Management

2012 Canadian Guidelines for the Diagnosis and Management of Fibromyalgia Syndrome

Mary-Ann Fitzcharles1,2, Peter A. Ste-Marie2,3, Don L. Goldenberg4, John X. Pereira5, Susan Abbey6, Manon Choinière7, Gordon Ko8, Dwight Moulin9, Pantelis Panopalis1, Johanne Proulx10, Yoram Shir2

2.1 What are the treatment strategies for fibromyalgia?

There is currently no cure for FM and treatment recommendations should be directed to reduction of symptoms and maintenance of optimal function, with patient outcome goals clearly defined at outset. Symptom based management, taking into account the heterogeneous nature of this condition, can help direct a patient tailored approach [131]. Ideal management includes both non-pharmacologic and pharmacologic treatments in a multimodal approach, with active patient participation fostered by a strong patient-centered locus of control [132]. The essence of the evidence is that there is no “gold standard” of treatment; with responses mostly modest at best. Self-efficacy and adherence to treatment recommendations will favourably influence outcome [133]. Although attempts have been made to subgroup FM patients in order to direct treatments, these remain preliminary [32, 134-136].

Recommendations:
13. A treatment strategy for patients with fibromyalgia should incorporate principles of self-management using a multimodal approach [Level 1 [131, 132], Grade A]. It is recommended that attention should be paid to individual symptoms in a patient tailored approach, with close monitoring and regular follow-up, particularly in the early stages of management [Level 5 [131] Grade D].

14. Patients should be encouraged to identify specific goals regarding health status and quality of life at the initiation of treatment, with re-evaluation of goals during the follow-up [Level 5 [102], Grade D].

2.2 Non-pharmacologic treatment

Non-pharmacologic treatments have a positive effect with improvements in self-reported outcome measures including physical status, FM symptoms, psychological status and daily functioning, but unfortunately many studies have been poorly executed [132]. In this meta-analysis of 49 outcome studies published 10 years ago, non-pharmacologic treatments appeared more effective than pharmacological interventions. Although no single strategy outperforms others, education, exercise activity, cognitive behavioural therapy (CBT), and multidisciplinary therapy, incorporating at least 1 educational/psychological therapy with 1 exercise therapy, will offer an advantage [137, 138].

2.2.1 Self-management strategies

Education and active participation with reassurance regarding “no harm” caused by physical activity should be the focal point of treatment, especially if a patient is passive regarding health and lifestyle practices [139]. Education can improve attitudes, coping skills, and help shift the locus of control towards a patient orientated approach. A positive attitude and patient-centered internal locus of control with positive expectations strongly determines response to treatment [140]. Self-efficacy and good social support promoted healthy lifestyle practices in 198 women with FM [141]. Self-efficacy enhancement programs may be a valuable inclusion in the treatment of FM patients [142]. Pacing of daily activities can improve day to day function [143].

Recommendation:
15. Non pharmacologic strategies with active patient participation should be an integral component of the therapeutic plan for the management of fibromyalgia [Level 1 [132, 137], Grade A]. Encouraging self-efficacy and social support will facilitate the practice of health promoting lifestyles [Level 3 [141, 142], Grade D].

16. Persons with fibromyalgia should be encouraged to pursue as normal a life pattern as possible, using pacing and/or graded incremental activity to maintain or improve function [Level 4 [143, 144], Grade D].

2.2.2 Multicomponent therapy

Multicomponent therapy is currently recognized to comprise at least one educational or other psychological therapy and at least one exercise therapy, although there is no accepted formal definition. Ideal care will therefore be given by a team of individuals, rather than reliance on contact with a single healthcare professional. A recent meta-analysis has shown that multicomponent treatment is effective in the short term for improving key symptoms of FM including pain, fatigue, depression and quality of life, but disappointingly without evidence for continued effect other than maintenance of physical fitness [137].

