Biology and therapy of fibromyalgia. New therapies in fibromyalgia

Serotonin and norepinephrine reuptake inhibitors

There is emerging evidence that fibromyalgia is associated with aberrant central nervous system processing of pain [1–4]. Although the American College of Rheumatology criteria for fibromyalgia [5] require tenderness in 11 out of 18 discrete regions, patients with fibromyalgia have increased sensitivity to pressure pain throughout the body. Fibromyalgia patients often develop an increased response to painful stimuli (hyperalgesia) and experience pain from normally non-noxious stimuli (allodynia) [6]. Both hyperalgesia and allodynia reflect an enhanced central nervous system processing of painful stimuli that is characteristic of central sensitization [7].

Serotonergic and noradrenergic neurons are implicated in the mediation of endogenous pain inhibitory mechanisms through the descending inhibitory pain pathways in the brain and spinal cord [8–10]. Dysfunction in serotonin and nor-epinephrine in these pain inhibitory pathways may contribute to the central sensitization and hyperexcitability of the spinal and supraspinal pain transmitting pathways and manifest as persistent pain associated with fibromyalgia and some other chronic pain conditions [11–15]. Medications that increase the activity of serotonin and norepinephrine may correct a functional deficit of serotonin and norepinephrine neuro-transmission in these descending inhibitory pain pathways and, therefore, help reduce pain.

Alpha 2 delta ligands

In parallel with the development of selective SNRIs for fibromyalgia, another approach is being explored using medications that bind to the α₂δ subunit of voltage-gated calcium channels, resulting in decreased calcium influx at nerve terminals and subsequent reduction in the release of several neurotransmitters thought to play a role in pain processing, such as glutamate and substance P [10, 67]. Pregabalin is an alpha 2 delta ligand that has analgesic, anxiolytic-like, and anticonvulsant activity and is approved by the FDA for the treatment in adults of diabetic peripheral neuropathic pain, postherpetic neuralgia, and adjunctive therapy in partial onset seizures [54].

A multicenter, randomized, placebo-controlled, 8 week, monotherapy trial tested the safety and efficacy of pregabalin 150, 300, or 450 mg/day administered 3 times daily in equal doses in 529 patients with fibromyalgia (91% female) [67]. The primary outcome measure was a daily paper pain diary in which patients selected a number on a numerical scale from 0 (no pain) to 10 (worst possible pain) that best described their pain during the past 24 hours. The outcomes that responded significantly to pregabalin 450 mg/day compared with placebo were the mean weekly pain (diary) score, the Short-form McGill Pain Questionnaire total score and VAS pain score [68], daily sleep (diary) score (a 0 to 10 numerical scale on the quality of sleep), the Medical Outcomes Study Sleep scale [69], Multidimensional Assessment of Fatigue [70], Clinical/Patient Global Impression of Change, and SF-36 domains of social functioning, bodily pain, vitality, and general health perception. A significantly larger proportion of patients receiving pregabalin 450 mg/day (28.9%) experienced a ≥50% reduction in the pain (diary) score compared with the placebo group (13.2%). Compared with placebo, pregabalin 300 mg/day significantly improved sleep as measured by both the daily sleep diary and the Medical Outcomes Study Sleep scale, significantly improved fatigue, the SF-36 domain of general health perception, and the global change assessments by the patients and clinicians. Patients taking 150 mg/day of pregabalin also reported improved sleep on the Medical Outcomes Study Sleep Scale and improvement in general health perception compared with placebo.

Pregabalin was generally well tolerated and most adverse events were mild or moderate in severity. The most common side effects were dizziness and somnolence, which tended to be dose related across the pregabalin groups. Few patients withdrew due to these symptoms. The median duration of dizziness in patients who did not withdraw from the study was 15 days in those taking 450 mg/day of pregabalin; the mean duration for somnolence was 18 days in the same group. Other side effects that were more frequent in the pregabalin group included abnormal thinking, euphoria, dry mouth, peripheral edema, and weight gain.

Unlike the duloxetine and milnacipran studies, patients in the pregabalin trial were not evaluated for the presence of comorbid psychiatric disorders. However, anxiety and depressive symptoms were assessed using the Hospital Anxiety and Depression Scale [71], and the mean baseline scores were mild. There were no significant changes in the Hospital Anxiety and Depression Scale anxiety or depressive scores at endpoint from those at baseline, which suggests that the improvement in pain was probably independent of any improvement in anxiety or depressive symptoms.

