Fibromyalgia: A review of management options

Evidence-based recommendations utilize an integrated approach that combines nonpharmacologic approaches (specifically patient education, exercise, and cognitive behavioral therapy) and pharmacologic approaches in the management of fibromyalgia.

Key Points


Characterized by widespread musculoskeletal pain, fatigue, and sleep disturbances, fibromyalgia (FM) is a debilitating syndrome affecting approximately 2% of the US population. Disordered central pain processing likely plays a role in the pathogenesis of FM and treatment strategies primarily focus on alleviating pain and addressing associated symptoms and comorbid conditions. Despite evidence suggesting efficacy of various agents that act on the central nervous system and modulate pain perception (ie, antidepressants, anticonvulsants, and muscle relaxants), no one drug or class of drugs has proven to completely address all symptoms of FM. Evidence-based recommendations utilize an integrated approach that combines nonpharmacologic approaches (specifically patient education, exercise, and cognitive behavioral therapy) and pharmacologic approaches in the management of FM. (Formulary. 2009; 44:362-373.)

The second most common diagnosis after osteoarthritis in patients seen by rheumatologists, fibromyalgia (FM) is a chronic and debilitating central pain disorder.1 FM affects approximately 2% of the US population, with prevalence rates of 3.4% in women and 0.5% in men.2 Characterized by widespread musculoskeletal pain, fatigue, and sleep disturbances, the lack of overt inflammation or joint destruction often associated with numerous other rheumatologic disorders makes the diagnosis and management of FM difficult. Symptoms typically appear between the ages of 20 and 55, but FM can be diagnosed at any age.3 In addition, patients with FM often present with a number of comorbid chronic medical and psychiatric illnesses or pain syndromes.4 Consequences associated with FM include daytime fatigue, impaired concentration, poor job performance, and decreased patient self-efficacy beliefs.1 Treatment of FM focuses on reducing pain and improving sleep and overall quality of life.

The clinical presentation of FM is heterogeneous and in addition to the ACR criteria, other symptoms commonly occur. Musculoskeletal symptoms of FM include widespread pain at multiple sites, stiffness, sensation of hurting all over, and diffuse soft tissue swelling.4 Nonmusculoskeletal symptoms often include difficulty falling or staying asleep, fatigue, paresthesias, and difficulties with concentration and memory. The pain associated with FM can be variable and is often described as a widespread, deep, burning, or gnawing ache.4,7 Physical or emotional stress, nonrestorative sleep, and a decrease in physical activity often worsen symptoms. Fibromyalgia may occur concurrently with hypothyroidism, and other commonly comorbid conditions include anxiety and depressive disorders, insomnia, migraine headache, irritable bowel syndrome, restless leg syndrome, temporomandibular pain syndrome, and Raynaud's phenomenon.4

While the exact cause of FM remains unknown, genetic influences, physical or psychological trauma or stress, disturbances in the neuroendocrine and autonomic nervous systems, abnormalities in pain perception, and various biochemical changes are all proposed to play a role in its etiology.1,6-9 Many of these findings individually are not specific to FM or sufficient to explain the pain associated with FM. However, it is well accepted that patients with FM experience pain differently than pain-free controls and they do so in the absence of any identifiable underlying disease.1,6

Many of the available pharmacotherapeutic treatment options are based on the proposed pathophysiology of FM and associated comorbid conditions. Recommendations for the management of FM published by the American Pain Society (APS) in 2004 and the European League Against Rheumatism (EULAR) in 2007 employ differing criteria for evidence-based ratings, yet both sets of recommendations support the incorporation of nonpharmacologic and pharmacologic strategies.10,11

Data from well-controlled studies support the use of education, exercise, and cognitive-behavioral therapy (CBT) in patients with FM. While not curative or equally effective in all patients, these approaches can be employed individually or in combination to improve a patient's general health or as augmentation to pharmacotherapy.12

Providing patients and their families with information regarding the cause and course of FM and realistic expectations and potential benefits of various treatment modalities can lead to significant improvements in patient self-efficacy, pain control, sleep disturbances, mood, and overall quality of life.10-13 A meta-analysis of 6 trials indicates that aerobic exercise at American College of Sports Medicine recommended intensity levels improves physical functioning, tender point pain pressure threshold, global well-being, and pain perception in patients with FM.14 In addition, aerobic exercise has been found to be effective in decreasing depression and anxiety in patients with FM when compared to nonexercising controls.12 Because an abrupt increase in activity may often worsen FM symptoms, beginning with a low-intensity exercise with a gradual increase in activity is recommended.12 Literature has confirmed the positive effects of psychological and behavioral therapy, in the form of CBT, on pain, sleep disturbances, fatigue, mood, and physical function in FM.12,15

Combinations of education, exercise, and CBT seem to provide better outcomes than when these strategies are used alone.9 In one study, when combined with education, exercise significantly improved aerobic performance, overall well-being, fatigue, and sleep in FM patients as compared to wait-list controls.16 Several randomized controlled trials (RCTs) that combined CBT and/or education with exercise found significant decreases in pain severity and improvements in patient self-efficacy and 6-minute walk distance.15 The complex pathophysiology and the presence of multiple symptoms make the pharmacotherapy of FM challenging. Regardless, pharmacologic treatment approaches are the primary strategy for the management of FM. Agents that act on the central nervous system and modulate pain perception, including antidepressants, anticonvulsants, muscle relaxants, and analgesics, have been used with varying success and are supported by varying levels of evidence. Three medications used to treat FM (duloxetine, milnacipran, and pregabalin) have earned FDA approval.17-19

Disturbances in serotonin (5-HT), norepinephrine (NE), and dopamine (DA) have been proposed as underlying causes of FM, and numerous antidepressants have been evaluated as treatment options. Two meta-analyses, one evaluating 26 RCTs (placebo, usual care, or other well-defined treatment) and the other evaluating 18 randomized placebo-controlled trials, found that the short-term use of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), dual serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs) can reduce symptoms of pain, fatigue, sleep disturbances, and depressed mood and increase health-related quality of life (HRQOL) in patients with FM.20,21 No study in either of the meta-analyses measured serum antidepressant levels or controlled for the concomitant use of analgesic medications. Limitations to the use of antidepressants in patients with FM include no published studies evaluating long-term use (range, 4-28 weeks) or adverse effects, and a paucity of data evaluating effectiveness in patients <18 and >65 years of age, in non-white patients, in male patients, and in patients with comorbidities (other than mood or anxiety disorders).20,21 Furthermore, there is no evidence to support cost-effectiveness of antidepressants in FM.

