Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis.

Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. Over half of patients receive 2 or more analgesics and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind RCTs evaluating combinations of two or more drugs versus placebo and/or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects, and risk-of-bias was assessed. Meta-analyses compared combination to monotherapy wherever two or more similar studies were available. Forty studies (4,741 participants) were included. Studies were heterogenous with respect to various characteristics including dose titration methods and administration (i.e. simultaneous versus sequential) of the combination. Few combinations involved a non-sedating drug and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared to monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy - as second- or third-line treatment - in situations where monotherapy is insufficient should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving non-sedating agents, and to identify clinical settings and specific combinations that safely provided added benefit.