There is currently limited information on effectiveness of combination psychological and pharmacologic treatments, strategies that can be applied in clinical practice and may yield positive results. Catastrophizing, defined as viewing situations or symptoms as being much worse than they truly are, is recognized to have negative effects on outcome in chronic pain patients, and strategies aimed at reduction are desirable. The results of an ongoing combined pharmacologic and psychological intervention study aimed at reducing catastrophizing in FM patients will be of interest [145]. Other resources such as self-help groups, patient forums and information sessions, when information is reliable, can improve patient knowledge and can enhance locus of control.

Recommendation:
17. The attainment of effective coping skills and promotion of self-management can be facilitated by multicomponent therapy [Level 5 [137], Grade D].

2.2.3 Psychological interventions

Untreated psychological distress, depression in particular, is a barrier to optimal health status. As psychological status affects quality of life, attention to previous or current co morbid psychological complaints is required [146-148]. Medical and psychiatric comorbidity was a strong determinant of the number of physician visits for 180 FM women, which could be interpreted as a surrogate for patient distress and poor psychological status [146]. In turn, improved psychological status and physical activity associate with reduced pain intensity in FM [149].

Even in the absence of overt psychopathology, psychological interventions such as traditional CBT, group therapy sessions or motivational interviewing may be helpful. CBT helps patients to cope better with pain by improving pain-related behaviour, self-efficacy, and overall physical functioning, but without evidence for long-term effect when applied alone [150, 151]. Overall improvement in depression and less use of analgesic medication was reported in a controlled study of CBT in 60 patients [152]. When CBT was combined with an aerobic exercise program over a three week period, there was sustained improvement in multiple outcomes up to one year, suggesting that the CBT facilitated adherence to a physical exercise regimen [153]. As CBT is more costly than an education program alone, and may not be easily accessible for many, limited programs via the internet, telephone interview or an attenuated program may be useful [154, 155].

Other modalities to address attitudes and psychological status include motivational interviewing or group sessions. Motivational interviewing, by means of six telephone calls over a ten week period improved adherence to an exercise program [156]. Group sessions that incorporate education, a psychological intervention, as well as an exercise component have some benefit in the short-term, up to six months [157, 158]. Other psychological interventions reporting some benefit include written emotional expression, psychomotor therapy, meditation-based stress reduction program and EMG-biofeedback therapy [159-162]. Even a brief interdisciplinary program lasting one and a half days has shown positive effect in patients with FM [163]. Chronic pain self-management programs are increasingly available to address this need.

Distraction, by means of pleasant imagery, had better effect on pain reduction in FM patients, than focused attention imagery towards active control of pain mechanisms [164]. Hypnosis with analgesia suggestion showed a positive effect on pain compared to hypnosis with relaxation suggestion or relaxation alone in a study of 45 patients [165]. Guided imagery by means of audiotaped scripts improved functional status as well as self-efficacy for managing pain in a randomised controlled trial (RCT) of 48 patients [166]. However the authors of a recent systematic review and meta-analysis of hypnosis/guided imagery call for improved methodology before conclusions regarding the key domains of FM can be drawn [167]. Mind-body therapies can improve self-efficacy, although alone have not been shown to affect specific symptoms of FM [168]. In a systematic review of thirteen trials, mind-body therapies combined with an exercise program were more effective than waiting list or “treatment as usual” [168].

Transcranial magnetic stimulation (TMS), a treatment modality used to manage psychological/psychiatric illness, reduced pain and depressive symptoms in FM patients in one study, with no effect in a second study [169, 170]. Transcranial direct current stimulation to the primary motor cortex, but not the dorsolateral prefrontal cortex, was associated with improved sleep efficiency, reduced arousals and improvement in FM symptoms [171].

As fear of pain and activity is reported by almost 40% of FM patients and is associated with greater disability, depressed mood and pain severity, fear avoidance should be addressed to maintain adherence to exercise recommendations [172]. Patients with FM identified more problems than those with ankylosing spondylitis and perceived themselves to be more negatively affected by their condition [173]. Attention to pain has been associated with increased pain related fear and pain severity.

Recommendations:
18. Interventions that improve self-efficacy should be encouraged to help patients cope with symptoms of fibromyalgia [Level 1 [168], Grade A].