The most studied TCA, amitriptyline, possesses the strongest evidence for efficacy in improving pain (P<0.001), fatigue (P<0.003), sleep (P<0.001), and HRQOL (P<0.04) associated with FM.22 The antidepressant effects of amitriptyline were not determined to be significant (P<0.076), likely due to the fact that doses of 12.5 to 50 mg/day, less than those required for antidepressant activity, were used.22 To minimize the anticholinergic side effects (ie, dry mouth, constipation, tachycardia, and urinary retention) commonly associated with TCAs, an initial low dose of 10 mg of amitriptyline taken 2 to 3 hours before bedtime with dosage escalations of 10 to 25 mg per week (as tolerated) to a target dose of 25 to 50 mg is recommended.20,21 Nortriptyline was found not to be superior to placebo in the only study evaluating its effectiveness in FM.22 Randomized, placebo-controlled trials evaluating fluoxetine, citalopram, sertraline, and paroxetine in FM have produced inconsistent and varied results.20,21 Overall, when compared to placebo, SSRIs significantly improved symptoms of pain (P<0.04), depressed mood (P<0.02), and HRQOL (P<0.03); no significant improvements in fatigue or sleep disturbances were observed.21

One randomized, double-blind crossover study (n=19; mean age 42.9±9.6 years) evaluated fluoxetine (20 mg), amitriptyline (25 mg), a combination of both agents, and placebo over four 6-week periods in patients with FM.23 Patients were evaluated on the first and last days of each trial period and both fluoxetine and amitriptyline were more effective than placebo in improving pain (P<0.001, fluoxetine; P=0.02, amitriptyline), sleep disturbances (P=0.04, fluoxetine; P<0.001, amitriptyline), and global well being (P=0.02, fluoxetine; P=0.02, amitriptyline). No correlation between reduced pain and the number of tender points was found. When given in combination, fluoxetine and amitriptyline were approximately two times more effective than either agent given alone.23 One 6-week RCT evaluating fluoxetine (20 mg/day) in women (fluoxetine, n=21; placebo n=41) found a significant improvement in sleep quality (P=0.03) and depressive symptoms (P=0.04), but no significant improvement in pain or other symptoms of FM.24 A second 12-week RCT that evaluated fluoxetine (10-80 mg/day) in women (21-71 years) with fibromyalgia found that, based on intent-to-treat analysis, those who received fluoxetine (n=25) experienced significant improvements in pain (P=0.002), fatigue (P=0.05), and depression (P=0.07) when compared to the placebo group (n=26).25 No significant improvements were seen in overall physical or work impairment, feeling tired on awakening, stiffness, anxiety, or the number of tender points. A randomized, double-blind, crossover study of two 2-week trials separated by a 2-week washout phase compared the effects of fluoxetine (20 mg in the morning; placebo at bedtime) and amitriptyline (25 mg at bedtime; placebo in the morning) on exercise performance in women (n=15) with FM.26 A positive effect on high-intensity exercise performance was observed with both agents.

Two RCTs have evaluated citalopram in the treatment of FM.27,28 In one trial, no differences in pain, fatigue, sleep, or mood symptoms were observed in the 22 patients randomly assigned to receive citalopram (20 mg/day for 4 weeks followed by an increase to 40 mg/day for 4 weeks) and the 21 patients who received placebo.27 The second trial evaluated citalopram (20-40 mg/day; n=21) and placebo (n=19) in female patients with FM.28 At the end of the 16-week study period, citalopram significantly improved depressive symptoms (P<0.01) and sleep (P<0.01). However, no significant differences between the 2 groups were observed in pain symptoms and overall physical functioning.28

An RCT of 40 patients with FM compared paroxetine (20 mg/day for 2 weeks, followed by 40 mg/day) to amitriptyline (10 mg/day for 2 weeks, followed by 20 mg/day).29 While both treatment groups experienced significant improvements in pain, sleep, and depression symptoms (all, P<0.05), the effects of amitriptyline were greater. In addition, the benefit of amitriptyline for fatigue was significantly greater (P<0.05). The effects of controlled-release paroxetine (12.5 to 62.5 mg/day) in FM, as measured by the Fibromyalgia Impact Questionnaire (FIQ), was evaluated in an RCT of 116 subjects over a 12-week period.30 Significantly more patients in the controlled-release paroxetine group reported improvements in the overall FIQ score (P=0.016) and the fatigue, anxiety, and days felt good FIQ subscores (all, P<0.05). Paroxetine failed to separate from placebo on the pain and tender point FIQ subscores.30

Data from the SSRI studies discussed previously suggest that serotonergic activity alone is not sufficient to improve FM symptoms. Adverse effects commonly seen with SSRIs as a class include nausea, vomiting, sexual dysfunction, and insomnia.

As evidenced by the efficacy of amitriptyline in FM, dual modulation of 5-HT and NE appears to play an important role in the effective treatment of chronic pain. Short-term studies (<6 months) indicate a benefit to the use of venlafaxine, duloxetine, and milnacipran in fibromyalgia. The strongest evidence for the efficacy of SNRIs in reducing pain is with duloxetine and milnacipran, and both agents are FDA approved for the treatment of FM.17,18,20,21

Venlafaxine, primarily a 5-HT reuptake inhibitor at doses <150 mg/day, has been evaluated in two open-label and one RCT for the treatment of FM.31,32,34 Fifteen subjects (13 women; 2 men) with a mean age of 48 years received venlafaxine (range, 37.5-300 mg/day; mean 167±76 mg/day) over an 8-week period.31 Nine subjects reported concurrent Axis I disorders, primarily major depressive disorder (MDD) and anxiety disorder. Following the study period, significant improvement from baseline was reported in pain, fatigue, sleep quality, feeling on awakening, and morning stiffness (all, P≤0.01).31 In a second study, a fixed dose of venlafaxine (75 mg/day) was evaluated in 15 women with FM.32 Following a 12-week study period, significant improvement in the mean intensity of pain, the disability caused by fibromyalgia, and depression and anxiety scores were reported (all, P=0.0001). There was no correlation between improvement in any of these measures and the presence or history of a psychiatric disorder, and the improvement in pain and disability associated with fibromyalgia was independent of venlafaxine's antidepressant and anxiolytic effects.32 Limitations of both of these studies evaluating venlafaxine in FM include an open-label design, lack of placebo or active control groups, lack of measurement of tender points, and small sample size. The results of the two open label studies previously discussed were not replicated in an RCT in which patients in the fixed-dose venlafaxine (75 mg/day) arm did not experience significant improvements in pain, fatigue, sleep, or mood compared to subjects in the placebo arm.33 Constipation, dry mouth, fatigue, headache, insomnia, and nausea were commonly reported adverse effects associated with the use of venlafaxine in these trials.31-33