Another recent study examined the effects of pregabalin compared with alprazolam and placebo on aspects of sleep in 24 healthy adult volunteers who received pregabalin 150 mg three times a day, alprazolam 1 mg three times a day, or placebo three times a day for three days [72]. Compared with placebo, pregabalin significantly increased slow-wave sleep both as a proportion of the total sleep period and the duration of stage 4 sleep. Alprazolam, on the other hand, significantly reduced slow-wave sleep. Both pregabalin and alprazolam produced significant reduction in sleep-onset latency compared with placebo. Pregabalin also significantly reduced the number of awakenings of more than 1 minute in duration. Pregabalin's enhancement of slow-wave sleep could be very important in many patients with fibromyalgia in whom there is a reduction in slow-wave sleep.

In summary, the results of the first published, randomized, controlled trial of an alpha 2 delta ligand, pregabalin, in fibromyalgia demonstrated that pregabalin monotherapy reduced pain and improved other key symptom domains of fibromyalgia, such as fatigue and sleep. In addition, pregabalin treatment was associated with improvement in health-related quality of life and global assessments.

Sedative-hypnotic medication

Although there continues to be debate about the role of sleep disturbance in the pathogenesis of fibromyalgia, many patients with fibromyalgia experience disrupted or non-restorative sleep and benefit from treatment. A few controlled studies have examined sedative hypnotics in the treatment of fibromyalgia. The short-acting non-benzodiazepine sedatives zolpidem and zopiclone improved sleep in patients with fibromyalgia but did not improve pain, limiting their usefulness in fibromyalgia as monotherapy [73–75]. While the combination of alprazolam and ibuprofen was somewhat beneficial in a pilot trial of fibromyalgia [76], another study found no significant benefit of another benzodiazepine, bromazepan, over placebo in the treatment of fibromyalgia [77].

Gamma-hydroxybutyrate (GHB) is a precursor of gamma-aminobutyric acid (GABA) with marked sedative properties. Sodium oxybate, the sodium salt of GHB, was granted an Orphan Drug Status by the FDA for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy, which was classified as an orphan (rare) disease [54]. A preliminary, 4 week, double-blind, placebo-controlled crossover trial of 24 women with fibromyalgia suggested that sodium oxybate reduced symptoms of pain and fatigue, decreased the tender point index, and increased slow-wave sleep and decreased alpha intrusion on polysomnography [78]. A recently completed 8 week study of sodium oxybate monotherapy evaluated 4.5 g or 6 g per day taken in two equally divided doses (bedtime and 2.5 to 4 hours later) in 188 patients with fibromyalgia [79]. The primary outcome, a composite of changes from baseline in three co-primary, self-report measures (pain visual analog scale from electronic diaries, the FIQ, and the patient global assessment) improved significantly with both dosages of sodium oxybate compared to placebo. Both dosages were also significantly superior to placebo in improvement of sleep quality; the tender point count improved only in the higher sodium oxybate dose compared to placebo. The direct relationship between change in pain and insomnia suggested that the improvement in pain was related to improved sleep. Sodium oxybate was well tolerated; the most common side effects were nausea and dizziness.

Despite the results of this proof-of-principle study, GHB's abuse potential and its use in cases of date rape [80] will likely limit the usefulness of sodium oxybate in patients with fibromyalgia. A recent study evaluating the relative abuse liability of hypnotic drugs reported that GHB was associated with a high likelihood of abuse. Furthermore, GHB, along with pentobarbital and methaqualone, were more likely to be lethal at supratherapeutic doses than any of the other hypnotics [81]. Finally, patients with chronic pain may be especially at risk for the development of problematic hypnotic use [81].

Because of the risk of abuse, sodium oxybate for the treatment of narcolepsy is only available through a Risk Management Program that was designed to maximize physician and patient education about the safe use of the drug and minimize potential diversion or abuse by limiting distribution through a central pharmacy. This risk management program has appeared to be effective in preventing diversion and limiting abuse in patients with narcolepsy, although the evaluation of the program is ongoing [82]. It is not clear, however, whether this program would be effective in the much larger group of patients (mostly women) with fibromyalgia, who have chronic pain and frequent psychiatric comorbidities that might make them more vulnerable to the abuse potential of sodium oxybate.

Safer alternatives for the management of insomnia include low-dose tricyclic agents, and, more recently, the alpha 2 delta ligand pregabalin or a related compound, gabapentin, which have sedative properties, improve slow-wave sleep, and relieve pain [72, 83].