19. Psychological evaluation and/or counselling may be helpful for persons with fibromyalgia in view of the associated psychological distress [Level 5, Consensus], and patients should be encouraged to acknowledge this distress when present and be informed about the negative impact this may have on wellbeing [Level 3 [149], Grade D].

20. CBT even for a short time is useful and can help reduce fear of pain and fear of activity [Level 1 [150, 151], Grade A].

2.2.4 Exercise

Exercise has overall benefit on global well-being, physical function and pain and is currently recommended as the first step of a multimodal treatment strategy [174-178]. Exercise may take a number of forms such as aerobic, strengthening, water, home based or group programs. In a Cochrane review of 16 trials, 7 of which were high quality, supervised aerobic exercise improved physical capacity and FM symptoms [176]. The evidence for effect of strengthening exercises is less clear as studies are rated as low quality [174, 175]. In a meta-analysis of 45 studies, ten of which were eligible for inclusion, exercise, which included aerobic, strength training, pool and multi-component exercise, successfully improved pain in the short-term; but with a call for long-term studies [179]. Water exercise, or combined with education, is associated with improvements in both physical and emotional aspects of FM, but with a question as to whether the benefit is derived from the aerobic exercise component that almost always accompanies water exercise [180-185].

A Pilates exercise program over a 12 week period improved pain compared to a relaxation program, but this effect was not sustained due to poor adherence to treatment [186]. Tai Chi is an exercise activity that combines both a physical and mental component and is ideally suited to persons with FM, with report of improved function and quality of life [187-189]. When traditional yoga was compared to yoga combined with a yoga touch technique “Tui Na”, improvement was more sustained in the yoga group only [190].

Although FM patients often report poor exercise capacity, reduced cardiorespiratory fitness was similar to controls, suggesting that FM patients overscore their perception of exertion [191]. A report of subjective muscle pain may be a barrier to optimal exercise activity [192]. In the absence of a single exercise program outperforming others, patients should be encouraged to choose an activity either land based or water, that is enjoyable, easy to follow, convenient and within budget in order to improve adherence.

Recommendation:
21. Persons with fibromyalgia should participate in a graduated exercise program of their choosing to obtain global health benefits and probable effects on fibromyalgia symptoms [Level 1 [174-178, 184, 185], Grade A].

2.2.5 Complementary and alternative medicines (CAMs)

CAMs are commonly used by FM patients with studies reporting over 90% use [193]. CAMs may be divided into four broad categories, namely products ingested, practitioner administered treatments, dietary interventions and treatments in the spiritual domain. There is little or poor evidence for efficacy of any intervention, with many studies having suboptimal design and reporting effects in small cohorts of patients. In a systematic review that also included the Chinese literature, Cao et al reported that there were some positive effects of Chinese herbal medicine on pain reduction in FM, compared with conventional medications [194]. However, the systematic review by De Silva et al, reported that there was insufficient evidence for the use of ingested or topically applied complementary agents for the management of FM symptoms [195]. Similarly, studies of homeopathy treatment, often of poor quality, indicate that this treatment cannot be recommended [196].

Acupuncture has been evaluated by at least two meta-analyses and three systematic reviews without showing evidence for prolonged effect on symptoms of FM, other than immediate pain reduction following treatment [194, 197-200]. However, when combined with other treatments including exercise and tricyclic antidepressants (TCAs), there was improvement in all measures of pain [201]. Similar to Tai Chi, Qigong with origins in Eastern medicine, but with differences in breathing patterns and meditation, has been shown to have some effect for up to four months when studied in 57 FM patients [202]. Chiropractic treatment, specifically manipulation, has also not been shown to have any appreciable effect on symptoms of FM, but may be useful for patients presenting with associated mechanical low-back pain [203, 204]. Hydrotherapy, which includes spa-, balneo-, and thalassotherapy has been evaluated in at least one meta-analysis and three systematic reviews and has shown short term benefits for pain and health related quality of life (HRQOL), although studies are mostly of low quality [180, 183-185]. Interestingly, most hydrotherapy programs also include an exercise component which may have important positive effects [184].

