Combination pharmacotherapy for neuropathic pain: current evidence and future directions

Current drugs reduce neuropathic pain and improve mood and quality of life. However, as single agents they are limited by incomplete efficacy and dose-limiting adverse effects. Recent experimental and clinical data support the potential of combination pharmacotherapy for neuropathic pain. Therapeutic benefits may include greater efficacy, lower doses and fewer adverse effects. Due to potential adverse, as well as beneficial, drug interactions, safety and efficacy of specific combinations must be empirically evaluated. Techniques such as isobolographic analysis, response-surface modeling and other model-free tests have been used in order to characterize analgesic interactions as antagonistic, additive or synergistic. Whether synergistic or not, a clinically useful combination could simply have additive or even subadditive analgesia, provided that there is less additivity for side effects. Despite widespread clinical use, there are surprisingly few published observations on combination therapy for neuropathic pain. This review discusses future directions and proposes research strategies aimed at bridging current knowledge gaps, including safety, compliance and cost-effectiveness; discovering optimal drug combinations and dose ratios; comparing concurrent with sequential combination therapy; and combining more than two drugs. Continued close integration of basic and clinical sciences is crucial in further harnessing the potential of combination pharmacotherapy in neuropathic pain.