Opiates

There is controversy about the use of opiates to manage the pain associated with fibromyalgia because of the abuse potential of these agents and the lack of data supporting their efficacy in fibromyalgia. However, a survey of academic medical centers in the US reported that about 14% of fibromyalgia patients were treated with opiates [84]. A small, double-blind, placebo-controlled study found that intravenous administration of morphine in nine patients with fibromyalgia did not result in a reduction of pain intensity [85]. A recent, four year, non-randomized study of opiates in fibromyalgia discovered that the fibromyalgia patients taking opiates did not experience significant improvement in pain at the four year follow-up compared with baseline, and reported increased depression in the last two years of the study [86]. These results suggest that opiates may not have a role in the long-term management of fibromyalgia. In addition, there is emerging evidence that opioid-induced hyperalgesia might limit the usefulness of opioids in controlling chronic pain [87]. Although the mechanisms by which opioids promote pain are not completely understood, recent animal studies suggest that chronic use of opioids induces neuroadaptive changes mediated, in part, through the NK-1 receptor, that result in enhancement of nociceptive input [88]. These results raise the possibility that prolonged treatment of pain with opiates may actually cause unintentional harm to patients [88].

Tramadol is a novel analgesic with weak agonist activity at the mu opiate receptor combined with dual serotonin and norepinephrine reuptake inhibition that may exert anti-nociceptive effects within both the ascending and descending pain pathways. Three controlled studies have evaluated the efficacy of tramadol in fibromyalgia. The first small study used a double-blind crossover design to compare single-dose intravenous tramadol 100 mg with placebo in 12 patients with fibromyalgia. Patients receiving tramadol experienced a 20.6% reduction in pain compared with an increase of 19.8% of pain in the placebo group [89]. The second study of tramadol began with a three week, open-label phase of tramadol 50 to 400 mg/day followed by a six-week double-blind phase in which only patients who tolerated tramadol and perceived benefit were enrolled [90]. The primary measure of efficacy was the time to exit from the double-blind phase because of inadequate pain relief. One hundred patients with fibromyalgia were enrolled in the open-label phase; 69% tolerated and perceived benefit from tramadol and were randomized to tramadol or placebo. Significantly fewer patients on tramadol discontinued during the double-blind phase because of inadequate pain relief. This study is limited by the possible unblinding of patients in the double-blind phase after open-label treatment with tramadol. Finally, a multicenter, double-blind, randomized, placebo-controlled, 91 day study examined the efficacy of the combination of tramadol (37.5 mg) and acetaminophen (325 mg) in 315 patients with fibromyalgia. Patients taking tramadol and acetaminophen (4 ± 1.8 tablets per day) were significantly more likely than placebo-treated subjects to continue treatment and experience an improvement in pain and physical function [91]. Treatment emergent adverse events were reported by significantly more patients in the tramadol/acetaminophen group (75.6%) than the placebo group (55.8%). The most common side effects in the tramadol/acetaminophen group were nausea, dizziness, somnolence, and constipation. A post hoc analysis of the data from this trial revealed that the patients who had the most reduction in pain severity (≥25 mm on the 0 to 100 mm visual analog scale) from baseline had significantly greater improvement in health-related quality of life than those with less reduction in pain. When comparing treatment groups, improvements in the SF-36 physical functioning, role-physical, bodily pain, and physical component summary scores were significantly greater in the tramadol/acetominophen than the placebo group [92].

Although tramadol is currently marketed as an analgesic without scheduling under the US Controlled Substances Act, it is under review for possible control, and it should be used with caution because of recent reports of classic opioid withdrawal with discontinuation and dose reduction and increasing reports of abuse and dependence [93].

Other pharmacological studies in fibromyalgia

Preliminary evidence from randomized, controlled studies supports the possibility that other pharmacological approaches hold promise for fibromyalgia, but more study is needed. Among these possible medications are the 5-HT₃ antagonists (e.g., ondansetron and tropisetron), which have analgesic effects. A randomized, placebo-controlled, double-blind, 10 day trial in 418 patients with fibromyalgia evaluated the short-term efficacy of tropisetron at doses of 5 mg/day, 10 mg/day, and 15 mg/day. Significant reduction in pain was noted only in those patients taking 5 mg/day and 10 mg/day, while the effects of tropisetron 15 mg/day were no different from placebo, suggesting a bell-shaped dose response curve [94]. Another, recent, randomized, placebo-controlled trial of 21 female fibromyalgia patients evaluated daily intravenous bolus injections of 5 mg tropisetron for 5 days and found significant improvement in pain in the tropisetron group compared to placebo [95]. The presence of 5-HT₃ receptors on both the inhibitory dorsal horn interneurons and the primary afferent fibers that relay nociceptive information from peripheral nociceptives to the dorsal horn may explain the pro- and anti-nociceptive effects of 5-HT₃ receptor blockade. The balance of these opposing effects may be dose-dependent and contribute to unpredictable results with tropisetron [96], but more study of longer-term treatment with 5-HT₃ antagonists is needed.