Recommendations:
22. Patients should be informed that there is currently insufficient evidence to support the recommendation of complementary and alternative medicine (CAM) treatments for the management of fibromyalgia symptoms, as they have mostly not been adequately evaluated regarding benefit [Level 1 [194, 195, 200], Grade A].

23. Patients should be encouraged to disclose use of CAMs to the healthcare professional who should be understanding and tolerant of this disclosure and should provide information on current evidence-based understanding of efficacy and risks where available [Level 5, Consensus].

2.3 Pharmacologic treatments

Symptom-based treatment represents a rational approach to pharmacologic choices, with drugs impacting more than one symptom adding advantage [111, 131]. There is a notion that the ideal treatment for FM is likely a combination of treatments, often in lower doses than reported in the study setting, with possible benefits of adherence. The traditional pharmacologic treatment paradigm begins with the use of simple analgesics and TCA’s. Other pharmacologic treatments including other antidepressants, gabapentinoids, dopaminergic agents and sleep modifiers are now more commonly used. Any treatment recommended requires repeated re-evaluation, with vigilance regarding continued benefit or side effects especially in the setting of polypharmacy. Pharmacologic adverse effects are seldom serious or life threatening but can be insidious and mistaken for FM symptoms, especially for opioid use [205]. Fatigue may be aggravated by gabapentinoids, antidepressants or analgesics; depression may be exacerbated by opioids; gastro-intestinal symptoms may be affected by non-steroidal anti-inflammatory agents (NSAIDs), opioids and antidepressants; sleep disturbance may be aggravated by opioids and antidepressants. Careful scrutiny of pharmacotherapy with reduction of excessive medication use resulted in an improved outcome for FM patients in a multidisciplinary setting [206].

Recommendations:
24. Physicians should identify the most bothersome symptom(s) in order to help direct pharmacologic treatments according to a symptom-based approach. An ideal pharmacologic choice may address multiple symptoms simultaneously and may require a combination of medications, in which case attention must be paid to drug interactions [Level 5 [111, 131], Grade D].

25. Pharmacologic treatments should be initiated in low doses with gradual and cautious upward titration to reduce medication intolerance [Level 5 [131], Grade D] with regular evaluation regarding continued efficacy and side effect profile, with the knowledge that drug side-effects may appear similar to symptoms of fibromyalgia [Level 5, Consensus].

26. Physicians prescribing medications for fibromyalgia should be open-minded and aware of the broader spectrum of agents available to treat symptoms, and should not confine treatments to a single category of medications [Level 5, Consensus].

2.3.1 Analgesic treatments (Acetaminophen and Nonsteroidal anti-inflammatory drugs [NSAIDs])

Although traditionally recommended as a step one agent in the analgesic ladder by the World Health Organization (WHO), acetaminophen has never been formally examined in FM other than when compounded with tramadol [207, 208]. It is generally a safe drug, but with caution regarding hepatotoxicity when doses above 2 grams a day are used continuously. When compounded with another analgesic prescription, supplementing with over-the-counter acetaminophen preparations may be dangerous [209, 210]. Acetaminophen modulates COX-1, COX-2 or COX-3 enzymes in the brain, impacts on neurogenic inflammation or serotonergic mechanisms, and can boost the endocannabinoid system [211-214]. Notwithstanding lack of evidence, patients preferred NSAID’s to acetaminophen, which were amongst the medications most commonly used [215-217]. As NSAID’s act mostly in the periphery, there is little rationale for their use, except perhaps for treatment of an associated condition such as osteoarthritis, but with attention to toxicity [218]. In order to limit side effects that can occur in the gastrointestinal, renal, and cardiovascular systems, NSAIDs should be used at the lowest dose and for the shortest periods of time [219-223].

Recommendation:
27. In line with the World Health Organisation step-up analgesic ladder, acetaminophen may be useful in some patients, but with attention to safe dosing [Level 5, Consensus].

28. In the event that NSAID’s are prescribed, particularly for associated conditions such as osteoarthritis, they should be used in the lowest dose and for the shortest period of time in view of possible serious adverse events [Level 5 [218, 219], Grade D].

