Efficacy and safety of gabapentinoid combination therapy versus monotherapy for the treatment of neuropathic pain

Background: Whether combining gabapentinoids with other agents yields superior efficacy and safety outcomes compared to gabapentinoid monotherapy in patients with neuropathic pain remains unknown. Objective: To compare the efficacy and safety of gabapentinoid combination therapy versus monotherapy in patients with neuropathic pain in head-to-head comparative studies. Methods: statistic. Results: Twenty-one clinical trials comprising 2204 patients were included in this meta-analysis. Gabapentinoid combination therapy was superior to monotherapy in reducing pain (MD = - 1.27, 95% CI = - 1.55 to - 0.99; n =18) and sleep interference scores (MD = - 0.92, 95% CI = - 1.40 to - 0.45; n =5) and increasing the PGIC response rate (RR = 1.80, 95% CI = 1.36 to 2.39; n =4). Subgroup analyses demonstrated that gabapentinoids, both gabapentin and pregabalin, achieved statistically significant greater pain reduction when combined with other gabapentinoids or antidepressants, dietary supplements, local anesthetic, non-pharmacological treatment, and opioids, whereas only a non-significant decreasing trend with immunomodulators. Notably, patients with painful diabetic neuropathy (PDN) and postherpetic neuralgia (PHN) may benefit more from combination therapy. Although combination therapy was associated with higher overall discontinuation rates and certain adverse events, these safety concerns were largely driven by opioid-gabapentinoid combinations; most other combinations had a safety profile comparable to monotherapy. Conclusion: Gabapentinoid combination therapy was more effective than monotherapy for neuropathic pain, but the benefit-risk profile of specific combinations warrants careful consideration in clinical decision-making. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251275655.