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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
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
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)
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
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
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
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
Affective – Emotional valence of pain
Anterior cingulate cortex
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
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
Medication trial (esp antidepressants, anticonvulsants)
Cognitive behavior therapy, counseling
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
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
Elevated lifetime rates of mood disorders in patients with FM
Elevated rates of mood disorders in first-degree relatives of FM patients
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
Dose 25 – 50 mg
Duration 6-26 weeks
All showed modest efficacy CYCLOBENZAPRINE
Four placebo-controlled trials
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
Physical and psychological benefits
May increase aerobic performance and tender point pain pressure threshold, and improve pain
Efficacy not maintained if exercise stops
Improvements in pain, fatigue, mood, and physical function
Improvement often sustained for months
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
Analgesic advice and non-pharmacologic treatment (trigger point injections)
OT, work rehab, ergonomics
Mental health professional
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