Understanding Fibromyalgia: From Pathogenesis to Treatment

By Thomas S. May

Although fibromyalgia (FM) is still considered controversial by some physicians, there is increasing evidence that it is a real and distinct disorder, affecting 3 to 6 million people in the United States. While a cure does not currently exist, a number of studies indicate that FM can be successfully managed through a combination of pharmacologic and non-pharmacologic treatments. Typically, neurologists do not see very many patients with FM per se; however, there is a lot of overlap among the symptoms of fibromyalgia and other neurologic disorders.

FM is characterized by widespread pain, as well as a lowered pain threshold. It is also frequently associated with disordered sleep, fatigue, and irritable bowel syndrome (IBS). This constellation of symptoms was first described in a 1904 paper by the British physician Sir William Gowers, who coined the term "fibrositis," based on his belief that the syndrome was due to inflamed muscle fibers.[1] However, since no evidence of inflammation could be found in subsequent studies, the word fibrositis was later abandoned in favor of the term fibromyalgia, which was introduced by Philip Hench in 1976.[2]

The next major contribution to the fibromyalgia literature was by Muhammad Yunus and colleagues, who in 1981 published a study comparing 50 patients diagnosed with primary fibromyalgia to 50 age-matched controls.[3] The authors found that patients with FM were typically females between the ages of 25 and 40 who complained of "diffuse musculoskeletal aches, pains or stiffness associated with tiredness, anxiety, poor sleep, headaches, irritable bowel syndrome, subjective swelling in the articular and periarticular areas and numbness." The investigators also noted that physical examination was characterized by the presence of multiple tender points at specific sites and the absence of joint swelling.

The signs and symptoms of FM were further defined in 1990, when the American College of Rheumatology published a formal set of diagnostic criteria for the diagnosis of fibromyalgia, based on a study of 293 patients with FM and 265 control subjects.[4] According to these criteria, patients can be diagnosed with fibromyalgia only in the presence of widespread pain that occurs in combination with tenderness at 11 or more of 18 specific tender point sites. 

Epidemiology and Genetics

The overall prevalence of FM is estimated to be approximately 2 percent, based on a community sample.[5] Prevalence generally increases with age, with the highest values attained between 60 and 79 years, declining slightly after age 80. Women are almost 10 times as likely to be affected as men are, after controlling for age--if tender points are used for the diagnosis of FM. If, however, the diagnosis is not based on tender points, the difference between women and men is less profound, with a sex ratio of 1.5 to 1.

Genetic predispositions appear to play an important role in the development of FM, according to several studies. For example, in a 2004 study, Lesley Arnold and colleagues found that FM aggregated strongly in families, with an odds ratio (OR) of 8.5 for FM among family members of a person with the disorder.[6] The authors also found an increased prevalence (OR 1.8) of major mood disorders among family members of patients with FM.

Genetic susceptibility to FM could, at least in part, be explained by the presence of a cathechol-O-methyltransferase (COMT) gene polymorphism, which is associated with reduced tolerance to painful stimuli, according to a paper published in Science.[7] Other studies have also found that certain unique variations, or polymorphisms, in the COMT gene, as well as the serotonin transporter gene, probably contribute to the development of FM.[8]^,[9]

Pathophysiology

Trying to determine the pathological substrate of fibromyalgia has been fraught with difficulties, as biopsies of tender points have, initially, failed to reveal any abnormalities, or the findings could not be replicated. Some earlier studies reported muscle biopsies showing ragged red fibers, which is a sign of mitochondrial disorders and would indicate abnormal energy metabolism in these patients.[10] Some studies using magnetic resonance (MR) spectroscopy were also suggestive of energy metabolism disorders.[11] However, subsequent research using better-matched controls, including patients with equivalent levels of deconditioning, could not confirm these earlier results, and failed to identify any detectable defects in muscle energy metabolism in patients with FM.[12] Furthermore, nerve conduction and electromyography (EMG) studies, in general, have been normal in these patients.

On the other hand, several studies have been published in the past decade or so that have found objective pathologic differences in FM patients vs. controls. In one 1994 study, for example, investigators demonstrated a 3-fold increase in substance P levels in the cerebrospinal fluid (CSF) of FM patients, compared to healthy controls.[13] In a more recent study, Korean scientists headed by Seong-Ho Kim found an increase in subtype 2D N-Methyl-D-Aspartate (NMDA) receptors (which have been implicated in peripheral nociceptive transmission) in the skin of 11 patients with FM, relative to 8 control subjects.[14] And in a 2007 paper, the same researcher reported the presence of ballooned Schwann cells in skin tissues taken from 13 patients with FM.[15] These deformed cells may contribute to the lower pain threshold levels observed in these patients, according to the author.