The efficacy and safety of duloxetine, an SNRI that is relatively balanced in its reuptake inhibition of 5-HT and NE across all doses, in FM has been evaluated in four double-blind RCTs and one 1-year open-label study.34-38 One 12-week study compared duloxetine 60 mg twice daily (120 mg/day) and placebo in 207 subjects (mean age 49 years) with FM, with (38%) or without comorbid MDD.34 The majority of subjects enrolled were female (89%) and white (87%). Regardless of baseline presence of MDD or anxiety symptoms, intent-to-treat analysis showed significant improvement in pain severity (measured by the Brief Pain Inventory [BPI], P=0.008), number and pain threshold of tender points (P=0.002), stiffness (P=0.048), and total FIQ score (P=0.027) in the duloxetine group, when compared to placebo. Interestingly, representing approximately 10% of the enrolled subjects, males (n=12) in the duloxetine group had no significant improvement in any of the outcome measures.34 A subsequent 12-week RCT compared 2 dosing regimens of duloxetine (60 mg either once or twice daily) to placebo in 354 women (mean age 49.6 years) with FM.35 The majority of subjects enrolled were white (90%) with 26% experiencing comorbid MDD. Both duloxetine groups showed significant improvement, when compared to placebo, in pain severity measured by BPI starting at week 1 (P<0.001) and continuing through the end of the study period. Furthermore, a significantly greater percentage of patients in the duloxetine groups (once daily: 55%, P<0.01; twice daily: 54%, P=0.002) reported response (defined as ≥30% reduction in the BPI score) versus placebo.35 As in the previous trial, the duloxetine-treatment effects were independent of comorbid depressive symptoms. When compared to each other, there were no significant differences between the two duloxetine doses for any outcomes measured. However, when compared to placebo, the twice-daily regimen significantly improved tender point measures, whereas the once-daily regimen did not.35 In a more recent study, 520 subjects (average age 51 years) were randomly assigned to receive a fixed dose of duloxetine (20 mg, 60 mg, or 120 mg once daily) or placebo over a 6-month period.36 As with previous duloxetine trials, the majority of patients were women (94.8%) and white (84.2%). At the end of the 3-month acute phase, only those treated with duloxetine 60 mg/day and 120 mg/day experienced significantly greater improvements in pain severity compared with the placebo group (P≤0.05 and P≤0.001, respectively).36 As a result, the duloxetine 20 mg/day group was titrated to 60 mg/day for the 3-month continuation phase. At the 6-month study endpoint, all three groups of patients treated with duloxetine reported significantly reduced pain severity from baseline compared with placebo, with only the duloxetine 20/60 mg/day and duloxetine 120 mg/day groups reporting significantly greater global improvement. No significant improvements in general fatigue, mean tender point threshold, or total FIQ scores were found between any of the duloxetine- or placebo-treated groups. No gender differences in response were found, and duloxetine was efficacious in patients with and without comorbid MDD.36 An additional 27-week RCT evaluating duloxetine in 330 patients with FM (93% female) compared duloxetine (60 mg or 120 mg daily; n=162) with placebo (n=168).37 Duloxetine was initiated at 30 mg daily and titrated to 60 mg once daily after 1 week. In patients with an inadequate response (<50% reduction in BPI average pain score) with duloxetine 60 mg once daily after 8 weeks, the duloxetine dose was increased to 120 mg once daily. Results, reported as combined data for patients receiving duloxetine 60 mg once daily or 120 mg once daily, indicated no significant difference between the duloxetine-treated group and placebo in least squares mean change in BPI average pain scores and total patient global impressions of improvement (PGI-I) score from baseline.37 However, significant improvements were found in the duloxetine-treated group compared with placebo in several secondary endpoints including FIQ pain scores (P=0.03), BPI least pain score (P=0.046), clinical global impressions scale (CGI-S) score (P=0.011), and the Beck Depression Inventory-II total score (P=0.017). In addition, significantly fewer patients in the duloxetine-treated group discontinued due to lack of efficacy (P<0.05).37 Data from these studies were used to support the FDA approval of duloxetine 60 mg once daily as a safe and effective treatment option for patients with FM.17

Long-term safety and tolerability data on duloxetine in FM are based on two 1-year studies and one pooled-analysis report of five clinical trials.38-40 In a 60-week safety study (n=350; 96% female), patients received duloxetine 30 mg once daily for 1 week and then 60 mg once daily for 7 weeks in an open-labeled fashion.38 Patients were then randomly assigned to receive duloxetine 60 mg or 120 once daily in a double-blind manner for an additional 52 weeks. In patients with no response to duloxetine 60 mg/day during the open-labeled phase an increase to duloxetine 120 mg daily in the subsequent randomized double-blind phase appeared to provide no additional benefit. No significant differences in BPI average pain scores were found between patients randomly assigned to receive 60 mg or 120 mg during the double-blind phase.38 A 6-month extension of two phase 3 placebo-controlled trials indicates long-term tolerability of duloxetine 60 mg and 120 mg once daily to be similar to that reported in placebo-controlled trials of 3 to 6 months in duration.36,37,39 Duloxetine is generally well-tolerated, and commonly reported adverse effects (≥5%) include nausea, dry mouth, constipation, decreased appetite, somnolence, and hyperhidrosis.17,39,40