2.3.2 Opioid treatments

Tramadol, an opioid with more than one analgesic mechanism, is the only opioid that has been studied in FM, with positive effect on pain and improved quality of life [208, 224]. Treatment trials in patients with non- cancer pain, including some with FM, report that opioids offer good short-term analgesia, although treatments are often discontinued [225]. Due to lack of evidence opioid use is not recommended by any previous FM guidelines [7, 9, 226].

Opioids are used by up to 30% of FM patients and are perceived to provide best symptom relief when surveyed by internet [205, 216]. Opioids are associated with negative psychosocial effects including unstable psychiatric disorder, history of substance abuse, unemployment and disability payments [205]. The role of the endogenous opioid system in pain expression in FM is open to debate, with reports of down as well as upregulation of opioid receptors, elevated levels of cerebrospinal fluid enkephalin and variable response to naltrexone, an opioid antagonist [112, 227]. Naltrexone had no important effect on pain sensitivity or mood when studied in 20 women with FM, and was also not associated with self-reported opioid withdrawal symptoms, suggesting a limited role of the endogenous opioid system [227].

In clinical practice opioids may be useful in selected patients, but with caution. Treatments should be initiated with weaker opioid agonists such as codeine or tramadol, before moving to the stronger opioids, but without any convincing evidence. The analgesic properties of codeine are dependent upon conversion to morphine via the cytochrome P450 isoenzyme 2D6, an enzyme absent in up to 10% of individuals, or by ultra-metabolism with resulting toxic effects [228].

Currently, tramadol, tapentadol and methadone are analgesic agents with multiple effects. The parent compound tramadol has added serotonin and norepinephrine effects, whereas tapentadol has effects on noradrenergic receptors. Tramadol is predominantly metabolized via the cytochrome-P450 (CYP) isoenzyme 2D6, whereas tapentadol is metabolized to a non-active component via hepatic glucuronidation resulting in less drug-drug interactions. These agents could be used for pain relief as a step up from acetaminophen and prior to the use of more potent opioid analgesics.

The progressive increase in opioid prescription has seen a parallel increase in their use as drugs of abuse, with reports of increased deaths associated with overdosing especially when combined alcohol or benzodiazepines [229-232]. Guidelines for safe and effective use of opioids for chronic pain have been published by the APS and also in Canada, with notes of caution [233, 234]. Physicians should practice responsible prescribing behaviours, pay attention to physical and psychosocial aspects, and constantly re-evaluate the risk benefit ratio. Long term effects of chronic opioid use are not yet fully clarified, but effects on mood, cognitive function, hormonal effects and increased pain due to hyperalgesia, need to be constantly re-evaluated [234]. Although extended-release formulations are touted as advantageous, evidence is lacking.

Recommendations:
29. A trial of opioids, beginning with a weak opioid such as tramadol, should be reserved for treatment of patients with moderate to severe pain that is unresponsive to other treatment modalities [Level 2 [208, 224], Grade D].

30. Strong opioid use is discouraged, and patients who continue to use opioids should show improved pain and function. Healthcare professionals must monitor for continued efficacy, side effects or evidence of aberrant drug behaviours [Level 5 [233], Grade D].

2.3.3 Cannabinoid treatments

Clinical cannabinoid use for pain relief remains controversial [235, 236]. The endocannabinoid system influences both inflammatory and pain pathways with two cannabinoid receptors distributed throughout the body [237]. Prescription cannabinoids are available in Canada as an oromucosal extract of cannabis based medicine, or the oral agents, dronabinol and nabilone. Herbal cannabis, whether smoked or ingested, is illegal without Health Canada exemption.

In a small trial of 40 patients over a 4 week period, nabilone was associated with improved pain, functional status, and anxiety compared to the placebo group, but with more side effects in the nabilone group [238]. In a comparator study of nabilone and amitriptyline addressing sleep disturbance, both agents performed equivalently for sleep, but without effect on pain or quality of life and with more adverse effects in the cannabinoid treatment group [239]. In a recent systematic review of 18 randomized controlled trials in chronic non cancer pain, 2 of which were for FM, cannabinoids were superior to placebo for analgesic effect, with some also showing improvement in sleep [236]. Long term effects of therapeutic cannabinoid treatment in FM are not known.