Functional magnetic resonance imaging (fMRI) studies of brain activation patterns have also uncovered some evidence of augmented pain processing in patients with fibromyalgia. For example, in a 2002 study, Richard Gracely and colleagues were able to document markedly different patterns of brain activation in response to mild pressure in FM patients, as compared to healthy controls.[16]

The study involved applying pressure with gradually increasing intensity to the left thumbnail beds of 16 right-handed patients with FM and 16 right-handed matched controls. The researcher found that patients with FM experienced pain at much lower pressures (mean = 1.4 kg/cm²) than did the control subjects (mean = 2.7 kg/cm²), indicating significantly (P < 0.001) lowered pain threshold in FM.

During the procedure, participants had their brain activity recorded using fMRI, and these recording showed that painful stimulation resulted in similar brain activation patterns in both groups. Increased fMRI signal occurred in 7 regions common to both groups, including the ipsilateral cerebellum, contralateral putamen, inferior parietal lobule, and superior temporal gyrus, and decreased signal was observed in 1 common region (the ipsilateral primary somatosensory cortex). However, when the investigators applied the same low levels of pressure to all subjects, which did not cause pain in healthy subjects but was experienced as painful by FM patients, the stimulation resulted in only 2 regions of increased signal in healthy controls, and neither of these regions coincided with a region of activation in patients.

These findings provide support for the hypothesis that there is cortical or subcortical augmentation of pain processing in fibromyalgia, according to the authors. Furthermore, the scientists do not believe that these data are consistent with increased labeling (i.e., patients just deciding to call a stimulus painful, without actually experiencing pain), since there is evidence of increased activation in brain regions associated with pain processing in response to the stimulus in question.

Neuropathic Pain

Based on currently available evidence, fibromyalgia is thought to involve abnormal pain processing at various parts of the central nervous system. Although there is no clear indication as to how this actually occurs in FM, a lot of work has been done on abnormal pain processing in peripheral neuropathies. Studies using animal models, as well as research done in humans, have contributed to our understanding of the processes and mechanisms involved in neuropathic pain.  

One of the human studies in this area involved patients with celiac disease who had multi-focal numbness and pain.[17] The researchers removed and analyzed small samples of skin tissue from the patients, and they found evidence of reduced epidermal nerve fiber (ENF) densities in some of the tissue samples examined. Based on these findings, the investigators concluded that patients with celiac disease "may have neuropathy involving small fibers, which can be demonstrated by results of a skin biopsy assessing ENF density."

In a review paper published in 2006 in Neuron, James Campbell and Richard Meyer outlined some other possible mechanisms of neuropathic pain.[18] According to the authors, neuropathic pain reflects both peripheral and central sensitization mechanisms. Abnormal signals arise not only from injured axons but also from the intact nociceptors that share the innervation territory of the injured nerve, Campbell and Meyer argue. They list the following mechanisms as being possible contributors to neuropathic pain:

·            increased or altered sodium channel expression

·            α-receptor expression, sympathetic sprouting

·            decreased inhibition of pain pathways

·            peripheral sensitization of injured and/or intact nociceptors

·            central sensitization caused by changes in NMDA receptors (resulting from ongoing afferent fiber discharge), loss of inhibitory interneurons in the dorsal horn, or aberrant resprouting after nerve damage (See Sidebar 1)

SIDEBAR 1 - Central Sensitization

Mechanisms of central sensitization include the following:

·            Enlargement of the receptive field (area in the periphery where a stimulus will activate neurons).

·            Increase in a response to a suprathreshold input (amplified response to a painful stimulus).

·            Previously subthreshold inputs reach threshold and initiate action potential discharge (previously nonpainful stimuli become painful).

The process of central sensitization starts early in deafferentation. Following peripheral nerve injury, the peripheral nociceptor fibers release excitatory neurotransmitters, particularly glutamate and aspartate, both of which are excitatory in nature. These excitatory neurotransmitters activate a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, which cause calcium influx from voltage-gated Ca++ channels. Neurokinins and substance P interact with the NK-1 receptors, also leading to calcium entry. Activating these receptors removes the magnesium plug from the NMDA receptors, allowing more calcium entry into the cell. Calcium then acts as an important secondary messenger. It activates nitric oxide, leads to immediate early gene expression, and phosphorylates numerous receptors at the level of the dorsal horn, including the NMDA receptors, leading to a decreased threshold of the dorsal horn neurons and to ectopic discharges. This phenomenon is referred to as central sensitization. The pathophysiologic changes suggest that modulation of central sensitization can be accomplished by NMDA-blocking agents, NK-1 receptor blocking agents, or by calcium channel modulators.