Milnacipran, an SNRI with 3-fold higher potency for NE than 5-HT reuptake inhibition, has been evaluated in several RCTs for the treatment of FM.18,41-43 A 12-week double-blind, phase II RCT (a 4-week dose escalation phase followed by an 8-week observation phase) compared milnacipran 100 mg twice daily (n=46) and milnacipran 200 mg once daily (n=51) to placebo (n=28) in subjects with FM (mean age range: 46.2-48.0 years; ≥96% female; ≥79% white).41 When compared to those in the placebo group, subjects in both dosing regimens of milnacipran reported significantly greater improvements in global well-being (once daily: 77%, P=0.008; twice daily: 73%, P=0.013; placebo: 38%). When secondary outcomes were assessed, data indicated that a significantly greater percentage of patients in the milnacipran twice-daily dosing group, but not the once-daily dosing group, reported at least a 50% reduction in pain intensity when compared to those who received placebo (once daily: 22%, P=0.55; twice daily: 37%, P=0.,04; placebo: 14%).41 As a result, analysis of secondary outcomes focused on the twice-daily dosing regimen and significant improvements were reported in fatigue (P=0.032), some measures of pain (P=0.032), and morning stiffness (P=0.047). Although the trend toward improvement favored the milnacipran twice-daily group, no statistically significant differences in total FIQ scores, sleep scores, or improvement in depression and anxiety symptoms were found when compared to placebo. It is important to note that in this study, a higher percentage of patients with comorbid MDD were enrolled in the placebo group (32% vs 11.34% in the milnacipran groups combined). Equal response rates were observed in patients receiving milnacipran regardless of comorbid MDD; however, placebo response rate in patients with comorbid MDD was 33% compared to 5% in non-depressed patients, leading to significantly greater overall efficacy in the non-depressed patients.41

Data from 2 multicenter RCTs evaluating the efficacy and tolerability of milnacipran were used to support its FDA indication for fibromyalgia.42,43 In the first trial, individuals (age range 18-70 years; mean age 50.2 years) with FM were randomly assigned to receive milnacipran 100 mg/day (50 mg twice daily; n=399), milnacipran 200 mg/day (100 mg twice daily; n=396), or placebo (n=401).42 The majority of subjects were female (96.2%) and white (93.5%), and efficacy was determined after a 15-week study period using rates of FM composite responders (those who had clinically meaningful improvement in pain, global status, and physical function from baseline), and FM pain composite responders (those who met the response criteria for pain and global impression of change in overall severity of FM from baseline).42 At week 15, a significantly greater number of those treated with either milnacipran dose were determined to be FM composite responders (100 mg/day, P=0.01; 200 mg/day, P=0.02) and FM pain composite responders (100 mg/day, P=0.03; 200 mg/day, P=0.004) compared with those who received placebo. In addition, compared with placebo, milnacipran-treated subjects reported significant improvements in pain and global status scores from baseline (all, P<0.001). Only those randomly assigned to receive milnacipran 100 mg/day reported significant improvements in functional status and fatigue compared with placebo (P<0.001).42 In the second trial, subjects were randomly assigned to receive milnacipran 100 mg/day (n=224), milnacipran 200 mg/day (n=441), or placebo (n=223).43 Using the same two FM composite responder measures as in the previously discussed trial, subjects were evaluated at weeks 15 and 27. When compared to placebo, a significantly greater number of subjects receiving milnacipran met criteria as FM composite responders at week 15 (100 mg/day, P=0.028; 200 mg/day, P=0.017). The percentage of FM pain composite responders in the milnacipran 100 mg/day group was greater than placebo, but only the group treated with milnacipran 200 mg/day had a significantly greater percentage of FM pain composite responders at week 15 (P=0.032).43 At week 27, while a greater percentage of milnacipran-treated subjects met criteria for FM composite responders and FM pain composite responders when compared to placebo, only the FM pain composite responder rate in the 200 mg/day group reached statistical significance. Relative to placebo, treatment with milnacipran 200 mg/day significantly improved pain (P<0.05), global assessment (P<0.001), and physical functioning scores, and reduced fatigue (P=0.016) at both weeks 15 and 27.43 Subjects receiving milnacipran 100 mg/day showed significant improvement in global assessment and fatigue at week 15 only and improvement in physical functioning at week 27 only. No differences in sleep quality were noted between either of the milnacipran-treated groups and placebo.43 The most commonly reported adverse events associated with milnacipran (both doses) in these two trials were nausea (37%), headache (18%), and constipation (16%). Adverse events occurring with an incidence of ≥5% and twice as much as placebo were constipation, hot flush, hyperhidrosis, vomiting, palpitations, increased heart rate, dry mouth, and hypertension.18,42,43 The recommended starting dose of milnacipran for FM is 12.5 mg once daily, titrated over a 1-week period to 100 mg/day (50 mg twice daily).18 The dose may be increased to 200 mg/day based on patient response and tolerability.

The nonselective and irreversible MAOIs phenelzine and tranylcypromine have been available in the United States for many years. When taken concomitantly with tyramine-containing foods, the potentially fatal hypertensive crisis limits widespread use and these agents are not recommended in FM. Two "second-generation" MAOIs (moclobemide and pirlindole), currently unavailable in the United States, have been studied in FM.44,46 These agents are specific and reversible inhibitors of MAO-A, which preferentially catabolizes NE and 5-HT, and are less likely to potentiate the pressor effects of tyramine.44-46 One double-blind RCT evaluating moclobemide (450-600 mg/day) failed to demonstrate significant improvements in FM symptoms in women (n=130) with no psychiatric comorbidities when compared to amitriptyline (25-37.5 mg/day) over a 12-week period.44 A second trial compared moclobemide (150 mg twice daily) to placebo over a 6-week period in 60 patients with FM; all patients also participated in relaxation exercises.45 Data evaluating improvement from baseline between the 2 treatment groups showed that tender point, depression, and pain scores were significantly more decreased; and fatigue, insomnia, and patients' and physicians' global assessments were also significantly more improved in the moclobemide group. Pirlindole (75 mg twice daily) for the treatment of FM has been evaluated in one trial, a 4-week double-blind, placebo-controlled pilot study (n=100).46 When compared to baseline scores, subjects randomly assigned to receive pirlindole reported significant improvements in all parameters (pain, morning stiffness, tender point scores, fatigue, sleep disturbances, and global improvement) evaluated (P<0.05). However at the end of the 4-week treatment period, pirlindole was significantly superior to placebo (P<0.05) on only 4 parameters (pain and tender point scores, and global evaluation by the patient and investigator) and exhibited no effect on depressed mood.46 While studies suggest that reversible MAO-AIs may be effective in FM, larger studies evaluating efficacy and tolerability are needed.