Recommendation:
31. A trial of a prescribed pharmacologic cannabinoid may be considered in a patient with fibromyalgia, particularly in the setting of important sleep disturbance [Level 3 [236, 238, 239], Grade C].

2.3.4 Antidepressants with pain modulating effects

Antidepressant medications have an effect on pain in treatment of FM independent of the effect on mood, by influencing diffuse noxious inhibitory control (DNIC) via augmentation of serotonin and norepinephrine [111]. Beginning with the tricyclic antidepressants (TCA’s) and the selective serotonin reuptake inhibitors (SSRI’s), recent study has focussed on the serotonin norepinephrine reuptake inhibitors (SNRI’s) [240-248]. Two early meta-analyses reported a favourable effect on pain, sleep disturbance, fatigue and overall well-being in FM patients [240, 242]. As the term antidepressant may induce bias and stigma, the term pain modulator has been proposed [249].

TCA’s in doses lower than used to treat depression have been the cornerstone drug treatment for FM. When 21 trials were meta-analysed, 16 with TCAs, these latter when compared to placebo showed a larger effect size for improved sleep, but with modest effect on other symptoms [240]. In a recent systematic review of 10 TCA trials, short term efficacy up to 8 weeks for lower doses but not higher doses was noted for pain, sleep, fatigue and global patient and physician impression [245]. Amitriptyline, with low cost and on provincial formularies, remains a reasonable choice, but limited by anticholingeric and antihistaminic side effects (eg, mouth dryness, weight gain, and drowsiness) and questions regarding long-term sustained efficacy [245]. Nortriptyline is less effective than amitriptyline [250]. Cost due to healthcare resource use/costs was less for those prescribed TCA’s compared to pregabalin [25].

Cyclobenzaprine, technically a muscle relaxant, structurally similar to the TCAs, has shown moderate benefit for global improvement with an odds ratio (OR) of 3.0 (95% CI 1.6-5.6) [251]. When used in doses of 1-4 mg at night, there was improvement in sleep physiology, fatigue and depression [24].

Due to the side effects of TCAs, evaluation of other antidepressants was prompted. When 26 studies evaluated antidepressants in FM by meta-analysis, 13 for amitriptyline, 12 for SSRIs (5 paroxetine, 4 fluoxetine, 2 citalopram, 1 sertraline), and 3 for SNRIs (2 duloxetine, 1 milnacipran), all agents with the exception of citalopram, showed a positive effect on pain, fatigue, depression, sleep and quality of life [248]. In a subsequent meta-analysis by the same group examining 18 RCTs with a median duration of 8 weeks (range 4-28), the effect size for pain reduction was most evident for TCAs, with SSRIs and SNRIs showing a smaller effect [243]. There have been no high quality RCTs examining venlafaxine in FM, an agent with predominant effect on serotonin at low dose and norepinephrine at higher dose, but with possible benefit [138].

Duloxetine, the only antidepressant approved by Health Canada for the treatment of FM, and milnacipran, currently not available in Canada, are SNRI’s with effect on pain and functioning in FM patients. For duloxetine, pain effect is independent of effect on mood, and some response is seen within 8 weeks [252, 253]. In a Cochrane systematic review of 3 studies, duloxetine in a dose of 60mg or 120mg daily was effective for pain relief over 12 and 28 weeks [244]. When duloxetine was studied up to one year, significant adverse events were few, but 29% of patients experienced troublesome side-effects including nausea, headache, dry-mouth and insomnia, with discontinuation of treatment in 16-20% of patients [244, 254]. The risk of suicide in patients of all age groups treated with any antidepressant should be appreciated. These agents have potential for interactions with other serotonin-elevating agents such as tramadol however serotonin syndrome is rare, but appropriate monitoring is required.

In the setting of overall equivalency of effect on symptoms, side effect profile and cost considerations should be taken into account. When factors influencing initiation of drugs were examined in a database of almost 120,000 FM patients, TCA’s, SSRI’s, duloxetine, tramadol and gabapentin were initiated almost equally in about 5% of individuals, with 9% initiating pregabalin, and 60% initiating non tramadol opioids. [255]. Prior treatment with pregabalin was associated with initiation of duloxetine [255].