[END OF SIDEBAR 1]

Peripheral nerve damage can have a number of consequences, such as:

·            ectopic spontaneous discharges from injured fibers or neuromas[19]

·            increased expression of voltage-sensitive sodium channels [20]^,[21]

·            increased expression of the alpha-3 (fetal) sodium channel[22]

Clinical Features

The clinical features of fibromyalgia include:³

·            Diffuse pain, with involvement of the axial muscles and the trapezius, is among the cardinal features. (Table 1 lists some other common areas of involvement.)

·            Conditions frequently associated with FM include fatigue, irritable bowel syndrome, tension headaches, and depression.

·            Sleep disorders are also common in FM, occurring in about 70-90 percent of patients.

·            Symptoms are chronic but tend to fluctuate during the day, and are often exacerbated by cold, humid weather, anxiety, fatigue, sedentary state, or overactivity.

·            The disease is typically chronic, but approximately 20 percent of patients go into remission after about 2 years.

·            FM is not a progressive disorder.

Table 1:

TABLE 1 - Common Areas of Involvement

Diagnostic Criteria

In 1990, the American College of Rheumathology established a set of guidelines, or diagnostic criteria, for the diagnosis of fibromyalgia.⁴ These guidelines were based on a study of about 550 patients from 16 centers. About half of the subjects had been diagnosed with FM at each center by the participating physicians’ usual method of diagnosis. The other (control) subjects had syndromes that could be confused with fibromyalgia. They included patients with whiplash, lumbar and cervical spine disease, as well as patients who were being evaluated for lupus and rheumatoid arthritis but who did not meet definitive criteria for these diseases.

Approximately 70 percent of the controls had "widespread pain," which was defined as follows: "Pain on the left side of the body, pain on the right side of the body, pain above the waist, and pain below the waist." In addition, axial skeletal pain also had to be present.⁴

The investigators found that fibromyalgia patients could be identified with the greatest accuracy (as measured by the mean of sensitivity and specificity) when both of the following were present:

1. Widespread pain for at least 3 months.
2. At least 11 of 18 so-called "tender points" throughout the body.

According to the guidelines, tender points must actually be painful--not just tender--when pressure of approximately 4 kg/cm² is applied by digital palpation (using the thumb or two fingers), which is generally sufficient to cause whiteness in the examiner's nail bed.

The locations of the 18 tender points are as follows:

·            the suboccipital muscle insertions

·            the midpoint of the upper border of the trapezius

·            the supraspinatus above the medial border of the scapular spine

·            the upper outer quadrants of the buttocks

·            the greater trochanter posterior to the trochanter prominence

·            the anterior aspects of the intertransverse spaces at C5-C7

·            the second rib at the second costochondral junctions

·            the lateral epicondyle 2 cm distal to the epicondyles

·            the medial fat pad proximal to the joint line at the knee

Figure 1:

FIGURE 1 - Location of Tender Points

A number of “control tender points” were also identified in the 1990 guidelines, including the right forearm at the dorsal distal third of the forearm and the midpoint of the dorsal right third metatarsal of the foot. However, the significance of these control points is not clear, as subsequent studies have found that they may also be tender. 

Problems with Diagnosing FM

Despite the existence of published, clear diagnostic criteria, the diagnosis of fibromyalgia has remained controversial. In a 1994 article, Peter Croft and colleagues at the University of Manchester questioned the validity of fibromyalgia as a distinct disorder, based on a population study of 177 patients in the North-West of England.[23]

An assessment of these patients revealed that most of those with chronic widespread pain did not have high tender point counts (i.e., 11 or more), and most subjects with high tender point counts did not have chronic widespread pain. The investigators also found that tender points were associated with pain but were separately related to other measures of distress, such as depression, fatigue, and poor sleep. On the basis of these results, the authors concluded that "fibromyalgia does not seem to be a distinct entity in the general population."

