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. 2018 Feb 19;2(2):CD010585.
doi: 10.1002/14651858.CD010585.pub2.

Combination pharmacotherapy for the treatment of fibromyalgia in adults

Joelle Thorpe  1 , Bonnie Shum, R Andrew Moore, Philip J Wiffen, Ian Gilron
Affiliations

Combination pharmacotherapy for the treatment of fibromyalgia in adults

Joelle Thorpe et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries.

Selection criteria: 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.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

JT: none known.

BS: none known.

RAM has received grant support from Grünenthal relating to individual, patient‐level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attending boards with RB on understanding pharmacokinetics of drug uptake (2015). He has received honoraria from Omega Pharma (2016) and Futura Pharma (2016) for providing advice on trial and data analysis methods.

PW: none known.

IG is an anaesthesiologist and conducts clinical trials in acute and chronic pain conditions. He has received lecture/consultancy fees from Biogen (2016) and Adynxx (2015). IG, who is the lead and corresponding author on one of the included studies in this review, did not participate in data extraction or assessments pertaining to that study.

This review was identified in a 2019 audit as not meeting the current definition of the Cochrane Commercial Sponsorship policy. At the time of its publication it was compliant with the interpretation of the existing policy. As with all reviews, new and updated, at update this review will be revised according to 2020 policy update.

Figures

1
1
Flow diagram
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

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References to ongoing studies

NCT00991848 {published data only}
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NCT01323374 {published data only}
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NCT01850420 {published data only}
    1. A study of IMC-1 in patients with fibromyalgia. Ongoing study. May 2013. Contact author for more information.

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