The use of nonsteroidal anti-inflammatory agents (NSAIDs), such as ibuprofen and naproxen, for FM is common, yet objective evidence supporting efficacy of these agents is lacking. One double-blind, placebo-controlled trial of 46 subjects with FM evaluated ibuprofen over a 3-week period followed by an additional 3-week open-label period.47 While patients in both treatment arms reported significant improvements in number of pain sites, fatigue, swelling feeling, and tender points, when compared to baseline, no significant differences in any of these symptoms of FM were found between the placebo and the ibuprofen groups. One small study (n=62) examining the effects of naproxen alone (500 mg twice daily), amitriptyline alone (25 mg at bedtime), the 2 in combination, or placebo over a 6-week period in patients with FM, found that only amitriptyline was associated with significant improvement in all outcome parameters, including patient and physician global assessments, patient pain, sleep difficulties, fatigue on awakening, and tender point score.48 Opioid analgesics are widely used for the treatment of numerous chronic pain conditions, including FM.1 However, as with NSAIDs, data to support the use of mu-opioid receptor agonists (ie, morphine and related compounds) in the treatment of FM is lacking. It has been postulated that patients with FM may have a reduced opioid binding site, resulting in decreased efficacy and/or higher dosage requirements of opioid analgesics.49 In addition, concern regarding the adverse effect profile of these agents, particularly the potential for the development of tolerance to the analgesic effects and physical dependence, further limits the use of these agents for FM-associated pain.50

Tramadol, a synthetic codeine analog that exerts its analgesic effects via weak mu-opioid receptor agonist activity combined with inhibition of 5-HT and NE reuptake, has been found effective for the treatment of FM in 3 RCTs, 2 when used as monotherapy and 1 when used in combination with acetaminophen.50-53 Assessment of pain control carried out at baseline and at 15 min and 2 hours after administration of each dose found effective spontaneous pain control in 20.6% of patients treated with tramadol compared with a 19.8% increase in spontaneous pain in the placebo-treated patients, in one double-blind, crossover study.51 The authors concluded that long-term tramadol administration may provide pain relief in patients with FM. In a second study, 100 patients with FM were treated with tramadol during an open-label phase.52 Based on Kaplan-Meier cumulative estimates comparing the 2 treatment groups, the time to exit from the double-blind phase because of inadequate pain relief (primary efficacy outcome measure) was significantly lower in the tramadol group. A more recent trial compared the combination of tramadol/acetaminophen (37.5 mg/325 mg tablets; 4 times/day, as needed; n=156) with placebo (n=157) over a 91-day period in subjects with moderate-to-severe FM (94% women; mean age 50±10 years).53 Compared with placebo, cumulative time to discontinuation (primary end point) and overall discontinuation for any reason were significantly lower in the tramadol/acetaminophen-treated group. Using the same patient population in the previously discussed tramadol/acetaminophen study, it was found that effective pain relief with tramadol/acetaminophen significantly increased HRQOL.54

Gabapentin and pregabalin, structural derivatives of gamma-amino butyric acid (GABA) possessing analgesic, anxiolytic, and anticonvulsant activity, have been evaluated in short-term and long-term studies of patients with FM.55,56 The analgesic effects of these two agents are believed to be mediated via binding at the alpha-2-delta subunit of presynaptic voltage-gated calcium channels, ubiquitously distributed throughout the central and peripheral nervous systems. The resulting attenuation of Ca2+ ion influx modulates the excessive release of substances associated with neuronal excitation (ie, glutamate) and substance P.55,56

Gabapentin, FDA approved as an anticonvulsant and for the treatment of postherpetic neuralgia, has been evaluated in one 12-week, double-blind RCT in patients with FM (90% women; 97.3% white).55,57 Gabapentin 1,200 to 2,400 mg/day (median dose=1,800 mg/day; n=75) was significantly more effective in improving pain severity (P=0.015), sleep quality (P=0.001), and total FIQ scores (P=0.001), compared with placebo (n=75).55 Improvements in mean tender point threshold or symptoms of depression were not significantly different between the 2 treatment groups. Compared to placebo, adverse effects reported significantly more often in the gabapentin group included dizziness (25.3%; P<0.05), sedation (24%; P<0.001), lightheadedness (14.7%; P<0.01), and weight gain (8%; P<0.05).55

Pregabalin is FDA approved for the adjunctive treatment of partial onset seizures and the treatment of several pain syndromes, including diabetic peripheral neuropathy, postherpetic neuralgia, and FM.19 An 8-week multicenter RCT dose finding study compared pregabalin 150, 300, and 450 mg/day (n=398) with placebo (n=131) in patients with FM (91.5% women; 93.2% white).58 Compared with placebo, pregabalin 450 mg/day significantly improved average daily pain severity (P≤0.001) and significantly more patients in this treatment group were classified as responders (≥50% reduction in pain from baseline; P=0.003). Significant improvements in sleep quality, fatigue, and HRQOL scores were reported by patients who received pregabalin 300 mg/day or 450 mg/day relative to placebo (all, P<0.05).58 One RCT evaluated 3 doses of pregabalin (300, 450, and 600 mg/day) in patients with FM who initially responded during a 6-week open-label phase.59 Responders (defined as >50% decrease in mean pain scores and "much improved" or "very much improved" on patient global impression of change [PGIC] from baseline) were randomly assigned to continue their current dose of pregabalin (n=279) or be switched to placebo (n=287). At the end of the 6-month double-blind phase, significantly more patients in the pregabalin group maintained therapeutic response (>30% decrease from open-label baseline) compared with those who were switched to placebo (61% vs 32%; P<0.001). In addition, time to loss of therapeutic response was significantly longer in the pregabalin-treated group (P<0.001 vs placebo). As with numerous previous trials evaluating pharmacotherapy in FM, the majority of patients were women (93%), white (88%), and were an average of 50 years of age.59 Two phase 3 trials evaluated efficacy and safety of pregabalin (twice-daily doses of 300, 450, or 600 mg/day) or placebo over a 13-week (n=748) or 14-week (n=750) period.60,61 Compared to placebo, all 3 pregabalin-treated groups had statistically significant improvement (seen as early as week 1) in mean changes in pain, PGIC, and sleep assessment scores (all, P<0.05).60,61 In one study, total FIQ score improvements were greater, but not statistically significant, relative to placebo.60 In the second study, significant improvements in total FIQ scores were seen only with the 450 mg/day (P=0.004) and 600 mg/day (P=0.003) doses.61 In a 1-year open-label extension (n=429) to the 13-week study, pregabalin (150-600 mg/day) was associated with continued improvements in pain from baseline.62