In an editorial that appeared in the Journal of Neurology in 1996, Thomas Bohr raised a number of other issues with the diagnosis of fibromyalgia.[24] He pointed out, for example, that the diagnostic criteria were circular, in that patients were diagnosed based on tender points, and they were then subjected to a study to confirm that the tender points were useful. He also argued that it is difficult to come up with sensitivity and specificity values for diagnostic criteria when there is no gold standard.

Bohr also noted that the psychiatric aspects of this disorder were frequently downplayed. He argued that many aspects of the syndrome were based on self-reports, and that these self-reports were often amplified, compared to the functional observations of patients. To avoid these problems, Bohr suggested that, instead of validating the diagnosis of fibromyalgia, clinicians should use neutral terms or non-histologic terms such as "aches and pains," "chronic pain syndrome," "somatoform pain disorder," or "pain amplification syndrome."

In another editorial, entitled "The Problem with Fibromyalgia," John Kissel, head of the Department of Neurology at Ohio State University, addressed many of the same concerns that had been raised by Bohr.[25] Kissel agreed that the diagnostic criteria were based on circular reasoning, and that there were no gold standards. He argued, however, that this was also true of many other neurologic disorders that are considered "real diseases," such as migraine and most of the other headache syndromes. "Even diagnostic criteria for conditions as 'organic' as systemic vasculitis were derived in large part using so-called circular reasoning," he wrote.

Kissel also acknowledged that a number of poor quality studies had been published relating to fibromyalgia. But he also pointed out that many of the newer studies were well-controlled, and included prospective, randomized, double-blind, placebo-controlled trials. "[These studies] have permitted better delineation of the epidemiology, clinical features, and effective treatment approaches for the syndrome, as well as some provocative findings that have led to the formulation of testable hypotheses concerning pathophysiology."

Kissel also argued that it was counterproductive to deny the existence of FM, considering that it may affect up to 2 percent of the population, and that there were an estimated $16 billion spent on health-care costs and disability claims related to this disorder in the United States each year. "Rather than debating terminology or simply denying that patients with fibromyalgia merit neuromuscular consultation," physicians should be encouraged to expand their knowledge base by reviewing the relevant literature, according to Kissel. "Only in this way will the neuromuscular community be able to contribute intelligently to the debate on this syndrome, and, more importantly, design rational studies that contribute to finding solutions for the many problems in pathogenesis and treatment raised by patients with idiopathic myalgia syndromes."

Initial Assessment and Differential Diagnosis

The basic evaluation of a patient with suspected fibromyalgia should include laboratory tests such as complete blood count (CBC), urinalysis, erythrocyte sedimentation rate (ESR), and thyroid studies. Based on findings on history and examination, other serologic tests, X-rays, creatinine kinase (CK), and electromyography (EMG), may also be done, taking into consideration other possible diagnoses. Additionally, patients with daytime sleepiness, loud snoring, or suspected sleep apnea should undergo a sleep study.

The following guidelines can help differentiate between fibromyalgia and other disorders with similar symptoms:[26]

Rheumatoid Arthritis: Pain and morning stiffness are common in both fibromyalgia and rheumatoid arthritis, but with rheumatoid arthritis, typically there is joint swelling and often systemic involvement; whereas, these rarely occur in FM. Laboratory tests such as erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and X-rays can also be helpful in differentiating between the two disorders.

Polymyalgia Rheumatica: Polymyalgia rheumatica is more common among the elderly, while fibromyalgia tends to occur at a younger age. Furthermore, systemic complaints such jaw claudication are suggestive of polymyalgia rheumatica. The sedimentation rate (ESR) is also helpful in separating these disorders.

Lyme Disease: Lyme disease can cause symptoms that could be confused with FM, but it tends to occur in endemic areas only. Furthermore, there is often a rash with Lyme disease, and serologies could also be present.

Systemic Lupus Erythematosus (SLE) and Lupus: Both SLE and vasculitis generally have organ involvement, as well as joint swelling. Some laboratory tests (e.g., anti-neutrophil cytoplasmic antibodies, or ANCAs, for vasculitis) and biopsies can help separate these disorders.

Inflammatory Myopathy: In inflammatory myopathy, pain is present in only about a third of the patients, but weakness is much more common in this disorder than it is in FM. Other signs suggestive of inflammatory myopathy, as opposed to FM, include elevated creatinine kinase (CK) levels, as well as abnormal muscle biopsy and electromyography (EMG) tests.

Metabolic Myopathy:  Metabolic myopathies should be considered in patients with unexplained muscle pain or fatigue. But while fatigue in metabolic myopathies is generally exercise-induced, people with fibromyalgia tend to have more constant fatigue, or in some cases, fatigue that prevents them from exercising.