Recommendations:
32. The pain-modulating effects of antidepressant medications should be explained to patients with fibromyalgia in order to dispel the concept of a primarily psychological complaint [Level 5 [249], Grade D].

33. All categories of antidepressant medications including TCAs, SSRIs and SNRIs may be used for treatment of pain and other symptoms in patients with fibromyalgia [Level 1 [243, 248], Grade A], with choice driven by available evidence for efficacy, physician knowledge, patient characteristics, and attention to side effect profile [Level 5, Consensus].

2.3.5 Anticonvulsants with pain modulating effects (a2-d ligand drugs)

Analgesic effects of anticonvulsants have been recognized since the 1970’s with initial reports of carbamazepine for treatment of facial pain [256]. Subsequent effects on neuropathic pain prompted study in FM. These drugs act as neuromodulators to dampen neuronal excitability, although the precise mechanism of action is unclear [257]. They act at a number of sites, including voltage-gated ion channels, ligand-gated ion channels, receptors of glutamate and N-methyl-D-aspartate (NMDA), and receptors for γ-aminobutyric acid (GABA) and glycine [258]. The inhibitory neurotransmitter GABA served as a structural template for development of the gabapentinoids (a2-d ligand drugs), including gabapentin and pregabalin, although neither binds appreciably to GABA receptors.

Gabapentinoids, classified as second-generation anticonvulsants, have shown clinical efficacy in the treatment of FM, although the clinical meaningful effect may be small [259-261]. Moore reports that only a minority of patients will have substantial benefit, with more having moderate benefit [262]. In an analysis of 127 RCT’s, with five studies included for meta-analysis, there was strong evidence for reduced pain, improved sleep and quality of life for gabapentin and pregabalin, independent of anxiolytic effects [259]. Effect on fatigue and anxiety were less substantial.

Both gabapentin and pregabalin are well absorbed after oral administration, have good bioavailability, and are excreted unchanged by the kidneys, requiring dosage adjustment in the presence of renal impairment [263]. There are few serious side effects or drug interactions, but adverse side effects including cognitive changes, weight gain and oedema lead to discontinuation or failure to achieve optimal doses. High doses of pregabalin used in trials and recommended by formularies (300, 450, 600 mg/day) are seldom used in clinical practice. When used as monotherapy, pregabalin improved pain, global assessment and function, and sleep at doses of 450mg/day, but not 300 or 600mg/day [26]. Average daily dosing of pregabalin was noted to increase from about 150mg/day at initiation of treatment to about 300mg/day over 12-months in a US administrative claims database [264]. A new prescription for pregabalin was associated with reduced use of NSAIDs, anticonvulsants and other combination therapies, whereas gabapentin was associated with increased prescriptions for opioids, SNRIs, anticonvulsants, benzodiazepines and topical agents [265].

Recommendation:
34. Anticonvulsant medication use should be explained as having pain-modulating properties and treatment should begin with the lowest possible dose followed by up titration, with attention to adverse events [Level 1 [259, 261, 262], Grade A].

2.3.6 Other pharmacologic agents

Novel pharmacologic agents, each with unique mechanisms of action, may eventually be useful for FM pain management, although evidence is preliminary. The categories of drugs include dopaminergic agents, sodium oxybate, 5-hydroxytryptamine 3 receptor antagonists, and N-methyl D-aspartate (NMDA) receptor antagonists.

Anti-parkinsonian drugs that augment dopamine are an effective treatment for restless legs, a frequent association with FM. Pramipexole was studied in 60 FM patients at a dose of 4.5mg per day, and reduced pain by one third, although use is tempered by gastrointestinal side effects [266]. In contrast, terguride, a partial dopamine agonist, showed no advantage over placebo in a study of 99 patients [267]. There have been reports of impulse control disorders associated with these agents [268].