The FREEDOM study, a 6-week open-label phase followed by a 26-week double-blind treatment period, focused on evaluating relapse and the durability of effect of 3 pregabalin doses or placebo in patients with FM (mean age 48.4-49.6 years; ≥91% women; >88% white).63 During the open-label phase optimal pregabalin dosages were determined during weeks 1 to 3, and during weeks 4 to 6 patients continued to receive their optimal fixed dose (300, 450, or 600 mg/day). On completion of the open-label phase (n=663), only those patients who achieved >50% decrease in pain and a PGIC self-rating of "much" or "very much improved" were randomly assigned to double-blind continued treatment with their optimal fixed dose of pregabalin (n=279) or placebo (n=287).63 Following the 26-week double-blind period, time to loss of therapeutic response (<30% reduction in pain from open-label baseline or self-rating of worsening FM) was significantly longer for pregabalin-treated patients than for patients who received placebo (P<0.001). Further underscoring the negative effects of pregabalin discontinuation in responders with FM, by day 19 of the double-blind phase one-half of the placebo-treated patients no longer maintained a therapeutic response while more than half of the pregabalin-treated patients continued to maintain a therapeutic response throughout the entire 26 weeks. By the end of the double-blind phase, 61% of the placebo-treated patients and 32% of the pregabalin-treated patients experienced a loss in therapeutic response (P<0.001). The authors concluded that, in those who respond, pregabalin demonstrates durability of effect for FM-associated pain.63

Although pregabalin has been reported to have anxiolytic effects, improvement in pain symptoms with pregabalin, when compared with placebo, is not dependent on improvements in comorbid anxiety or depression symptoms in patients with FM.64 In addition, similar to gabapentin, pregabalin analgesic effects do not seem to result in improvements in tender point pain threshold.56 The recommended starting dose of pregabalin for FM is 75 mg twice daily (150 mg/day). Dependent on efficacy and tolerability, the dose may be increased over a 1-week period to a target dose of 150 mg twice daily (300 mg/day).19 For patients who do not experience a benefit with 300 mg/day, a further increase to a maximum of 450 mg/day (225 mg twice daily), if tolerated, is warranted. Doses above 450 mg/day are less well tolerated and there is no evidence that higher doses are more efficacious.19 The most commonly reported adverse effects in FM studies evaluating pregabalin included dizziness (38% vs 9%) and somnolence (20% vs 4%), which tended to be dose-related.19,56 Other common adverse effects (≥5% incidence and occurring more often than placebo) associated with pregabalin in FM include weight gain (11% vs 2%), blurred vision (8% vs 1%), dry mouth (8% vs 2%), constipation (7% vs 2%), fatigue (7% vs. 4%), and peripheral edema (6% vs 2%).19

Cyclobenzaprine, a muscle relaxant structurally and pharmacologically similar to the TCAs, has been shown to be beneficial in FM.1,9,13 A meta-analysis of five randomized, placebo-controlled studies evaluating cyclobenzaprine in FM found moderate improvements in sleep quality, pain, and overall global functioning.65 No improvements in fatigue or tender point scores were noted in any of the studies reviewed. Collectively, the 5 studies were conducted over a period of 2 to 24 weeks (median study duration 6 weeks) and included a total of 312 patients (n=56-69 patients per study). The majority of patients were female (≤95%), averaging 46 years of age. Cyclobenzaprine was dosed 10 to 40 mg/day (<30 mg/day dosed once daily), with doses generally starting at 10 mg at bedtime and titrated as tolerated. Noted limitations to the studies evaluated included short duration, small number of patients, a high drop-out rate (on average, only 71% of cyclobenzaprine-treated and 57% of placebo-treated patients completed studies), and no follow-up after study completion. Eighty percent of patients taking cyclobenzaprine experienced an adverse effect, with next-morning drowsiness and dry mouth most often reported.1,65

There are no large, well-controlled studies evaluating benzodiazepines or non-benzodiazepine sedative hypnotics in patients with FM, and there is no evidence to support the use of these agents in FM.1,4,13 Studies of zopiclone and zolpidem, 2 non-benzodiazepine sedative hypnotic agents, in FM suggest that despite improving subjective sleep complaints, these agents do not improve pain symptoms associated with FM.1

Gamma hydroxybutyrate (GHB), a metabolite of gamma aminobutyric acid with sedative properties, has been evaluated in four RCTs in patients with FM.66-69 The commercial form of GHB, sodium oxybate, is FDA approved for the treatment of excessive daytime sleepiness and cataplexy associated with narcolepsy.70 In one small crossover trial of 24 female patients with FM, the effects of sodium oxybate (6 mg/night) were compared with placebo over two 1-month periods (separated by a 2-week washout period).66 Sodium oxybate significantly reduced subjective symptoms of pain and fatigue from baseline (P<0.005 vs placebo). In addition, compared with placebo, sodium oxybate significantly improved objective measures of sleep (measured by polysomnography) such as sleep latency, total sleep time, enhanced slow-wave sleep, and reduced high-frequency alpha-wave intrusion into slow-wave sleep (P<0.05). An 8-week, proof-of-concept, dose-ranging RCT evaluated the safety and efficacy of 2 doses of sodium oxybate (4.5 g/night and 6.0 g/night) compared to placebo in 188 patients with FM (>90% female; >89.1% white).67 Statistically significant improvements in the composite score from baseline for pain, total FIQ score, and PGIC score were reported for both groups of sodium-oxybate treated patients when compared to placebo (4.5 g/night, P<0.005; 6 g/night, P<0.05). Furthermore, each of these 3 variables improved significantly when analyzed separately. Response rates of ≥30% for the composite score were significantly higher in both active treatment arms relative to placebo (4.5 g/night, P=0.007; 6 g/night, P=0.04), but not statistically different from each other. Patients receiving either dose of sodium oxybate also experienced significant improvements in sleep and fatigue (all, P≤0.05).67