Polyneuropathy: While paresthesias are common in fibromyalgia, patients with polyneuropathy generally have sensory loss, and nerve conduction studies tend to be abnormal. In patients with small fiber neuropathy where nerve conduction studies are normal, counting epidermal nerve fibers in skin tissue (obtained through biopsy) can aid in the diagnosis.

Hypothyroidism: The classic symptoms of hyperthyroidism, weight gain and cold intolerance, as well as thyroid stimulating hormone (TSH) levels in the blood, can help identify this disorder.

Arthritis: Diagnosis can be made with the help of various imaging modalities.

Irritable Bowel Disease (IBD) with Arthropathy: Because fibromyalgia is associated with IBD, it is possible that IBD with extra intestinal manifestations of arthritis could be confused with FM. However, the presence of joint swelling would be indicative of arthritis. A GI evaluation can also help distinguish between these two disorders.

Treatment Options

Treatment options for FM include both pharmacologic and nonpharmacologic interventions, and they can be divided into three major categories: 1) interventions that have proved efficacious in empirical studies; 2) treatments that have been found to be ineffective; and 3) interventions that have not been adequately tested (See Table 2 and 3).[27]

Table 2:

TABLE 2 -Beneficial Treatments

Table 3:

TABLE 3 - Unproven Treatments

Exercise

The benefits of exercise in FM were first demonstrated in 1988, in a 20-week study of high-intensity exercises versus flexibility training.[28] The study enrolled 42 patients with primary fibromyalgia, who were randomized into a 20-week program consisting of either cardiovascular fitness (CVR) training or simple flexibility exercises (FLEX) that did not lead to enhanced cardiovascular fitness. After 20 weeks, patients receiving CVR training showed significantly improved cardiovascular fitness scores compared with those receiving FLEX training. The investigators also found that high-intensity aerobic exercise resulted in improvements in tender point thresholds, fitness, and global assessments.

In another study, researchers performed a systematic (Cochrane) review of exercise in FM.[29] The authors evaluated 16 trials and determined that 7 of these were high enough quality, in terms of adequate randomization, blinded assessments, and defined primary outcomes, to be included in the analysis. The results of these high-quality trials indicated that aerobic exercise led to an increase of 28 percent in tender point pain pressure thresholds; whereas, in the control population, there was a 7 percent downward progression. Based on these data, the researchers concluded that supervised aerobic exercise training had beneficial effects on FM symptoms. The authors also noted that strength training may also have benefits on some FM symptoms, but there was no strong evidence to support this conclusion.

TCAs

Antidepressant medications are frequently used for the treatment of fibromyalgia. Some antidepressants exert their mood altering effects by inhibiting the reuptake of norepinephrine (NE) and/or serotonin (5HT). (See Sidebar 2) Others, such as amitriptyline, which is a strong sodium channel blocker and belongs in the class of tricyclic antidepressants (TCAs), are also thought to affect the perception of pain, in addition to their antidepressant effect.

SIDEBAR 2 - Mechanism of Antidepressants:

Antidepressants have been a mainstay in the treatment of neuropathic pain. They are believed to exert an antineuralgic effect by inhibiting the reuptake of the biogenic amines norepinephrine and serotonin, thereby enhancing inhibition from the brain stem to the spinal cord.

The TCAs are divided into 2 major categories: secondary and tertiary amines. The tertiary amines, which include drugs such as amitriptyline and clomipramine, inhibit the uptake of norepinephrine and serotonin. The secondary amines, which include drugs such as nortriptyline and desipramine, are relatively selective norepinephrine reuptake inhibitors. The TCAs exert other effects, including modulation of the sodium channels, anticholinergic effects, and antihistaminic effects. SNRIs inhibit the reuptake of serotonin and norepinephrine but do not have the sodium channel modulating effects of the TCAs.

[END OF SIDEBAR 2]

In a review article published in the journal Psychosomatics in 2000, Lesley Arnold and colleagues evaluated the efficacy of tricyclic antidepressants in fibromyalgia.[30] The authors performed a meta-analysis of 9 controlled trials involving tricyclic agents, and calculated effect sizes for measurements of physician and patient overall assessment, pain, stiffness, tenderness, fatigue, and sleep quality. The researchers found that, compared with placebo, "tricyclic agents were associated with effect sizes that were substantially larger than zero for all measurements." The largest improvement was associated with measures of sleep quality, and the smallest improvement was found in measures of stiffness and tenderness (see Figure 2).