Gamma-hydroxybutyric acid (GHB), a naturally occurring substance, likely synthesized from GABA in neurones, has an agonist action at two receptor sites [269]. Binding to the GHB receptor is excitatory, whereas binding to the GABAB receptor is inhibitory. GHB has a biphasic effect on dopamine release, with high concentration inhibiting release from the GABAB receptor and low concentrations stimulating dopamine release from the GHB receptor, accounting for the dual sedative and subsequent activating effects, as well as addictive properties. In a study of 188 FM patients treated with sodium oxybate, benefit was observed for both pain and subjective sleep quality, with good tolerability apart from nausea and dizziness reported by one third of patients, but concerns regarding long term use and potential for addiction remain [270]. The improvement in sleep seen with sodium oxybate may be due to reduction of alpha intrusion and increase in slow-wave sleep, as well as boosting of growth hormone levels [271]. FDA approval for treatment of FM was denied due to concerns of abuse [272].

The 5-hydroxytryptamine-3 (5-HT3) receptor antagonist dolasetron, infused monthly over a period of 3 months, reduced pain intensity [273]. When evaluated in two studies, tropisetron, a selective, oral competitive 5-HT3-receptor antagonist, improved pain in the short term [274, 275]. In contrast, the 5-HT-2 receptor blocker ritanserin showed no effect on the key symptoms of FM over 16 weeks [276].

There are no studies in FM of NMDA receptor antagonists including ketamine, dextromethorphan, amantadine, memantine, and methadone, agents moderating chronic pain. When pain mechanisms were examined in FM using ketamine, some patients demonstrated reduced local and referred pain areas, supporting the concept of central hypersensitization [277]. Cognitive and psychological side effects of ketamine preclude current use for FM.

Peripheral pain generators may augment sensitization in FM. Lidocaine, the local anesthetic agent active on sodium channels, was tested by local injection and intravenously. Local injection into the trapezius region reduced local pain threshold at the injection site, whereas intravenous lidocaine showed a modest effect on pain in 75 patients followed for four weeks [278, 279]. When trigger point injections, joint injections or myofascial release techniques were tested, reduced pain persisted for three weeks [280, 281]. Therefore, attention to local factors may have some place in the treatment of FM. Botulinum toxin-A injections have been studied in small uncontrolled pilot studies with conflicting report of efficacy [282, 283] .

Agents without effect in FM include dehydroepiandrosterone in postmenopausal women, human interferon-alpha, and the antiviral agent valacyclovir [284-286]. Growth hormone injections, evaluated in two studies, improved overall symptoms but safety concerns and cost issues preclude recommendation [287, 288].

Subjective sleep improved with zopiclone in two studies of 41 and 33 patients, but without change in polysomnography [289, 290]. Very low doses of cyclobenzaprine increased restorative sleep, with improvement in fatigue and pain [24]. A combination treatment with tenoxicam and bromazepan may have some effect in FM, although a study of 164 patients over 8 weeks showed no significant difference compared to placebo [291]. Quetiapine, an atypical second generation antipsychotic agent, commonly used off-label for sleep, reduced FIQ stiffness and fatigue, but not FIQ pain [292]. Melatonin, with potential to improve sleep was tested in a pilot study of 21 patients over 4 weeks with some suggestion of improvement [293].

A common trend for all of the aforementioned agents is lack of concrete evidence, either for or against use in FM. Larger well-designed RCTs are required to provide evidence for use.

Recommendation:
35. Physicians should be aware that only pregabalin and duloxetine have Health Canada approval for management of fibromyalgia symptoms and all other pharmacologic treatments constitute “off label use” [Level 5, Consensus].

1 Division of Rheumatology, McGill University, Montreal, Quebec, Canada
2Alan Edwards Pain Management Unit, McGill University Health Center, Montreal, Quebec, Canada
3Faculty of Law, Université de Montréal, Montreal, Quebec, Canada
4Division of Rheumatology, Tufts University School of Medicine, Boston, Massachusetts, USA
5Department of Family Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
6Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
7Centre de la recherche du Centre hospitalier de l’Université de Montréal; Department of Anesthesiology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
8Division of Physiatry, University of Toronto, Toronto, Ontario, Canada
9Departments of Clinical Neurological Sciences and Oncology, University of Western Ontario, London, Ontario, Canada
10Patient representative