Central sensitization, a possible pathogenic mechanism of the chronic pain associated with fibromyalgia, is mediated, in part, by the binding of excitatory amino acids (glutamate and aspartate) to the NMDA receptor. NMDA antagonists may inhibit or attenuate central sensitization [97] and potentially reduce pain associated with fibromyalgia. In one clinical study, 48 female patients with fibromyalgia were treated with an open-label combination of tramadol 200 mg/day and increasing doses of dextromethorphan (50 to 200 mg/day), titrated to therapeutic effect or tolerability. Fifty-eight percent (28 of 48) responded to the addition of dextromethorphan and entered a double-blind phase in which the patients were randomized to dextromethorphan and tramadol or tramadol and placebo. A Kaplan-Meier drop-out analysis showed that significantly fewer patients on dextromethorphan and tramadol discontinued treatment compared with patients on tramadol alone [98]. More study of NMDA receptor antagonists is needed before clinical recommendations can be made regarding the use of these agents. Interestingly, a study looking at the effects of dextromethorphan on temporal summation of pain in patients with fibromyalgia compared to normal controls found that dextromethorphan had similar effects in both groups on reduction in wind-up from repeated thermal and mechanical pressure stimulation of the skin. These results suggest that patients with fibromyalgia do not have substantially altered NMDA receptor mechanisms and other mechanisms, such as enhanced descending facilitation, should be considered for the pain associated with fibromyalgia [99].

Finally, pramipexole, a dopamine 3 receptor agonist, was tested in patients with fibromyalgia in a 14 week, single-center, randomized, placebo-controlled study in which prami-pexole was added on to existing pharmacological and non-pharmacological therapies [100]. The rationale for testing a dopamine 3 agonist in fibromyalgia is based on evidence that excessive adrenergic arousal may fragment sleep, and enhancement of dopaminergic neurotransmission at the D3 receptors in the mesoliombic hippocampus may reduce expression of arousal and improve sleep. Compared with the placebo group, those patients receiving pramipexole titrated over 12 weeks to 4.5 mg every evening had gradual and significant improvement in pain, fatigue, function, and global status. A gradual titration of pramipexole was well tolerated; weight loss and increased anxiety were significantly more common in patients on pramipexole.

Sleep was not assessed in the study, despite the proposed role of pramipexole in reducing adrenergic arousal in patients with fibromyalgia; therefore, the mechanism by which pramipexole improved the symptoms of fibromyalgia is unclear. The study was also difficult to interpret because the participants were taking concomitant medications (about half on narcotic analgesics) for fibromyalgia.

Limitations of pharmacological treatment studies in fibromyalgia

The pharmacological treatment studies of fibromyalgia are limited for several reasons. First, many of the medication trials were of short duration, and there is a need for more data on the long-term efficacy of medications in the treatment of fibromyalgia, a chronic condition. Second, although most fibromyalgia clinical trials assessed change in the intensity of pain as the primary outcome, they have inconsistently evaluated other associated symptoms, such as sleep disturbance, fatigue, depression, anxiety, cognition, or function and health-related quality of life, which reduce the comparability and clinical applicability of the trials. Third, medication clinical trials have used dissimilar measures to assess symptom and functional domains. Fourth, the primary outcome measure of most recent fibromyalgia trials has been the mean reduction of pain in the patients receiving a treatment compared with those receiving placebo. Although this approach provides information about the overall efficacy of a particular treatment in reducing pain, it does not determine the proportion of patients who experience clinically important improvement. Fifth, there is a lack of consensus about the definition of clinically meaningful reduction in pain for fibromyalgia clinical trials. In addition, it is unclear whether improvement in pain intensity alone should define response to treatment in fibromyalgia, which is a syndrome characterized by multiple symptoms in addition to pain. Standardized, operationally defined outcome measures of fibromyalgia activity and improvement would greatly enhance the comparability, validity, and clinical applicability of fibromyalgia trials. Sixth, patients with fibromyalgia frequently have comorbid disorders that may affect their response to treatment. Despite evidence of elevated prevalence rates of mood and anxiety disorders in patients with fibromyalgia and their possible prognostic significance, few clinical trials systematically evaluated patients for comorbid psychiatric disorders. Seventh, most trials excluded patients with pain from some other disorders, such as rheumatoid arthritis, inflammatory arthritis or autoimmune disease, and future trials should examine the efficacy of medications in these patients. Finally, the majority of patients studied in the trials were women, which reflects the much higher prevalence of fibromyalgia in women [101]. The results of the studies may not, therefore, be generalizable to men with fibromyalgia.

