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

2026-04-13
Frontiers in physiology 17
- Dandan Li
- Yang He
- Zhiqiang Fan
- Zhen Chen
- Guiming Deng
- Linqi Ouyang

PubMed: 42051748
DOI: 10.3389/fphys.2026.1802999

Study Design

Type: Systematic Review
Sample size: n = 2,204
Population: patients with neuropathic pain
Methods: Systematic review and meta-analysis; PubMed, Web of Science, Embase, and Cochrane Library were systematically searched from inception to November 4, 2025; data abstraction and quality assessment per PRISMA and Cochrane risk-of-bias tool

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

PubMed, Web of Science, Embase, and Cochrane Library were systematically searched from inception to November 4, 2025. Data abstraction and quality assessment were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline and the Cochrane risk-of-bias tool, respectively. Pain scores (standardized to a 0-10 scale) were the primary outcomes, sleep interference scores, Patient Global Impression of Change (PGIC) and adverse events were the secondary outcomes. Study screening and selection were performed independently by 2 reviewers, with any disagreements resolved by a third adjudicator. Heterogeneity among studies was assessed using the I² 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.