Cannabinoids for fibromyalgia
This review is one of a series on drugs used to treat fibromyalgia. Fibromyalgia is a clinically well‐defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co‐exists with sleep problems and fatigue affecting approximately 2% of the general population. People often report high disability levels and poor health‐related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Cannabis has been used for millennia to reduce pain and other somatic and psychological symptoms.
To assess the efficacy, tolerability and safety of cannabinoids for fibromyalgia symptoms in adults.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE to April 2016, together with reference lists of retrieved papers and reviews, three clinical trial registries, and contact with trial authors.
We selected randomised controlled trials of at least four weeks' duration of any formulation of cannabis products used for the treatment of adults with fibromyalgia.
Data collection and analysis
Two review authors independently extracted the data of all included studies and assessed risk of bias. We resolved discrepancies by discussion. We performed analysis using three tiers of evidence. First tier evidence was derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention‐to‐treat analysis without imputation for drop‐outs; at least 200 participants in the comparison, eight to 12 weeks' duration, parallel design), second tier evidence from data that did not meet one or more of these criteria and were considered at some risk of bias but with adequate numbers (i.e. data from at least 200 participants) in the comparison, and third tier evidence from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation).
We included two studies with 72 participants. Overall, the two studies were at moderate risk of bias. The evidence was derived from group mean data and completer analysis (very low quality evidence overall). We rated the quality of all outcomes according to GRADE as very low due to indirectness, imprecision and potential reporting bias.
The primary outcomes in our review were participant‐reported pain relief of 50% or greater, Patient Global Impression of Change (PGIC) much or very much improved, withdrawal due to adverse events (tolerability) and serious adverse events (safety). Nabilone was compared to placebo and to amitriptyline in one study each. Study sizes were 32 and 40 participants. One study used a cross‐over design and one used a parallel group design; study duration was four or six weeks. Both studies used nabilone, a synthetic cannabinoid, with a bedtime dosage of 1 mg/day. No study reported the proportion of participants experiencing at least 30% or 50% pain relief or who were very much improved. No study provided first or second tier (high to moderate quality) evidence for an outcome of efficacy, tolerability and safety. Third tier (very low quality) evidence indicated greater reduction of pain and limitations of HRQoL compared to placebo in one study. There were no significant differences to placebo noted for fatigue and depression (very low quality evidence). Third tier evidence indicated better effects of nabilone on sleep than amitriptyline (very low quality evidence). There were no significant differences between the two drugs noted for pain, mood and HRQoL (very low quality evidence). More participants dropped out due to adverse events in the nabilone groups (4/52 participants) than in the control groups (1/20 in placebo and 0/32 in amitriptyline group). The most frequent adverse events were dizziness, nausea, dry mouth and drowsiness (six participants with nabilone). Neither study reported serious adverse events during the period of both studies. We planned to create a GRADE 'Summary of findings' table, but due to the scarcity of data we were unable to do this. We found no relevant study with herbal cannabis, plant‐based cannabinoids or synthetic cannabinoids other than nabilone in fibromyalgia.
We found no convincing, unbiased, high quality evidence suggesting that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia.
Brian Walitt, Petra Klose, Mary-Ann Fitzcharles, Tudor Phillips, Winfried Häuser
Plain language summary
Cannabis products for people with fibromyalgia
Fibromyalgia is characterised by chronic (longer than three months) widespread pain that often co‐exists with sleep problems, problems with thinking and fatigue (exhaustion). People often report severe limitations of daily functioning and poor health‐related quality of life. Therapies focus on reducing key symptoms and disability, and improving health‐related quality of life. Cannabis has been used for 3000 years to reduce pain and other symptoms, such as loss of appetite and anxiety.
Key results and quality of the evidence
In April 2016 we searched for reports of clinical trials that used cannabis products to treat symptoms in adults with fibromyalgia. We found two small, moderate quality studies, of four and six weeks long, including 72 participants. Both studies tested nabilone, a synthetic (man‐made) cannabis product, comparing it with placebo (a dummy pill) or amitriptyline (an antidepressant frequently used in the treatment of fibromyalgia).
Nabilone did not convincingly relieve fibromyalgia symptoms (pain, sleep, fatigue) better than placebo or amitriptyline (very low quality evidence). Compared with placebo and amitriptyline, more people experienced side effects and left the study due to side effects (very low quality evidence). There were no serious side effects reported. We found no relevant study with herbal cannabis, plant‐based cannabinoids or other synthetic cannabinoids than nabilone in fibromyalgia.
There was not enough high quality evidence available to draw any robust conclusions. We found no studies on medical cannabis in fibromyalgia.
Brian Walitt, Petra Klose, Mary-Ann Fitzcharles, Tudor Phillips, Winfried Häuser
Implications for practice
For people with fibromyalgia
Clinical trial evidence on the use of cannabis products in fibromyalgia was limited to two small studies with short‐term duration. No convincing, unbiased evidence suggests that nabilone is of value in treating people with fibromyalgia. The tolerability of nabilone was low in people with fibromyalgia. Adverse events (particularly somnolence, dizziness, vertigo) may limit its clinical usefulness. We found no relevant study with herbal cannabis, plant‐based cannabinoids or other synthetic cannabinoids than nabilone in fibromyalgia.
Herbal, plant‐based and synthetic cannabis products are not licensed for fibromyalgia in any country. Other than one weak recommendation from a trial of a pharmacological cannabinoid preparation in people with fibromyalgia in the setting of important sleep disturbance in the Canadian fibromyalgia guidelines (Fitzcharles 2013), there is no other current guideline recommendation for use of any cannabis preparation in the management of fibromyalgia.
For policy makers
The use of herbal cannabis at present cannot be considered evidence‐based and this should be explained to people requesting this treatment (in jurisdictions where it is allowed, e.g. Canada and Israel).
Randomised controlled trials with cannabis products may be worth funding, as there are few confirmed effective drug treatments, in order to establish the efficacy and safety of cannabinoids compared to established treatments in this population.
Implications for research
To establish whether cannabis products can have a place in the treatment of fibromyalgia would require large (at least 200 participants), randomised, double‐blind, parallel group or enriched enrolment randomised withdrawal (EERW) studies, of adequate duration (greater than 12 weeks), with outcome measures that are relevant to clinical practice (responder analysis), and analysis that does use baseline observation carried forward imputation for withdrawals.
It might be expected that, at best, only a few people with fibromyalgia will benefit from long term use of cannabis products, and cohort studies in fibromyalgia link cannabis use to negative health‐related measures (Ste‐Marie 2012). A further area of research would be to identify clinical and demographic characteristics that predict which people are likely to benefit or to be harmed from cannabis products, in order to target treatment more effectively.
Studies in any continent and the inclusion of people with major medical diseases and mental disorders are necessary to provide external validity of the study findings.
Responder criteria for pain, global impression of change and health‐related quality of life have been established (Bennett 2009; Dworkin 2008). Responder criteria for sleep problems and fatigue have not yet been developed.
Comparison between active treatments
Any comparisons should be made with placebo and other drugs with known efficacy, such as pregabalin. In addition, studies comparing single therapies (e.g. cannabis products) versus combination therapies (e.g. cannabis products and aerobic exercise) are necessary.