that may be involved Genes that may be involved 5-HT 2A receptor polymorphism T/T phenotype 2 5-HT 2A receptor polymorphism T/T phenotype 2 Serotonin transporter 3 Serotonin transporter 3 Dopamine D4 receptor exon III repeat polymorphism 4 Dopamine D4 receptor exon III repeat polymorphism 4 COMT (catecholamine o-methyl transferase) 5 COMT (catecholamine o-methyl transferase) 5 Familial predisposition 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 disorder 1 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 1 Genes that may be involved Genes that may be involved 5-HT 2A receptor polymorphism T/T phenotype 2 5-HT 2A receptor polymorphism T/T phenotype 2 Serotonin transporter 3 Serotonin transporter 3 Dopamine D4 receptor exon III repeat polymorphism 4 Dopamine D4 receptor exon III repeat polymorphism 4 COMT (catecholamine o-methyl transferase) 5 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.

20. Pain Matrix – Pain is Processed in at Least Three Domains in CNS Sensory - Where it is and how much it hurts Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Primary and secondary somatosensory cortices Thalamus Thalamus Posterior insula Posterior insula Affective – Emotional valence of pain Affective – Emotional valence of pain Anterior cingulate cortex Anterior cingulate cortex Anterior insula Anterior insula Amygdala Amygdala Cognitive – Similar to affective plus pre-frontal regions Cognitive – Similar to affective plus pre-frontal regions Sensory - Where it is and how much it hurts Sensory - Where it is and how much it hurts Primary and secondary somatosensory cortices Primary and secondary somatosensory cortices Thalamus Thalamus Posterior insula Posterior insula Affective – Emotional valence of pain Affective – Emotional valence of pain Anterior cingulate cortex Anterior cingulate cortex Anterior insula Anterior insula Amygdala Amygdala Cognitive – Similar to affective plus pre-frontal regions Cognitive – Similar to affective plus pre-frontal regions Melzack et al. Science. 1965;150:971-979. Casey et al. Headache. 1969;8:141-153.

21. Specific Underlying Mechanisms in Fibromyalgia Global problem with sensory processing (i.e. interoception) Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones 1 FM patients equally sensitive to loudness of auditory tones 1 Insular hyper-reactivity consistently seen 2-4 Insular hyper-reactivity consistently seen 2-4 H-MRS studies of glutamate levels in posterior insula 5 H-MRS studies of glutamate levels in posterior insula 5 Global problem with sensory processing (i.e. interoception) Global problem with sensory processing (i.e. interoception) FM patients equally sensitive to loudness of auditory tones 1 FM patients equally sensitive to loudness of auditory tones 1 Insular hyper-reactivity consistently seen 2-4 Insular hyper-reactivity consistently seen 2-4 H-MRS studies of glutamate levels in posterior insula 5 H-MRS studies of glutamate levels in posterior insula 5 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).

22. Neuroimaging in Fibromyalgia Hypoperfusion of thalamus and head of the caudate nucleus Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception 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. 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. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans Changes in posterior insula glutamate in PET scans Hypoperfusion of thalamus and head of the caudate nucleus Hypoperfusion of thalamus and head of the caudate nucleus fMRI of cortical response to pain consistent with augmentated pain perception 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. 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. Castrophizing correlated with pain response in these medial brain regions. Changes in posterior insula glutamate in PET scans 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

23. Alterations in Descending Analgesic Activity in FM Opioids Normal or high levels of CSF enkephalins 1 Normal or high levels of CSF enkephalins 1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective 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 fibromyalgia 2 Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia 2Opioids Normal or high levels of CSF enkephalins 1 Normal or high levels of CSF enkephalins 1 Never administered in RCT, but most feel that opioids are ineffective or marginally effective 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 fibromyalgia 2 Harris recently used PET to show decreased mu-opioid receptor binding in fibromyalgia 2 Noradrenergic/Serotonergic Elevated levels of substance P in CSF in fibromyalgia 3 Elevated levels of substance P in CSF in fibromyalgia 3 Nearly any class of drug that raises both serotonin and norepinephrine levels has demonstrated efficacy in fibromyalgia 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.

24. Is There Any Effective Management of Fibromyalgia? All patients All patients Reassurance re diagnosis Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Promote return to normal activity, exercise Most patients Most patients Medication trial (esp antidepressants, anticonvulsants) Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Cognitive behavior therapy, counseling Physical rehabilitation Physical rehabilitation All patients All patients Reassurance re diagnosis Reassurance re diagnosis Give explanation, including, but not solely, psychological factors Give explanation, including, but not solely, psychological factors Promote return to normal activity, exercise Promote return to normal activity, exercise Most patients Most patients Medication trial (esp antidepressants, anticonvulsants) Medication trial (esp antidepressants, anticonvulsants) Cognitive behavior therapy, counseling Cognitive behavior therapy, counseling Physical rehabilitation Physical rehabilitation

25. 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 Confirm diagnosis Identify important symptom domains, their severity, and level of patient function Evaluate for comorbid medical and psychiatric disorders Modified from Arnold LM. Arthritis Res Ther 2006;8:212.

