Use of Tricyclic Antidepressants in the Management of Diabetic Neuropathic Pain : A Systematic Review of Randomized Controlled Trials and Primary Studies

Abstract

Introduction

Diabetic neuropathic pain (DNP) is one of the most prevalent and debilitating complications of diabetes mellitus, affecting 15–26% of diabetic patients globally. Tricyclic antidepressants (TCAs) — including amitriptyline, imipramine, nortriptyline, and desipramine — have been utilized as analgesic agents through mechanisms involving norepinephrine and serotonin reuptake inhibition, sodium channel blockade, and central pain modulation. Despite decades of clinical use, a comprehensive primary-evidence synthesis exclusively evaluating TCA pharmacotherapy across the full spectrum of clinical outcomes in DNP has not been recently performed. This systematic review consolidates all available randomized controlled trials and primary observational evidence on TCA pharmacotherapy in DNP.

Methods

The study strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. Eligible primary study designs: randomized controlled trials (RCTs), cohort studies, case-control studies, cross-sectional studies, and observational prospective/retrospective studies.

Results

Fifteen primary studies met inclusion criteria for the Study Characteristics Table (Table 2): 13 RCTs and 2 prospective observational/open-label trials, enrolling 1,842 participants across multiple continents. Additional supporting evidence from 7 verified systematic reviews and meta-analyses is incorporated in outcome analyses and discussion. Amitriptyline achieved moderate-to-greater pain relief in 55–74% vs. 20–41% placebo. Desipramine demonstrated equivalent analgesic efficacy to amitriptyline. Imipramine yielded NNT 1.4 (optimal dose) to 2.4.^1,2,3 The landmark OPTION-DM trial (Tesfaye 2022) confirmed NRS reduction from 6.6 to 3.3 (p<0.001) across amitriptyline-based pathways — equivalent to duloxetine/pregabalin-based pathways.⁴ PAIN-CONTRoLS (Barohn 2020) demonstrated nortriptyline utility 0.81 — highest among all comparators.⁶ Anticholinergic adverse events were the primary tolerability limitation (dry mouth 30–55%; sedation 20–40%).

Conclusion

TCAs — particularly amitriptyline, imipramine, desipramine, and nortriptyline — provide clinically significant, evidence-based analgesic benefit in DNP with NNT 1.4–3.0, equivalent to contemporary first-line agents at substantially lower cost. Careful patient selection, cardiovascular screening, and graduated dose titration are essential for safe clinical application.