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Joel Hirsh MD

Assistant Professor of Medicine

Dr. Hirsh's area of research interest is the impact of health literacy on rheumatologic diseases. Health literacy is the match between the literacy skills of individuals and the expectations and demands of health systems. He has published on the mismatch between the literacy demands of patient education materials and how health literacy affects the discrepancy between patient and provider assessment of rheumatoid arthritis disease activity. Dr. Hirsh and his colleagues at Denver Health plan ongoing research regarding the predictors of this discrepancy and what interventions might help doctors and patients achieve concordance.   





Fibromyalgia (FMS)


Joel Hirsh, M.D.


I.              Definition


  • Fibromyalgia (FMS) is a chronic non-inflammatory, non-autoimmune diffuse central pain processing syndrome. It is associated with diffuse tenderness on physical examination, fatigue, disturbed mood, unrefreshing sleep and general somatic hyperawareness.
  • There is no evidence that FMS is a primary disorder of muscle or connective tissue and patients with FMS are tender in areas where there is no muscle (e.g.: volar thumb).
  • Patients with FMS are also more sensitive to other sensory modalities in addition to pressure.


II.             Tender, Trigger and Control Points


  • The ACR classification criteria, which were developed to standardize research about FMS, require the presence of tenderness at 11 of 18 designated tender points existing both above and below the waist. Trigger points are associated with the myofascial pain syndrome and are characterized by both tenderness and radiation of discomfort. The volar forearm, forehead, and thumbnails are control points that in theory are non-tender with palpation. This construct is controversial, however. If the “central sensitization” theory is correct, shouldn’t patients with FMS have their pain amplified everywhere?


III.            Demographics


  • Fibromyalgia is largely a disorder of middle-aged women. An alternative diagnosis should be strongly considered in men, and persons that develop symptoms after the age of 55.


  • FMS is an extremely heterogeneous disorder in terms of its severity. Many patients either do not seek care for their symptoms or obtain a good deal of relief with simple interventions. These patients are rarely seen at tertiary centers, however, significantly influencing residents’ perspectives about FMS.


IV.           Primary vs. Secondary Fibromyalgia


  • This is an important distinction. Often students and residents training in rheumatology dichotomize fibromyalgia from the inflammatory arthritic disorders; i.e: does this person have a connective tissue disease or fibromyalgia? But FMS can often complicate existing autoimmune disorders. It is essential to be aware of this possibility in order to avoid more aggressive therapy of RA, SLE, etc with toxic medication that patients will not benefit from. A detailed physical examination and laboratory studies are essential in this setting.


V.            Etiology/Pathogenesis


  • Unknown, but evidence has accumulated which argues strongly that FMS is a central pain processing disorder. This hypothesis is supported by genetic and functional MRI studies. The idea that this disease is a bogus societal construct to describe somatization is out of vogue.


  • “The pathogenesis of fibromyalgia is the medicalization of misery” – Norton Hadler, MD.


  • If Dr. Hadler is right how can we explain the high prevalence of fibromyalgia in Pakistan and among the Amish?


  • What do we make of the association between widespread pain and subsequent increased incidence of cancer (and reduced cancer survival) and cardiovascular disease?


  • There is objective evidence of abnormalities, mainly involving central pain processing.


a. CNS/substance P:  The amplification of pain seen in FMS patients has made the CNS a target of much interest regarding the etiology of FMS. There is evidence that pain perception in FMS is in part due to changes in the CNS that result in amplification of nociceptive impulses. This process is known as “central sensitization” and is thought to result from the plasticity of neuronal synapses in response to past pain experiences. Substance P (SP) is a peptide neurokinin that has important roles in the process of nociception. The average CSF substance P level is 2-3 times higher in FMS patients compared to healthy normal controls.


b. CNS/genetic studies: Genetic studies suggest that FMS is polygenetic disorder involving pain and mood related neurotransmitters:


  • There is a strong familial predisposition to FMS. In one study the odds of FM in relative of a proband with FM versus the odds of FM in relative of a proband with RA was 8.5. 
  • FMS also co-aggregates with mood disorders in families. The odds of a major mood disorder in a relative of a proband with FM versus the odds of major mood disorder in a patient with RA was 1.8.
  • These finding argue that genetic factors are involved in the etiology of FM and that mood disorders and FMS likely share some inherited factors.
  • The genes that have been shown to predispose people to FMS are involved in pain and mood related neurotransmitters: Serotonin receptors, serotonin transporters, and Catecholamine-o-methyl transferase (COMT), an enzyme that breaks down catecholamines.
  • These genes are likely responsible for the deficiencies seen in neurotransmitters that inhibit nociceptive processing such as serotonin and norepinephrine and for the increased amounts of neurotransmitters involved in facilitating nociceptive processing like substance P and glutamate.
  • In an elegant study, healthy persons were tested for pain sensitivity and COMT haplotypes and followed prospectively for the development of temporo-mandibular disorder (TMD), a regional pain variant of FMS. This study showed that most people have average pain sensitivity, but that the individual variability in pain sensitivity between people is substantial. The incidence of TMD was twice as high among individuals having low pain sensitivity COMT haplotypes (5.6 cases per 100 person-years) compared to individuals having high pain sensitivity haplotypes (2.5 cases per 100 person-years).
  • It is likely that in the future that a “fibromyalgia genetic predisposition” genetic panel will be available, which would be able to predict the development and subtype of FMS in the face of the environmental stressors.


c. CNS/functional MRI:


  • Additional conclusive proof that patients with FMS are truly in pain are the findings of functional MRI (fMRI) studies.
  • fMRI takes advantage of magnetic movement of deoxygenated blood, allowing for the detection of stimuli associated neuronal activation and increased regional cerebral blood flow.
  • These studies reveal common regions and intensity of activation in patients and controls when pressure applied to the left thumb sufficient to evoke moderate pain, even though the patients required much less pressure than controls to cause similar amounts of pain.


d. Sleep disorders: Patients with FMS have been noted to have an arousal disturbance in their sleep EEG known as the alpha wave intrusion during stage 4 non-REM sleep. Alpha wave intrusion is associated with poor sleep and pain upon waking.


e. Endocrine dysfunction: Multiple studies have documented low levels of growth hormone (GH) and insulin-like growth factor I. This is of interest as the symptoms of growth hormone deficiency can include decreased exercise capacity and vague muscular symptoms. Alpha wave intrusion may be responsible for the low levels of GH as it is released during stages 3 and 4 sleep. GH administration was found to be helpful in one small study of patients with FMS, but concerns about its potential toxicities, endogenous suppression and cost have limited its utility. Levels of cortisol, thyroid hormone, female sex hormones, prolactin and melatonin have not been found to be outside the normal range.




VI.           Evaluation of Suspected FMS


  • It is of the utmost importance to do a complete and thoughtful H&P on these patients. Not everyone that hurts has FMS. The list of disorders that could present with FMS-like symptoms is extensive but the most important to remember are


Endocrine: Hypothyroidism, adrenal insufficiency, Cushing’s syndrome, hyperparathyroidism, and hypovitaminosis D (Controversial – pharmacologic doses of vitamin d do not reduce pain in FMS patients with baseline levels consistent with physiologic insufficiency 8-20 ng/ml)

GI: Hepatitis C, celiac sprue

Sleep disorders: OSA

Psychiatric: Major depressive disorder

Neurologic: MS, myotonic dystrophy type 2

Hematologic: Anemia

Rheumatologic: RA, connective tissue diseases, spondyloarthropathies


A.    History


  • In contradistinction to patients with inflammatory arthritic diseases that can usually specify where they hurt and disclose a history of morning stiffness, patients with fibromyalgia generally complain of diffuse, unrelenting pain from “head to toe” or “everywhere.” Patients with many diseases can certainly have a positive review of systems, but the scope and breadth of somatic complaints regarding sensory phenomenon detailed in ROS questionnaires helps to define FMS. Complaints of fatigue, difficulty falling asleep and non-restorative sleep are almost always present.