Summary of pharmacological trials in fibromyalgia

Systematic reviews of non-pharmacological modalities

Several systematic reviews of non-pharmacological treatments for fibromyalgia have been published since 1999. The first review was a meta-analysis of pharmacological and non-pharmacological treatment studies of fibromyalgia completed between 1966 and 1996 [102]. Studies of patients with fibromyalgia were included in the analysis if they had sufficient statistical information to calculate effect sizes on the outcome variables of physical status, self-report of fibromyalgia symptoms, psychological status, or daily functioning. The meta-analysis included 33 pharmacological and 16 non-pharmacological treatment studies. The pharmacological treatments included: tricyclic agents (tricyclic antidepres-sants or the muscle relaxant cyclobenzaprine, which is structurally a tricyclic); S-adenosylmethionine (SAMe); alpra-zolam; 5-hydroxytryptophan; the SSRIs fluoxetine and citalo-pram; the non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen and naproxen; prednisone; zolpidem; topical cap-saicin; a combination of malic acid and magnesium hydroxide; mexiletine (oral lidocaine); a combination of carisoprodol, paracetamol and caffeine; myanserine; chlormezanone; and an antidiencephalon immune serum. Non-pharmacological therapies included exercise, education, cognitive-behavioral therapy, electroacupuncture, acupuncture, and hypnotherapy. After combining effects sizes within the two classes of treatment for each outcome variable, both pharmacological and non-pharmacological treatments were associated with improvement in physical status, fibromyalgia symptoms, and psychological status; only non-pharmacological treatment improved daily functioning. Furthermore, non-pharmacological treatment was superior to pharmacological treatment on fibromyalgia symptoms. However, this meta-analysis was limited by pooling diverse pharmacological and non-pharmacological treatments, making it difficult to evaluate individual treatments, and by including studies that were of poor methodological quality.

Instead of evaluating non-pharmacological treatments as a group as was done in the Rossy and colleagues [102] meta-analysis described above, a subsequent systematic review focused only on mind-body therapies, which included autogenic training, relaxation exercises, meditation, cognitive-behavioral training, hypnosis, guided imagery, biofeedback, or education [103]. Thirteen randomized or quasi-randomized controlled trials conducted between 1966 and 1999 were evaluated with a best-evidence synthesis method that has been used in Cochrane systematic reviews. There were several important findings from this review. First, there was strong evidence that mind-body therapies were more effective for self-efficacy (a measurement of an individual's belief that she or he can cope effectively with a challenging situation) than waiting list or treatment as usual controls [104, 105]. However, improvements in self-efficacy did not correspond to improvements in other clinical measures. Indeed, the results suggested that mind-body therapies were not consistently better than waiting list or treatment as usual controls in the modulation of pain or improvement in function. Second, there was strong evidence that exercise was more effective than mind-body therapies for short-term improvement in pain intensity or tender point pain threshold and physical function [106, 107]. Third, patients with fibromyalgia who were also severely depressed did not respond well to mind-body therapies [104]. Finally, mind-body therapies with cognitive restructuring and coping components were not significantly better than education or attention controls. For example, in a controlled study, 131 outpatients with fibromyalgia were randomized to one of 3 conditions: a 12 session, combined educational and cognitive group intervention; an attention control condition consisting of group education plus group discussion; and a waiting list control. For the sample as a whole, very little improvement was found. The patients in the attention control condition with group education and discussion did somewhat better than those in the combined education and cognitive intervention with improved pain coping and pain control, although neither group experienced improvement in pain intensity [105]. Another controlled study of 71 patients with fibromyalgia evaluated a 10 week behavioral treatment program that consisted of 90 minute weekly group sessions of education, training in relaxation, behavioral goal setting and activity pacing, and involvement of a support person to promote adaptive coping techniques and encourage adherence to the protocol. Both the behavioral treatment and an education control that consisted of lectures and group discussion resulted in significant reductions in depression, self-reported pain behavior, observed pain behavior, and myalgic scores (a measure of pressure pain threshold). Pain levels were not reduced in either condition. Furthermore, the effect of the behavioral treatment condition was no better than the education control [108].

Another recent systematic review of randomized, controlled trials of several non-pharmacological treatments for fibromyalgia completed between 1980 and 2000 assessed methodological quality according to a set of formal criteria adapted from other Cochrane systematic reviews [109]. Interventions tested in the 25 reviewed trials included exercise therapy, educational intervention, relaxation therapy, cognitive-behavioral therapy, acupuncture, and forms of hydrotherapy. Aerobic exercise (nine studies), education (four studies), and relaxation (four studies) were the most frequently evaluated interventions. Although there was a lack of strong evidence to support any single intervention, there was preliminary support of moderate strength for aerobic exercise. Overall, the methodological quality of the studies was judged to be fairly low, mostly as a result of small samples with low mean power to detect a medium effect. Furthermore, 16 studies had blinded outcome assessments, but patients were blinded in only 6 studies. In contrast to the Rossy and colleagues [102] meta-analysis, which found favorable results for non-pharmacological therapies when grouped together, at the level of the specific non-pharmacological modalities assessed in this review, the evidence supporting their use in fibromyalgia was inconclusive due to the methodological limitations of most of the studies.