Figure 2:

FIGURE 2 - TCA Effects Sizes

Although reasonably effective, TCAs have a number of undesirable side effects, including sedation and weight gain (see Table 4).[31] Cardiac effects and orthostatic hypotension are a concern as well, so TCSa are generally not considered to be "ideal" medications in the management of FM.

Table 4:

TABLE 4 - Common Side Effects of TCAs

TCAs can be associated with numerous side effects. Because of their antihistaminic properties, TCAs can lead to sedation and weight gain. Dry mouth and constipation are secondary to their anticholinergic muscarinic properties. The TCAs also can cause postural hypotension, which, when coupled with their sedative effects, can result in falls, especially in elderly patients. In addition, the TCAs can cause cardiac arrhythmias and seizures in patients with heart disease and epilepsy, respectively. In general, the tertiary amines are associated with a significantly higher incidence of sedative and postural hypotension compared with the secondary amines.³¹

SSRIs

Another study by Arnold and colleagues assessed the efficacy of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with fibromyalgia.[32] The researchers enrolled 60 women (21 to 71 years old) with fibromyalgia, and randomly assigned them to receive either fluoxetine (10-80mg/d) or placebo for 12 weeks, in a double-blind, parallel-group, flexible-dose study. Primary outcome measures included the Fibromyalgia Impact Questionnaire (FIQ) total score (score range 0 to 80) and the FIQ pain score (score range 0–10). The McGill Pain Questionnaire, the change in the number of tender points, and total myalgic score were the secondary measures.

An analysis of the results showed that women who received fluoxetine (mean dose, 45±25mg/d) had significant (P = 0.005) improvement in the Fibromyalgia Impact Questionnaire total score, compared with subjects in the control group. Women who were given fluoxetine also had significant (P = 0.002) improvements in the FIQ pain score, the FIQ fatigue score (P = 0.05), as well as the McGill Pain Questionnaire (P = 0.01) and depression (P = 0.01) scores, compared to subjects who received placebo. Also, the number of tender points and total myalgic scores improved more in the fluoxetine group than in the placebo group. However, these differences did not reach statistical significance.

Based on these results, the investigators concluded that fluoxetine was effective on most outcome measures in women with fibromyalgia, while being generally well tolerated. They cautioned, however, that the study had several limitations, which may limit the generalizability of the results. They noted, for example, that, because the duration of treatment was only 12 weeks, the results may not necessarily be applicable to longer treatment periods.

Fluoxetine also appears to be efficacious when used in combination with the tricyclic antidepressant amitriptyline, according to a study by Don Goldenberg, and colleagues.[33] The study evaluated the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with FM. A total of 19 patients participated in this 4x6-week crossover study, in which they either received placebo, AM (25 mg), FL (20 mg), or a combination of the two medications. Patients were assessed on the first and last day of each trial period. Outcome measures included a tender point score, the FIQ, the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well-being, pain, sleep disturbance, fatigue, and feeling refreshed upon awakening.

The researchers calculated the percentage of change in outcome measures from the beginning to the end of the trial period for each treatment. Results showed that both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well-being, and sleep disturbances. Furthermore, the combined use of the two treatments was more effective than either medication alone. Additionally, there were statistically nonsignificant improvements in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. However, there were no clear trends regarding improvements in the number of tender points. According to the authors, these data indicate that both fluoxetine and amitriptyline are effective treatments for fibromyalgia, and they work better in combination than either medication alone.

Combined Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine (Effexor), an antidepressant that blocks the reuptake of both serotonin and norepinephrine, has also been investigated in patients with FM. In a 12-week, open-label study, 15 patients with fibromyalgia were assessed before and after treatment with venlafaxine (75 mg/day).[34] The primary outcome measures included the FIQ) total score and the FIQ pain score. The investigators used the BDI, as well as the Beck Anxiety, the Hamilton Anxiety, and the Hamilton Depression scales to assess anxiety and depression levels.         

Results showed that there were a significant improvements in the mean intensity of pain (P = 0.0001) and in the overall disability caused by fibromyalgia (P = 0.0001) during the 12 weeks of treatment. The depression and anxiety scores also decreased significantly from baseline to week 12. Interestingly, however, the improvement in the FIQ scores did not correlate with the decreases in depression and anxiety scores. These results indicate that venlafaxine is “quite promising in alleviating the pain and disability associated with fibromyalgia,” the investigators concluded. They also noted that this effect seemed to be independent of the medication’s anxiolytic and antidepressant properties.

