Combination pharmacotherapy for the treatment of fibromyalgia in adults
Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects.
To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults.
We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries.
Double‐blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain.
Data collection and analysis
From all studies, we extracted data on: participant‐reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain‐related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single‐agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table.
We identified 16 studies with 1474 participants. Three studies combined a non‐steroidal anti‐inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5‐hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.
Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta‐analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient‐reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.
Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain‐related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.
Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache.
There are few, large, high‐quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.
Joelle Thorpe, Bonnie Shum, R Andrew Moore, Philip J Wiffen, Ian Gilron
Plain language summary
Combinations of drugs versus single drugs to treat fibromyalgia pain in adults
There is no good evidence to prove or disprove that combining drugs is better than using single drugs for fibromyalgia.
People with fibromyalgia experience constant, widespread pain, sleep problems, and fatigue. Common drugs such as paracetamol (acetaminophen) and ibuprofen are not usually effective. Medicines used to treat epilepsy or depression can sometimes be effective for fibromyalgia and other forms of long‐lasting pain where there may be nerve damage. Many individuals with fibromyalgia take many different drugs to deal with pain. We did this review to find the evidence about using combinations of drugs compared to single drugs.
In September 2017 we searched for clinical trials where combinations of medicines were used for fibromyalgia pain in adults. We found 16 studies evaluating combinations of drugs versus one drug for fibromyalgia pain.
These studies looked at combinations of all sorts of different drugs, but did not provide enough data to draw any conclusions. Many of the studies did not directly compare a combination of drugs with each single drug. They sometimes compared a combination of medicines with only one of the medicines in the combination, or with only placebo. This limited our ability to make any conclusions.
Most studies did not report any of the outcomes important to people with fibromyalgia. Some studies showed that a combination of drugs is better at reducing pain than one drug alone, but other studies showed that one drug alone is better than a combination of drugs. Other studies did not find any difference between combinations of drugs and single drugs.
Side effects were not severe, and generally were not different between combination therapy and monotherapy.
Quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low‐quality evidence means that we are very uncertain about the results. High‐quality evidence means that we are very confident in the results. Overall, the quality of evidence for important outcomes was very low. None of the combinations of drugs provided enough information for our preferred outcomes. We think that new studies will be very likely to change any conclusions drawn from these studies.
Joelle Thorpe, Bonnie Shum, R Andrew Moore, Philip J Wiffen, Ian Gilron
Implications for practice
For people with fibromyalgia
There are currently no pharmacotherapy options for fibromyalgia that sufficiently treat all symptoms while avoiding the risk of adverse events that could make fibromyalgia symptoms worse. Further research is necessary before determining if combinations of medications with different mechanisms of action can reduce fibromyalgia symptoms and cause fewer side effects than monotherapy.
There are very few high‐quality clinical trials evaluating the efficacy of specific drug combinations for treating fibromyalgia, which precludes us from useful in‐depth meta‐analyses. As a result of this lack of data, clinical decisions about whether to treat fibromyalgia with monotherapy or combination pharmacotherapy may be based only on one or two double‐blind, randomised controlled trials and very small numbers of participants and events, depending on the drug combination in question. Individual studies point in different directions, to the superiority of combination therapy, to the superiority of monotherapy, or to no difference. In other words, whether or not combination pharmacotherapy is effective for treating fibromyalgia pain depends largely on the specific drugs under investigation, and generalisations are impossible.
Using the GRADE approach to assess each study, evidence varied for different drug combinations and was very low quality. Reasons for evidence being determined as very low quality varied across studies and drug combinations but generally included lack of directness (i.e. comparing a combination to only one or even none of its single‐agent components), small sample sizes, short trial duration, and other statistical analysis issues. Taken together, available evidence does not allow us to draw firm conclusions about any of the combinations included in this review.
Care should be taken when prescribing multimodal pharmacotherapy to ensure that adverse events are closely monitored and the risk for toxicity does not outweigh the potential benefits of combination therapy. Given some of the previous combinations studied, it should be emphasised that combining drugs that cause serotonin reuptake inhibition (e.g. amitriptyline, desipramine, duloxetine) with other serotonin reuptake inhibitors (e.g. tramadol) may cause ‘serotonin syndrome’ – a potentially fatal condition marked by altered mental status, hyperactivity, and neuromuscular dysfunction. It should also be noted that benzodiazepines are not recommended by the American Pain Society, the European League Against Rheumatism, or the Association of the Scientific Medical Societies in Germany for the treatment of fibromyalgia (Hauser 2010).
For policy makers and funders of the intervention
Based on the results of this systematic review, there is currently insufficient evidence to support the routine use of any specific drug combination for the treatment of fibromyalgia pain. However, there is some evidence to support the use of combination therapy for fibromyalgia and real‐world studies indicate that various drug combinations are widely used for this condition. These observations and knowledge gaps point to a compelling need for new and improved research to identify:
- favourable combinations that could improve patient care outcomes and
- unfavourable combinations that are either associated with unacceptable adverse effects or cost‐ineffective for this condition.
Implications for research
Many of the studies meeting our inclusion criteria for this review had similar issues with small sample sizes, low power, short trial duration, and incomplete comparisons (for example, comparing a combination with placebo only, or comparing a combination of two drugs with only one of the drugs given as a monotherapy). These shortcomings prevent us from drawing strong conclusions about whether medications with different mechanisms of action can act additively or synergistically when given in combination.
We suggest, as do many others (Calandre 2015; Dale 2016; Gerardi 2016; Han 2011), that more research is necessary. Given the compelling (but scant) evidence for combination pharmacotherapy found in several studies, future clinical trials evaluating combinations of the best‐tolerated and most effective treatments should be conducted. More studies testing the same types of combinations will enable meta‐analysis of multiple trials to determine which combinations (if any) are well‐tolerated and effective. As it stands, these issues have not been adequately addressed in the literature.
Special focus should be placed on designing studies that include treatment arms for the combination of two or more agents and for each individual agent in addition to a placebo arm (Mease 2008). Including a placebo group will ensure that methods to quantify outcome measures have assay sensitivity to detect a treatment effect. Including each agent as a monotherapy will allow us to conclude whether the combination of two agents is superior to each agent alone, which will help answer the question of whether multiple medications can act synergistically or additively. Future studies should be planned with later meta‐analysis in mind.
It is unclear whether radically different trial designs, such as that using an enriched‐enrolment, randomised withdrawal method would be appropriate for this clinical question, but it may be worth considering and has been used in fibromyalgia trials with some success (Moore 2015a). A different approach to consider might be a more pragmatic design that acknowledges that there are considerable differences between individuals in terms of drug response, and that these are not predictable (Moore 2010c). Such a design may be open to investigation of the effects of combinations in people with modest but inadequate response to one drug, mimicking an approach common in clinical practice.
Trials should report outcomes of known importance to people with fibromyalgia, such as pain scores and adverse events, and should also use several imputation methods for the large numbers who withdraw from treatment.
Comparison between active treatments
Studies involving other treatments including non‐pharmacological interventions may be valuable in this context. A multi‐component approach reflects current practice.