26. FM: From Mechanism to Treatment This is primarily a neural disease and central factors play a critical role This is primarily a neural disease and central factors play a critical role This is a polygenic disorder This is a polygenic disorder There is a deficiency of noradrenergic-serotonergic activity and/or excess levels of excitatory neurotransmitters 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 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 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 Treatments aimed at the periphery (ie, drugs, injections) are not very efficacious There will be sub-groups of FM needing different treatments 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 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 Exercise, sleep hygiene, and other behavioral interventions are effective therapies for biological reasons Cognitive therapies are effective in FM and have a biological substrate Cognitive therapies are effective in FM and have a biological substrate

27. Rationale for the Use of Central Nervous System Active Medications in FM No evidence for muscle pathology No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Current research supports role of augmented central pain mechanisms Genetic predisposition Genetic predisposition 5-HT 2A receptor polymorphism 5-HT 2A receptor polymorphism Pain severity in FM patients with T/T genotype Pain severity in FM patients with T/T genotype Frequency of S/S genotype in FM patients compared with healthy controls Frequency of S/S genotype in FM patients compared with healthy controls Incidence of COMT polymorphism in FM patients Incidence of COMT polymorphism in FM patients Substance P increased in CSF Substance P increased in CSF 5-HT and NE serum levels decreased in some studies 5-HT and NE serum levels decreased in some studies Imaging studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances Sleep disturbances No evidence for muscle pathology No evidence for muscle pathology Current research supports role of augmented central pain mechanisms Current research supports role of augmented central pain mechanisms Genetic predisposition Genetic predisposition 5-HT 2A receptor polymorphism 5-HT 2A receptor polymorphism Pain severity in FM patients with T/T genotype Pain severity in FM patients with T/T genotype Frequency of S/S genotype in FM patients compared with healthy controls Frequency of S/S genotype in FM patients compared with healthy controls Incidence of COMT polymorphism in FM patients Incidence of COMT polymorphism in FM patients Substance P increased in CSF Substance P increased in CSF 5-HT and NE serum levels decreased in some studies 5-HT and NE serum levels decreased in some studies Imaging studies Imaging studies Elevated lifetime rates of mood disorders in patients with FM Elevated lifetime rates of mood disorders in patients with FM Elevated rates of mood disorders in first-degree relatives of FM patients Elevated rates of mood disorders in first-degree relatives of FM patients Sleep disturbances 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..

28. Medications in FMS Strong evidence for efficacy Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Modest evidence for efficacy Tramadol, 200-300 mg/day Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine 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 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. Strong evidence for efficacy Strong evidence for efficacy Amitriptyline, 25-50 mg at bedtime Amitriptyline, 25-50 mg at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Cyclobenzaprine, 10-30 mgs at bedtime Pregabalin, 300-450 mg/day Pregabalin, 300-450 mg/day Gabepentin, 1600-2400 mg/day Gabepentin, 1600-2400 mg/day Duloxetine, 60-120 mg/day Duloxetine, 60-120 mg/day Milnacipran, 100-200 mg/day Milnacipran, 100-200 mg/day Modest evidence for efficacy Modest evidence for efficacy Tramadol, 200-300 mg/day Tramadol, 200-300 mg/day SSRIs (fluoxetine, sertraline) SSRIs (fluoxetine, sertraline) Weak evidence for efficacy: pramipexole, gamma hydroxybutyrate, growth hormone, 5-hydroxytryptamine, tropisetron, s-adenosyl-methionine 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 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.

29. Tricylics in Fibromyalgia AMITRIPTYLINE Four placebo- controlled trials Four placebo- controlled trials Goldenberg,1985 Goldenberg,1985 Carette,1986 Carette,1986 Carette,1994 Carette,1994 Dose 25 – 50 mg Dose 25 – 50 mg Duration 6-26 weeks Duration 6-26 weeks All showed modest efficacy All showed modest efficacyCYCLOBENZAPRINE Four placebo-controlled trials Four placebo-controlled trials Quimby, 1989 Quimby, 1989 Carette, 1994 Carette, 1994 Reynolds,1991 Reynolds,1991 Dose 10 – 40 mg Dose 10 – 40 mg Duration 4 – 12 weeks Duration 4 – 12 weeks 2 showed efficacy 2 showed efficacy Arnold L et al. Psychosomatics 2000;41:104-113.

30. 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

31. Arnold LM, et al. Pain 2005; 119:5-15. Phase III Study: Female Patients (N=354) -3 -2 0 0124681012 Weeks LS Mean Change from Baseline *** *** Placebo Duloxetine 60 mg QD Duloxetine 60 mg BID *P<.05 *P<.05 ***P.001 vs placebo *** *** *** *** *** *** *** * * *** *** Improvement in Average Pain Severity with Duloxetine ***

32. (J Rheumatol 2005;32:1975–85) Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran (3:1) Not currently available in US. Hlife 8 h, no liver metab Milnacipran

33. 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% constipation M – 16%, PL -4% hyperhidrosis M – 9%, PL - 2% hyperhidrosis M – 9%, PL - 2% NB – no sig hypertension or wt gain Milnacipran Phase III (3 months,) Milnacipran

34. 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) 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

35. Nonpharmacologic Strategies: Evidence of Efficacy 4 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) Modest Evidence Strength training AcupunctureHypnotherapy EMG biofeedback Balneotherapy (medicinal bathing) Transcranial electrical stimulation 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 Weak Evidence Chiropractic Manual and massage therapy Ultrasound No Evidence Tender-point injections Flexibility exercise

36. FM and Prognosis Children and individuals treated in primary care settings and those with recent onset of symptoms generally have a better 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 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.