Figure 3:

FIGURE 3 - Pregabalin Efficacy

Duloxetine is another combined serotonin-norepinephrine reuptake inhibitor that has been studied for fibromyalgia. It is indicated for the treatment of major depressive disorder, the management of neuropathic pain associated with diabetic peripheral neuropathy, and the treatment of generalized anxiety disorder. Although duloxetine has not been approved for the treatment of fibromyalgia, some published studies indicate that it is beneficial for patients with FM.

In a double-blind, multicenter trial, duloxetine was compared to placebo in the treatment of fibromyalgia patients with or without major depressive disorder.[35] The researchers enrolled a total of 207 subjects (89 percent female, mean age 49 years) with primary fibromyalgia. 38 percent of the participants also had comorbid major depressive disorder. Patients who were involved in disability reviews, as well as those with pain from

traumatic injury or structural or regional rheumatic disease, rheumatoid arthritis, inflammatory arthritis, or autoimmune disease were excluded from the trial.

After a 1-week, single-blind, placebo lead-in phase, 104 subjects were randomly assigned to receive duloxetine (60mg twice a day), while the remaining 103 subjects were assigned to receive placebo for a period of 12 weeks. Primary outcome measures were the FIQ total score (score range 0–80, with 0 indicating no impact) and FIQ pain score (score range 0–10). Secondary outcome measures included mean tender point pain threshold, number of tender points, FIQ fatigue, tiredness on awakening, and stiffness scores. The severity of depressive and anxiety symptoms was measured by the Beck Depression Inventory-II and the Beck Anxiety Inventory, respectively.

The investigators found that, compared with placebo-treated subjects, duloxetine-treated subjects improved significantly more (P = 0.027) on the FIQ total score, but the improvement in FIQ pain score was not statistically significant. (P =0.130). Most of the secondary outcome measures improved significantly more in the duloxetine group than in the control group. When the results were broken down according to the sex of the subjects, the analysis revealed that duloxetine-treated female subjects improved significantly on most efficacy measures, while duloxetine-treated male subjects did not respond significantly on any efficacy measure, when compared to placebo-treated subjects. The reasons for these sex differences in response are “unclear,” according to the authors. They did note, however, that the disparate presentations of fibromyalgia in women and men suggest that there might be sex differences in the pathophysiology of fibromyalgia, and these differences could affect the response to treatment.

In a follow-up to the above study the same group of researchers performed a randomized, double-blind, placebo-controlled trial to investigate the use of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder.[36] This 12-week clinical trial was aimed at assessing the safety and efficacy of two different doses of duloxetine (60 mg once per day and 60 mg twice per day) in this patient population.

354 female patients (mean age, 49.6 years) with primary fibromyalgia were enrolled in the study. 118 patients were administered duloxetine 60 mg once daily (QD), while another 116 were given duloxetine 60 mg twice daily (BID). The remaining 120 patients received placebo. The primary outcome was the Brief Pain Inventory average pain severity score and response to treatment was defined as a 30 percent or greater reduction in this score.  Compared with placebo, both duloxetine-treated groups improved significantly more (P < 0.001) on the Brief Pain Inventory average pain severity score. A significantly higher percentage of duloxetine-treated patients had a 30 percent or greater improvement in this score (duloxetine 60 mg QD (55 percent; P < 0.001); duloxetine 60 mg BID (54 percent; P = 0.002); placebo (33 percent)).

As in the previous study, the treatment effect of duloxetine on pain reduction was independent of the presence of major depressive disorder. Both doses of duloxetine were equally effective and were generally well tolerated. Common adverse events included nausea, dry mouth, and constipation (see Figure 4). Current clinical practice indicates that starting treatment at a relatively low dose (e.g., 20 mg per day) and raising it slowly (i.e., slow, careful titration) may help minimize these and other side effects.

Figure 4:

FIGURE 4 - Duloxetine Side Effects

Milnacipran is another combined serotonin-norepinephrine reuptake inhibitor that appears to be beneficial in FM, although it is only available in Europe at the present time. Milnacipran has been tested in a phase II clinical trial involving 125 patients with FM.[37] Participants were randomly assigned in a 3:3:2 ratio to receive milnacipran twice daily, milnacipran once daily, or placebo for 3 months in a double-blind dose-escalation trial; 92 percent of twice-daily and 81 percent of once-daily participants achieved dose escalation to the target milnacipran dose of 200 mg. The primary endpoint was the degree of reduction of pain.