Finally, a Cochrane review of randomized clinical trials assessed the effectiveness of multidisciplinary rehabilitation for patients with fibromyalgia [110]. The multidisciplinary program was required to consist of a physician's consultation, in addition to a psychological, social, or vocational intervention, or a combination of these. Only four randomized, controlled trials of fibromyalgia conducted between 1966 and 1998 met methodological inclusion criteria, although the overall quality of these studies was determined to be poor. Nonetheless, several findings from the review emerged that were consistent with some of the results from the above systematic reviews, which included some of the same studies. First, the effectiveness of aerobic exercise was neutral compared to stress management in the long-term treatment of pain, tenderness, or work capacity [107]. This conclusion differs from the Hadhazy and colleagues review [103], which focused on the short-term benefits of exercise among the participants who completed this trial [107]. Second, education combined with physical exercise was better than education alone in a long-term follow-up study [104]. Finally, as reviewed above, neither a combined education and cognitive group intervention nor behavioral therapy was more effective than education alone [105, 108].

Recent non-pharmacological treatment studies of fibromyalgia

Cognitive-behavioral therapy

The results of the aforementioned systematic reviews suggest that cognitive behavioral therapy (CBT) was no better than educational or attention controls in improving fibromyalgia. Since 2000, there have been other randomized, controlled studies that further explored the possible use of CBT in fibromyalgia. In the first study, 145 patients with fibromyalgia were randomized to either standard medical care that included pharmacological treatment and suggestions for aerobic fitness or the same standard medical treatment and the addition of six group cognitive behavioral therapy sessions over a four week period that were specifically aimed at improving physical function [131]. The CBT focused on instruction and practice of nine skills, including the relaxation response, visual imagery techniques, pacing skills, pleasant activity scheduling, communication and assertiveness training, cognitive restructuring principles, stress management, and problem solving. Patients in both groups were contacted monthly by phone to track health care use and CBT skills in those assigned to CBT. Significantly more (25%) of the 62 patients who completed the CBT protocol achieved a clinically meaningful and sustained improvement in physical functional status as measured by the physical component summary score of the SF-36 compared with the control group (12% of 60 completers). However, there were no significant differences between the control and CBT groups in change in sensory or affective pain scores as measured by the McGill Pain Questionnaire. Although the study was limited by the lack of monitoring of medication use in the two groups, the lack of an attention-placebo group, and the low level of adherence to CBT treatment (only 15% of patients consistently reached their stated monthly CBT goals), the study provided some evidence that targeted, brief, group CBT, in conjunction with standard medical care, might improve physical function in some patients with fibromyalgia.

A coping skills training (CST) intervention for adolescents with fibromyalgia was developed to include developmentally appropriate explanation and training guidelines as well as a parent training component [132]. The content, similar to adult CBT, included relaxation training, distraction techniques, calming statements, activity pacing, pleasant activity scheduling, and problem solving. Parents were given suggestions for encouraging the adolescent to manage their pain independently, maintain their normal day to day routines and guidance for reducing avoidance of school or social activities. In an 8 week study of this intervention added to standard medical care that was stabilized for at least 4 weeks prior to enrollment, 30 adolescents with fibromyalgia were randomly assigned to either CST or a self-monitoring condition in which patients monitored daily symptoms without instruction about behavioral change. After 8 weeks, patients were crossed over into the opposite treatment arm for an additional 8 weeks. At the end of 8 and 16 weeks, there were no significant differences in function disability or depressive symptoms between the CST and self-monitoring groups. However, the CST group showed significantly greater improvement than the control group for increase in pain-coping efficacy. These results are consistent with adult studies of CBT in which there have been inconsistent effects of CBT on pain reduction, although there have been improvements in function and the perception of control over pain.

Finally, CBT developed for the treatment of insomnia in patients with fibromyalgia was tested in 47 patients who were randomized to receive 6 weekly sessions of CBT, a control behavioral therapy (sleep hygiene education), or usual care (all patients continued any ongoing medical care) [133]. Patients receiving CBT achieved about 50% reduction in nocturnal wake time, compared with the sleep hygiene education group (20%) and the usual care group (3.5%). Both CBT and the sleep hygiene education showed benefits over usual care for reducing global insomnia symptoms, and for improving mental well-being and mood. However, only the sleep hygiene group reported significant improvement in pain compared with the usual care group. Therefore, sleep hygiene education and CBT may benefit fibromyalgia patients with chronic insomnia, but further study is needed with larger samples and greater experimental control through standardization of other medical treatment [133].