37. Patient, Family Education Primary care or specialist setting. Primary care or specialist setting. Core set of information should always be provided. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Recognize the wealth of patient misinformation. Encourage patient participation. Encourage patient participation. Primary care or specialist setting. Primary care or specialist setting. Core set of information should always be provided. Core set of information should always be provided. Pathophysiology best based on biopsychological illness model. Pathophysiology best based on biopsychological illness model. Anticipate common patient questions and concerns. Anticipate common patient questions and concerns. Recognize the wealth of patient misinformation. Recognize the wealth of patient misinformation. Encourage patient participation. Encourage patient participation.

38. Who Should Treat Fibromyalgia? More than 50% of visits are to primary care physicians More than 50% of visits are to primary care physicians Currently, 16% of FM visits are to rheumatologists Currently, 16% of FM visits are to rheumatologists The American College of Rheumatology suggest that rheumatologists serve as consultants (tertiary care) 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 Other specialists should include mental health professionals, physiatrists and pain management experts

39. Physical medicine/rehabilitation Physical medicine/rehabilitation Avoiding inactivity Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Cardiovascular fitness Stretching, strengthening Stretching, strengthening OT, work rehab, ergonomics OT, work rehab, ergonomics Mental health professional Mental health professional Psychopharmacology Psychopharmacology Counseling Counseling CBT CBT Physical medicine/rehabilitation Physical medicine/rehabilitation Avoiding inactivity Avoiding inactivity Analgesic advice and non-pharmacologic treatment (trigger point injections) Analgesic advice and non-pharmacologic treatment (trigger point injections) Cardiovascular fitness Cardiovascular fitness Stretching, strengthening Stretching, strengthening OT, work rehab, ergonomics OT, work rehab, ergonomics Mental health professional Mental health professional Psychopharmacology Psychopharmacology Counseling Counseling CBT CBT Multidisciplinary FM Treatment

40. Fibromyalgia Controversies Does the diagnostic label promote helplessness and disability? Does the diagnostic label promote helplessness and disability? Only one controlled study; it didnt Only one controlled study; it didnt Diagnosis should be reassuring and end doctor shopping Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Only if diagnosis is coupled with education Does the diagnostic label promote helplessness and disability? Does the diagnostic label promote helplessness and disability? Only one controlled study; it didnt Only one controlled study; it didnt Diagnosis should be reassuring and end doctor shopping Diagnosis should be reassuring and end doctor shopping Only if diagnosis is coupled with education Only if diagnosis is coupled with education

41. Fibromyalgia Controversies Does the diagnosis promote litigation? Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties This can lead to symptom amplification and rehabilitation difficulties Problems with causation Problems with causation Use headache or fatigue models Use headache or fatigue models Does the diagnosis promote litigation? Does the diagnosis promote litigation? Not because of the diagnosis but rather medico-legal misconceptions Not because of the diagnosis but rather medico-legal misconceptions This can lead to symptom amplification and rehabilitation difficulties This can lead to symptom amplification and rehabilitation difficulties Problems with causation Problems with causation Use headache or fatigue models Use headache or fatigue models

42. -505-10 Years relative to index date 0 50 100 415 0 420 0 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)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

43. Trial with low-dose tricyclic antidepressants, SSRI, SNRI, antiseizure medication 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.

44. 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.

45. Explaining the Typical Outcome in Fibromyalgia FM does not herald the onset of a systemic disease FM does not herald the onset of a systemic disease There is no progressive, structural or organ damage There is no progressive, structural or organ damage Most patients in specialty practice have chronic, persistent symptoms Most patients in specialty practice have chronic, persistent symptoms Primary care patients more commonly report complete remission of symptoms Primary care patients more commonly report complete remission of symptoms Most patients continue to work, but 10-15% are disabled Most patients continue to work, but 10-15% are disabled There is often adverse impact on work and leisure activities There is often adverse impact on work and leisure activities Most patients quality of life improves with medical management Most patients quality of life improves with medical management FM does not herald the onset of a systemic disease FM does not herald the onset of a systemic disease There is no progressive, structural or organ damage There is no progressive, structural or organ damage Most patients in specialty practice have chronic, persistent symptoms Most patients in specialty practice have chronic, persistent symptoms Primary care patients more commonly report complete remission of symptoms Primary care patients more commonly report complete remission of symptoms Most patients continue to work, but 10-15% are disabled Most patients continue to work, but 10-15% are disabled There is often adverse impact on work and leisure activities There is often adverse impact on work and leisure activities Most patients quality of life improves with medical management 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.

46. 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