B.    Physical Examination


  • Although patients with FMS have a great deal of joint pain, they do not have synovitis or joint deformity. The presence of these clearly indicates an alternative diagnosis. Tender point exam should be positive as discussed above.


C.    Laboratory Studies


  • CBC, CMP, TSH, and ESR should be routinely obtained in all patients suspected of having fibromyalgia. Antinuclear antibodies and rheumatoid factor should be obtained only if the ESR is abnormal and/or there are clear signs and symptoms that suggest a connective tissue disease. The diagnostic phase of the fibromyalgia patient – doctor relationship should be completed promptly. Embarking on wild zebra hunts is unwise as they lead to false hope of an entirely reversible condition and create a situation where it impossible to become well (the doctors can’t even figure out what’s wrong with me!). Laboratory testing is generally negative in FMS patients. A diagnosis of fibromyalgia should be looked at with a glance askance in a patient with a significantly abnormal laboratory testing.


VII.          Pharmacological Treatment of FM


  • Non-pharmacological therapies are key, but underutilized.
  • Medications effective in treating patients with fibromyalgia work by targeting the central neurological mechanisms of the disease.
  • There is no evidence for efficacy of therapies that are helpful in conditions associated with peripheral/tissue level pain such as non-steroidal anti-inflammatory drugs (NSAIDS) and opiods.
  • Patients with FMS should be treated like geriatric patients with a philosophy of “start low, go slow” given the high incidence of side effects. Don’t change two medications at one visit.


A.    Fatigue


  • The management of fatigue is problematic and is usually pursued in an oblique manner by trying to improve pain control and sleep issues. Non-pharmacologic therapies can help such as graded aerobic exercise. Two important rules for exercise are to emphasize that FMS is a “use it or lose it” situation. If someone hurts now when they walk a ½ mile, they will begin to hurt with less and less activity if they scale back their activity to reduce pain. It is also important to set realistic goals. FMS patients are plagued by failure to meet societal responsibilities at home and work. The initial exercise Rx should be tailored to set the FMS patient up for success.


  • Fluoxetine at average dose of 45 mg/d has been shown to improve the total score on the fibromyalgia impact questionnaire (FIQ) significantly, but differences in the total myalgic scores were not statistically significant.  Bupropion and fluoxetine cause the least sedation (and most agitation) and theoretically should help more with fatigue. Tricyclic Antidepressants (TCAs) are generally of more utility in the treatment of pain and sleep than fatigue.


  • Modafinil (Provigil) is FDA-approved to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy and shift work sleep disorder (SWSD); adjunctive therapy for obstructive sleep apnea/hypopnea syndrome (OSAHS) and has been used off-label to treat fatigue in MS. There are several open label studies of it in FMS, but no rigorous randomized control trials showing a benefit. It is very expensive ($349 for 30 tablets at


B.    Pain/TCAs

  • There is strong evidence from nine randomized controlled trials that TCAs work well for patients with FMS. They facilitate the descending analgesic pathway by inhibiting of the reuptake of serotonin and NE.
  • Amitriptyline is the TCA with the most anticholinergic properties and nortriptyline has the least. Cyclobenzaprine is marketed as a muscle relaxant, but has the chemical structure (and similar effects) of a TCA. Cyclobenzaprine has been shown to be helpful in FMS at doses as low as 2.5mg b.i.d. 


C.    Pain/SNRIs

  • The dual reuptake inhibitor, duloxetine (Cymbalta), has been shown to be effective by overall fibromyalgia impact questionnaire (FIQ) at a dose of 60mg p.o. b.i.d., but not by FIQ pain score. Similar results have been seen in trials of venlafaxine. Tramadol has a modest impact in FMS related to its properties also limiting the uptake of norepinephrine and serotonin.
  • Milnacipran is dual reuptake inhibitor not yet approved in US that has been proven to lead to a statistically significant improvement in pain VAS.
  • Patients using dual reuptake inhibitor need to be counseled regarding the high likelihood of nausea and monitored closely for the development of or exacerbation of hypertension (7% of patients on milnacipran will have a 15 mmHg or more increase in BP).