Other non-pharmacological therapies

A group treatment with a combination of mindfulness meditation and Qigong movement therapy was tested in 128 patients with fibromyalgia who were randomly assigned to either an 8 week course of this multimodal mind-body intervention or a control education support group. At the end of 8, 16, and 24 weeks, there were no significant differences between groups in change in pain, tenderness, walking, mood, or impact of fibromyalgia [134].

Another study evaluated social support as a primary intervention in patients with fibromyalgia [135]. In this study, 600 patients with fibromyalgia were randomized to either a social support group, a social support and education group, or a no-treatment control group that participated in assessment interviews only. The experimental groups met for 10, 2-hour weekly meetings followed by 10 monthly meetings. At the end of one year, there were no significant differences in reductions of health care costs for the groups. There were also no significant differences between groups in improvement in depression, self-efficacy, fibromyalgia impact, or fibromyalgia knowledge. The social support and education group reported significantly less helplessness compared with the other groups. Notably, attendance rates for the interventions were low, with experimental groups attending only about 40% of all meetings.

Complementary and alternative medicine

A 2003 review of studies conducted between 1975 and 2002 evaluating the use of complementary and alternative medicine in fibromyalgia concluded that, across the five classifications of complementary and alternative medicine, including alternative medical systems (e.g., acupuncture, homeopathy), biological-based therapy (e.g., nutritional supplements), dietary modifications, energy therapies (e.g., magnetic therapy), and manipulative and body-based systems (e.g., chiropractic care, massage), and mind-body interventions (e.g., relaxation, biofeedback, and hypnotherapy), no single modality was consistently effective [136]. Acupuncture had the strongest evidence for effectiveness while there was moderate evidence supporting the use of magnesium supplementation, S-adenosyl-L-methionine, and massage therapy.

However, two recent, randomized, controlled trials found that acupuncture was no better than control interventions in reduction of pain associated with fibromyalgia. The first study randomized 114 patients with fibromyalgia to either traditional needle placement with or without needle stimulation or to control groups of non-traditional needle location with or without needle stimulation [137]. All patients received a total of 18 treatments beginning once weekly, followed by twice weekly, and finally three times weekly. Clinically meaningful treatment response, defined by a 30% improvement in pain, occurred in 25% to 35% of all patients; there were no significant differences between groups on improvement in pain. These results suggest that there are no specific effects of acupuncture on pain reduction in patients with fibromyalgia.

A second study of acupuncture in fibromyalgia randomized 100 patients with fibromyalgia to 12 weeks of twice weekly acupuncture that was specifically designed to treat fibromyalgia, or 1 of 3 sham acupuncture treatments: acupuncture for an unrelated condition; needle insertion at non-acupoint locations; or non-insertive simulated acupuncture using a toothpick to mimic needle insertion [138]. The mean pain ratings among patients receiving acupuncture did not differ from that in the pooled sham acupuncture group. Therefore, consistent with the previous study, acupuncture was no better than sham treatment at relieving pain in fibromyalgia.

Limitations of non-pharmacological treatment studies in fibromyalgia

Non-pharmacological treatment studies of fibromyalgia are limited for several reasons [111, 118, 139]. First, there was variability in accounting or controlling for other interventions, particularly pharmacological treatment, making it difficult to isolate the effects of the non-pharmacological treatment on fibromyalgia. Second, there was also variability in the treatment intensity, duration, and frequency, making it difficult to identify the best treatment levels for patients with fibromyalgia. Third, diversity of treatment modalities limited comparisons between studies. For example, training modalities in exercise studies have included cycling, pool exercise, walking, muscle strength exercises, stretching, and others. The diversity of treatment elements was also evident in CBT studies, which varied in the skill sets that were taught and format of treatment (e.g., group or individual). Fourth, patient selection criteria in exercise studies have not consistently taken into account the baseline level of physical activity or fitness and the potential impact of these variables on the results. In addition, few studies identified comorbid mood or anxiety disorders, which may have affected the patients' response to treatment. Notably, patients with severe depression may not respond well to some non-pharmacological treatments, such as education and physical training [104]. The studies have not yet clarified which subgroups of patients with fibromyalgia might benefit from a specific mode of non-pharmacological treatment. Fifth, many studies had small sample sizes and high attrition rates in the treatment groups, making it difficult to identify benefits of the treatment. Indeed, adherence to CBT skills over an extended period of time has been problematic in studies of fibromyalgia [131]. Adherence with exercise programs, especially after the completion of the intervention, was also generally low. Furthermore, there was some discrepancy in several exercise studies between the prescribed exercise program and the actual performed exercise because of problems with patient tolerability. Furthermore, there was inconsistent reporting of specific adverse events from exercise such as exacerbation of pain. Sixth, several studies had no-treatment controls, which made it difficult to distinguish the specific effects of the treatment from the non-specific effects of attention or group experience or the role of subject expectancy on the results. Indeed, CBT studies that used attention or education controls found that CBT-supported skills added little to the outcome of the studies [105, 108]. Seventh, although some studies followed patients for more than one year after the intervention, most studies focused on short-term benefits of treatment in fibromyalgia, which is a chronic disorder. Eighth, as in pharmacological clinical trials of fibromyalgia, there was a lack of consensus about important symptom domains and outcome measures, making comparisons between studies difficult. Furthermore, it was unclear from some studies whether significant changes were actually clinically meaningful. In exercise studies, there were also multiple approaches to the assessment of aerobic capacity and performance. Furthermore, other health outcomes that might be affected by exercise, such as blood pressure, weight, or metabolic indicators have not been consistently tracked in exercise studies.