The authors reported that 72 percent of enrolled patients completed the study, with no significant differences in dropout rates among the 3 groups (30.4%, 27.5%, and 25.0% in the milnacipran QD, milnacipran BID, and placebo groups, respectively). The most frequent reasons for discontinuation in the overall population were adverse events (14.4%) followed by therapeutic failure (8.8%).  Both the once- and twice-daily groups showed statistically significant improvements in pain, as well as improvements in global well being, fatigue, and other domains. However, BID milnacipran was a more effective analgesic than QD milnacipran. Response rates for patients receiving milnacipran were equal in patients with and without comorbid depression, but placebo response rates were considerably higher in depressed patients, leading to significantly greater overall efficacy in the nondepressed group. The investigators also noted that the effect sizes obtained in this study were comparable to those that had been previously found with tricyclic antidepressants, and that the drug was generally well tolerated.

Pregabalin: FDA-Approved for FM

Currently, pregabalin is the only medication that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia. Despite the fact that pregabalin has "gaba" is in its name, it has no effect on gamma-aminobutyric acid (GABA). It is a medication that binds the α2-δ subunit of voltage-gated calcium channels. It also presynaptically reduces calcium influx and causes a decreased release of glutamate, substance P, and calcitonin gene related peptide (CGRP), all which are thought to relate to the generation of pain. And, although it is similar to gabapentin, pregabalin is somewhat more predictable (i.e., the range of doses needed to be tried during titration is easier to predict) because of its linear pharmacodynamics.

The efficacy and safety of pregabalin in fibromyalgia was evaluated in a double-blind, placebo-controlled trial, the results of which were published in the April 2005 issue of Arthritis & Rheumatism.[38] To be included, patients had to meet the 1990 American College of Rheumatology fibromyalgia criteria, and those who were receiving or applying for disability, or engaged in litigation were excluded from the study.

Patients were randomly assigned to receive either placebo or pregabalin at 150, 300, or 450 mg/day. Study medication was administered 3 times daily in equal doses for 8 weeks. The primary outcome variable was the comparison of end point mean pain scores, derived from daily diary ratings of pain intensity, between each of the pregabalin treatment groups and the placebo group.

Statistical analysis of the results showed that pregabalin at 450 mg/day significantly reduced the average severity of pain in the primary analysis compared with placebo (P ≤ 0.001), and significantly more patients in this group had 50 percent or greater improvement in pain at the end point (29 percent, versus 13 percent in the placebo group; P = 0.003). Pregabalin at 300 and 450 mg/day was associated with significant improvements in sleep quality, fatigue, and global measures of change. Pregabalin at 450 mg/day improved several domains of health-related quality of life. Rates of discontinuation due to adverse events were similar across all 4 treatment groups.

Treatment-emergent adverse events were reported by most patients in each group (78%, 88%, and 92% of patients in the 150, 300, and 450 mg/day pregabalin groups, respectively, and 77% of patients in the placebo group). Most adverse events were mild or moderate. Dizziness and somnolence were the two most frequently reported adverse events and tended to be dose-related across pregabalin groups (see Table 5).

On the basis of these results, the investigators concluded that pregabalin at 450 mg/day was efficacious for the treatment of FMS, reducing symptoms of pain, disturbed sleep, and fatigue compared with placebo. They also noted that pregabalin was well tolerated and improved global measures and health-related quality of life.

Table 5:

TABLE 5 - Pregabalin Side Effects

Conclusion: General Approach to Patients with FM

Based on the available evidence regarding the evaluation and treatment of patients with suspected fibromyalgia, authors of a comprehensive literature review on the topic published in the Journal of the American Medical Association in 2004 recommend a graded, step-by-step approach to these patients.²⁷

According to these recommendations, the first step should be to confirm the diagnosis and educate the patient about the condition. Physicians should explain to them that there are no definitive diagnostic tests, but the disorder does exist and it is unlikely to progress further.    

Patients should then be evaluated and treated for any comorbid illnesses, including mood disorders and sleep disturbances. An aerobic exercise program should also be initiated as soon as possible, as it seems to be clearly beneficial. Cognitive behavior therapy may also be helpful.

Pharmacotherapy with tricyclic or other types of antidepressants and/or other medications can also be added, as necessary. Combination therapy could be considered, targeting different drug mechanisms of action. Finally, if the patient still continues to do poorly, a specialty referral to a rheumatologist, a physiatrist, psychiatrist, or pain management specialist might be in order.

References 

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