The results of two phase 3 RCTs have been released by the manufacturer of sodium oxybate.68,69 In the first phase 2 trial, 548 patients with FM were randomized to receive sodium oxybate (4.5 g/night or 6 g/night) or placebo over a 14-week period.68 A significantly greater portion of patients receiving sodium oxybate (46.2% on 4.5 g/night; 39.3% on 6 g/night) reported a decrease in pain versus those who received placebo (27.3%). When compared to placebo, physical functioning and ability to perform daily tasks (as measured by FIQ) were significantly improved from baseline in the 4.5 g/night group and approached significance for the 6 g/night group.68 Data from a second phase 3 trial evaluating the same doses of sodium oxybate over a 14-week period (n=573) supported the results from the previous phase 3 trial.69 The percentage of patients who achieved ≥30% reduction in pain from baseline was statistically significantly higher in the sodium oxybate treatment groups (35% for each group vs 20% for placebo). In addition, physical functioning, ability to perform daily tasks, and fatigue were significantly improved for both groups compared with placebo.69 Commonly reported, dose-related adverse events (≥5% and ≥2 times the rate of placebo) in studies evaluating sodium oxybate in FM include headache, nausea, dizziness, vomiting, diarrhea, insomnia, anxiety, somnolence, fatigue, muscle spasms, and peripheral edema.68,69

The manufacturer has announced that a New Drug Application for the use of sodium oxybate in FM will be filed with the FDA by the end of 2009.69 However, despite evidence that supports the use of sodium oxybate in the treatment of FM, it is important to note several factors that may limit the widespread use of this agent: (1) due to its abuse potential, sodium oxybate is a controlled substance (C-III); (2) the short elimination half-life of sodium oxybate requires twice nightly dosing (first dose at bedtime; second dose 2.5-4 hours later); (3) sodium oxybate is currently available only through a special limited distribution program; and (4) sodium oxybate is formulated only as an oral solution.70

Pramipexole, a dopamine D3 receptor agonist with mild affinity for central alpha-2 receptors, was evaluated in a 14-week single-center double-blind, placebo-controlled trial involving 60 patients with FM.71 Patients were randomly assigned in a 2:1 ratio to receive either pramipexole (starting at 0.25 mg/day the first week and titrated to 4.5 mg/day for the last 3 weeks) or placebo. Continuation of other medications was allowed as long as the dosage was stable for at least 6 weeks prior to the start of the study.

The pramipexole group reported reduced fatigue and an increase in overall function, and a statistically significant reduction in pain (≥50% decrease) was reported in 42% of the pramipexole-treated patients versus 14% in the placebo group (P=0.008). The most commonly reported adverse effects in pramipexole-treated patients were nausea, weight loss (40% reported a loss of 5-25 pounds), and transient anxiety.71

There is strong evidence in the form of meta-analyses to support the use of amitriptyline and cyclobenzaprine in FM. The use of SNRIs, SSRIs, and anticonvulsants are supported by moderate evidence that suggests improvement in pain, sleep disturbances, fatigue, and overall quality of life in FM. Duloxetine, pregabalin, and milnacipran are identified as first-line therapies in current evidence-based treatment guidelines.12,17-19 Opioid analgesics, NSAIDs, and sedative hypnotic agents have a limited role in FM and are not recommended as first-line agents. Disadvantages of the use of multiple pharmacologic therapies include additive adverse effects and increased costs.

Dr Morin is associate professor, Department of Pharmacy Practice, Massachusetts College of Pharmacy and Health Sciences, School of Pharmacy – Worcester/Manchester

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.


1. Rao SG, Gendreau JF, Kranzler JD. Understanding the fibromyalgia syndrome. Psychopharmacol Bull. 2007;40:24-67.

2. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38:19-28.

3. Neumann L, Buskila D. Epidemiology of fibromyalgia. Curr Pain Headache Rep. 2003;7:362-368.

4. University of Texas, School of Nursing, Family Nurse Practitioner Program. Fibromyalgia treatment guideline. Available at: Accessed June 1, 2009.

5. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-72.

6. Abeles AM, Pillinger MH, Solitar BM, Abeles M. Narrative review: the pathophysiology of fibromyalgia. Ann Intern Med. 2007;146:726-734.

7. Krypel LL. Fibromyalgia: a review of its pathophysiology and drug treatment. J Pharm Practice. 2009;22:6-16.

8. Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia. Genetic aspects of fibromylagia syndrome. Arthritis Res Ther. 2006;8:218.

9. Bradley LA. Pathophysiologic mechanisms of fibromylagia and its related disorders. J Clin Psychiatry. 2008;69(suppl 2):6-13.

10. Buckhardt C, Goldenberg DL, Crofford LJ, et al. Guideline for the management of fibromyalgia syndrome pain in adults and children. Clinical practice guideline 4, Glenview, IL: American Pain Society; 2005.

11. Carville SF, Arendt-Nielsen S, Bliddal H, et al. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis. 2008;67:536-541.

12. Goldenberg DL. Multidisciplinary modalities in the treatment of fibromyalgia. J Clin Psychiatry. 2008;69(suppl 2):30-34.

13. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA. 2004;292:2388-2395.

14. Busch AJ, Schachter CL, Overend TJ, Peloso PM, Barber KA. Exercise for fibromyalgia: a systematic review. J Rheumatol. 2008;35:1130-1144.

15. Williams DA. Psychological and behavioral therapies in fibromyalgia and related syndromes. Best Pract Res Clin Rheumatol. 2003;17:649-665.

16. Gowans SE, deHueck A, Voss S, Richardson M. A randomized controlled trial of exercise and education for individuals with fibromyalgia. Arthritis Care Res. 1999;12:120-128.

17. Cymbalta (duloxetine) [prescribing information]. Indianapolis, IN: Eli Lilly; 2009. Accessed June 1, 2009.

18. Savella (milnacipran) [prescribing information]. New York, NY: Forest; 2009. Accessed June 1, 2009.

19. Lyrica (pregabalin) [prescribing information]. New York, NY: Pfizer; 2009. Accessed June 1, 2009.

20. Uceyler N, Hauser W, Sommer C. A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum. 2008;59:1279-1298.

21. Hauser W, Bernardy K, Uceyler N, Sommer C. Treatment of fibromylagia syndrome with antidepressants: a meta-analysis. JAMA. 2009;301:198-209.

22. Heymann RE, Helfenstein M, Feldman D. A double-blind, randomized, controlled study of amitriptyline, nortriptyline and placebo in patients with fibromyalgia: an analysis of outcome measures. Clin Exp Rheumatol. 2001;19:697-702.

23. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-1859.

24. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23(5):255-259.

25. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE. A randomized, placebo controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112:191-197.

26. Ozerbil O, Okudan N, Gokbel H, Levendoglu F. Comparison of the effects of two antidepressants on exercise performance of the female patients with fibromyalgia. Clin Rheumatol. 2006;25:495-497.