                  D. Pain/anticonvulsants

  • Gabapentin and pregabalin reduce calcium influx at nerve terminals inhibiting release of neurotransmitters such glutamate and substance P. High doses of pregabalin (450mg/d) improve pain, sleep and fatigue. Pregabalin at a dose of 300mg/d of pregabalin is not effective for pain, but does improve sleep. 150mg/d of pregabalin is ineffective globally. Pregabalin has not been shown to help patients that have failed gabapentin or patients with extensive psychiatric co-morbidity.
  • Common side effects are dizziness, somnolence, headache, dry mouth, and peripheral edema.
  • Gabapentin is also effective in FMS although sedation can limit effectiveness. One way to avoid this problem is to use 2/3 of dose in evening before sleep.


                  E. Pain/miscellaneous

  • A recent 14-week study suggested that pramipexole (Mirapex), a dopamine D3 receptor agonist with some affinity for the alpha2-adrenoreceptor, reduced pain and fatigue in patients with longstanding fibromyalgia when used at a high-dose of 4.5 mg every evening. Anxiety and mild weight loss were common side effects. Ropinarole (Requip) may have the same effects, but has not been well studied.
  • Mirtazapine (Remeron) is an antidepressant that selectively blocks the 5-HT2 and 5-HT3 serotonin receptors. It has been looked at in open studies with some improvement in pain and fatigue, but much improvement in sleep. Weight gain can limit its tolerability.
  • Pyridostigmine has been tested and found to be ineffective in improving most FMS symptoms with the exceptions of restorative sleep and anxiety.
  • Two recent studies have failed to show a benefit of acupuncture in the treatment of fibromyalgia in terms of pain, although it may benefit the sleep disturbance.


VIII.         Non-Pharmacologic Treatment

  • Catastrophizing is a term that describes the belief that pain is awful, horrible and unbearable. Several studies have shown that catastrophizing profoundly decreases pain thresholds and increases activation the sensory dimension of pain by fMRI.  Other maladaptive illness behaviors and the feeling that pain is entirely out of one’s control (external locus of control) are strong predictors of increased pain and poor function.

·         This is the scientific foundation supporting the use of cognitive behavioral therapy (CBT) in the treatment of fibromyalgia. CBT has been shown to benefit patients with FMS at least or more than medical therapy.

  • Exercise is a drug that increases levels of serotonin, endorphins, and norepinephrine. Strategies to successfully incorporate exercise into the routine of FMS patients include 1) waiting to start program until meds in place for several months, 2) utilizing low-impact aerobic exercises 3) starting with low-doses of daily exercise and advising patients not to overdose.


IX.           Fibromyalgia is a real disease.

  • Fibromyalgia is a real illness with objective evidence of augmented central pain processing.
  • FMS is polygenic disorder involving pain and mood related neurotransmitters.
  • Appropriate treatments address the neurological pathophysiology.
  • Non-pharmacolgical therapy is the key.
  • The diagnosis of  FMS construct alleviates patients’ stress about mysterious underlying conditions.
  • Doubting that patients with FMS are sick is counterproductive. Acceptance is the key. Patients can’t get better if they are constantly trying to prove that they are sick.


X.            References


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Goldenberg DL, Burckhardt C, and Crofford LJ. Management of fibromyalgia syndrome. JAMA 2004, 292:2388-2395.


Williams DA and Gracely RH. Functional magnetic resonance imaging findings in fibromyalgia. Arthritis Research & Therapy 2006, 8:224-232.


Giesecke T, Gracely RH, et al. The relationship between depression, clinical pain and experimental pain in a chronic pain cohort. Arthritis Rheum 2005, 52:1577-1584.


Cook DB, Lange G, et al. Functional imaging of pain in patients with primary fibromyalgia. J Rheum 2004, 31:364-368.


Geisser ME, Casely KL, et al. Perception of noxious and innocuous heat stimulation among healthy women and men with fibromyalgia: association with mood, somatic focus and catastrophizing. Pain 2003, 102:243-250.


Dan B, Hagit C, et al. An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits. Molecular Psychiatry 2004, 9:730-733.


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