Summary of non-pharmacological trials in fibromyalgia

Conclusions and recommendations for the treatment of fibromyalgia

The rapid growth of trials in fibromyalgia in recent years has resulted in new, evidence-based approaches to treatment. The American Pain Society (APS) developed guidelines for the optimal treatment of fibromyalgia, a summary of which was published in 2004 [140]. With the subsequent publication of new treatment data reviewed above, some updates to these guidelines may be necessary. The first recommended steps of the APS guidelines, which included confirmation of the diagnosis, education about fibromyalgia, and evaluation and treatment of comorbid disorders, such as mood and sleep disturbances, are still appropriate. However, the subsequent steps do not take the presence of comorbidity into account when recommending treatment for fibromyalgia. Recent evidence suggests that comorbidity and the presence and severity of symptom domains should be an important consideration when selecting initial treatments for fibromyalgia. In the APS guidelines, the first recommended pharmacological treatment is a trial of low dose tricyclic antidepressants or cyclobenzaprine. However, these medications are often poorly tolerated and, at low doses, are not effective for the treatment of mood or anxiety disorders, two common comorbid conditions. An alternative approach would be to recommend one of the new selective SNRIs as a first line treatment for pain in patients with or without depression or anxiety. One caveat related to the use of SNRIs or other medications with antidepressant effects in fibromyalgia is that they should not be used as monotherapy in patients with bipolar disorder, another frequently reported comorbid condition [141], because of the risk of increased mood instability. An alternative first line medication approach is an alpha 2 delta ligand, which may be particularly helpful in patients with prominent sleep disturbances or anxiety. For those patients who do not respond completely to mono-therapy with either an SNRI or an alpha 2 delta ligand, a combination of these medications should be considered, although studies of this and other combination pharmaco-therapy is still very limited [142].

In the APS guidelines, exercise was recommended early in treatment of fibromyalgia. However, recent studies indicate that the compliance with exercise is quite low and influenced by factors such as pain severity, stress, disability, depression, self-efficacy, social support, and barriers to exercise. Therefore, these issues should be addressed before recommending exercise. Studies suggest that exercise does not consistently improve major symptom domains such as pain, fatigue, sleep disturbance, or psychological symptoms. Patients with these symptoms may not be able to tolerate exercise and may in fact experience a worsening of pain with exercise. Consequently, these symptoms should be treated with medication (or other therapy as described below) first to increase the likelihood that the patients will be able to participate in exercise and benefit from the positive impact of exercise on cardiovascular fitness, pain pressure thresholds, global well being, and self-reported physical function. The patient's level of fitness should also be considered when suggesting specific exercises. For most patients, a gradual increase, as tolerated, in exercise to reach a goal of 30 to 60 minutes of low-moderate intensity aerobic exercise (e.g., walking, pool exercises, stationary bike) at least 2 to 3 times a week is best tolerated. Furthermore, studies suggest that supervised, group exercise interventions may be preferable to home-based exercise regimens, especially at the initiation of an exercise program.

Some patients who do not respond fully to medication alone or have prominent psychosocial problems might benefit from the addition of CBT or group education as an adjunct to their medical treatment. Group education with social support may help to reduce pain behaviors, feelings of helplessness, improve a sense of control over symptoms, and reduce the impact of fibromyalgia. CBT that addresses disability, function, or self-efficacy might also be helpful in overcoming some of the barriers to exercise, improving overall function, and regaining a sense of control in their lives. Combinations of exercise and education or CBT may be an option for patients who do not respond to a single approach, but more study of combination therapies is needed.