27. Norregaard J, Volkmann H, Danneskiold-Samsoe B. A randomized controlled trial of citalopram in the treatment of fibromyalgia. Pain. 1995;61:445-449.

28. Anderberg UM, Martenisdottir I, von Knorring L. Citalopram in patients with fibromyalgia – a randomized, double-blind, placebo-controlled study. Eur J Pain. 2000;4:27-35.

29. Capaci K, Hepguler S. Comparison of the effects of amitriptyline and paroxetine in the treatment of fibromyalgia syndrome. Pain Clinic. 2002;14:223-228.

30. Patkar AA, Masand PS, Krulewicz S, et al. A randomized, controlled trial of controlled release paroxetine in fibromyalgia. Am J Med. 2007;120:448-454.

31. Dwight MM, Arnold LM, O'Brien H, Metzger R, Morris-Park E, Keck PE. An open clinical trial of venlafaxine treatment of fibromyalgia. Psychosomatics. 1998;39:14-17.

32. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother. 2003;37:1561-1565.

33. Zijlstra TR, Barendregt PJ, van der Laar MA. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2002;46(suppl 9):S105.

34. Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974-2984.

35. Arnold L, Rosen A, Prichett Y, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without depressive disorder. Pain. 2005;119:5-15.

36. Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain. 2008;136:432-444.

37. Chappell AS, Bradley LA, Wiltse C, et al. A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia. In J Genl Med. 2008;1:91-102.

38. Chappell AS, Littlejohn G, Kajdasz DK, et al. A 1-year safety and efficacy study of duloxetine in patients with fibromyalgia. Clin J Pain. 2009;25:365-375.

39. Mease PJ, Russell IJ, Kajdasz DK, et al. Long-term safety, tolerability, and efficacy of duloxetine in the treatment of fibromyalgia. SeminArthritis Rheum. 2009 Jan 17 [Epub ahead of print].

40. Choy EHS, Mease PJ, Kajdasz DK, et al. Safety and tolerability of duloxetine in the treatment of patients with myalgia: pooled analysis of data from five clinical trials. Clin Rheumatol. 2009;28:1035-1044.

41. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol. 2005;32:1975-1985.

42. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther. 2008;30:1988-2004.

43. Mease PJ, Clauw DJ, Gendreau M, Rao SG, Kranzler J, Chen W, Palmer RH. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:398-409.

44. Hannonen P, Malminiemi K, Yii-Kerttula U, Isomeri R, Roponen P. A randomized double-blind, placebo-controlled study of moclobemide and amitriptyline in the treatment of fibromyalgia in females without psychiatric disorder. Br J Rheumatol. 1998;37:1279-1286.

45. Yavuzer G, Kapakdeveci A, Arasli T, Elhan A. Moclobemide treatment in primary fibromyalgia syndrome. Eur J Phys Med Rehabil. 1998;8:35-38.

46. Ginsberg F, Joos E, Geczy J, Brahwyler J, Vandekerckhove K, Famaey JP. A pilot randomized placebo-controlled study of pirlindole in the treatment of fibromyalgia. J Musculoskeletal Pain. 1998;6:5-17.

47. Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in primary fibromyalgia syndrome: a double blind, placebo controlled trial. J Rheumatol. 1989;16:527-532.

48. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986;29:1371-1377.

49. Harris RE, Clauw DJ, Scott DJ, et al. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27:10000-10006.

50 Gutstein HB, Akil H. Opioid analgesics, In: Brunton LL, Lazo JS, Parker KL, (eds): Goodman & Gilman's The Pharmacologic Basis of Therapeutics, 11th ed. New York: McGraw-Hill, 2006, chap 21.

51. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol Res. 1998;18:13-19.

52. Russell IJ, Kamin M, Bennett RM, Schintzer TJ, Green JA, Katz WA. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol. 2000;6:250-257.

53. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med. 2003;114:537-545.

54 Bennett RM, Schein J, Kosinski MR, Hewitt DJ, Jordan DM, Rosenthal NR. Impact of fibromyalgia pain on health-related quality of life before and after treatment with tramadol/acetaminophen. Arthritis Rheum. 2005;53:519-527.

55. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled, multicenter trial. Arthritis Rheum. 2007;56:1336-1344.

56. Lyseng-Williamson KA, Asif M, Siddiqui A. Pregabalin: a review of its use in fibromyalgia. Drugs. 2008;68:2205-2223.

57. Neurontin (gabapentin) [prescribing information]. New York, NY: Pfizer; 2009. Accessed June 1, 2009.

58. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:1264-1273.

59. Crofford LJ, Simpson S, Young JP, et al. A six-month, double-blind, placebo-controlled, durability of effect study of pregabalin for pain associated with fibromyalgia. Arthritis Rheum. 2006;54(suppl):L44.

60. Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol. 2008;35:502-514.

61. Arnold LM, Russell IJ, Diri EW, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9:792-805.

62. Fiorian H, Young Jr JP, Haig G, et al. Efficacy and safety of pregabalin as long-term treatment of pain associated with fibromyalgia: a 1-year, open-label study. Arthritis Rheum. 2007;56(suppl):S602.

63. Crofford LJ, Mease PJ, Simpson SL, et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136:419-431.

64. Arnold LM, Crofford LJ, Martin SA, Young JP, Sharma U. The effect of anxiety and depression on improvements in pain in a randomized, controlled trial of pregabalin for treatment of fibromyalgia. Pain Med. 2007;8:633-638.

65. Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. 2004;51:9-13.

66. Scharf MB, Baumann M, Berkowitz DV. The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol. 2003;30:1070-1074.

67. Russell IJ, Perkins AT, Michalek JE, and the Oxybate SXB-26 Fibromyalgia Syndrome Study Group. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum. 2009;60:299-309.

68. Jazz Pharmaceuticals, Inc. JZP-6 (sodium oxybate) for fibromyalgia. Available at: Accessed June 30, 2009.

69. Jazz Pharmaceuticals, Inc. Preliminary top-line results of second phase III study show highly significant decrease in pain and fatigue and improved daily function in fibromyalgia patients and confirm results of the first phase III study. Available at: Accessed June 30, 2009.

70. Xyrem (sodium oxybate) [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals; 2009. Accessed June 1, 2009.

71. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum. 2005;52:2495-2505.