# Combination therapy with pregabalin and thioctic acid offers safer pain control in diabetic neuropathy: a multicenter, double-blind, non-inferiority trial

## TL;DR

Combining low-dose pregabalin with thioctic acid provides similar pain relief for diabetic neuropathy as high-dose pregabalin, but with fewer side effects.

## Contribution

A fixed-dose combination of pregabalin and thioctic acid is shown to be non-inferior in efficacy and safer than high-dose pregabalin for diabetic neuropathy.

## Key findings

- The combination regimen was non-inferior to standard-dose pregabalin in reducing pain intensity.
- The combination group experienced fewer dose-limiting adverse events like dizziness and dry mouth.
- Subgroup analyses suggested better effects in patients with higher BMI or longer disease duration.

## Abstract

High-dose pregabalin is effective for painful diabetic peripheral neuropathy, but dose-dependent adverse effects limit its use. Thioctic acid (alpha-lipoic acid), a mitochondrial antioxidant with neuromodulatory properties, may improve tolerability without reducing efficacy when combined with lower doses of pregabalin. We conducted a multicenter, double-blind, parallel-group, non-inferiority trial at nine centers in Mexico between November 2017 and March 2020. Adults with painful diabetic peripheral neuropathy underwent pregabalin titration. Non-responders, defined as patients with <50% pain reduction, were randomized in a 1:1 ratio to receive pregabalin 150 mg twice daily or a fixed-dose combination of pregabalin 80 mg plus thioctic acid 400 mg twice daily for 12 weeks. The primary endpoint was mean pain intensity at week 12, measured using a 10-point visual analogue scale, analysed in the per-protocol population with a predefined non-inferiority margin of 0.735. Of 645 participants screened, 439 were randomized (220 to pregabalin and 219 to the combination). In the per-protocol population (n = 297), the adjusted mean between-group difference in pain scores was 0.04 (upper 99.17% confidence interval: 0.62), confirming the non-inferiority of the combination regimen compared with standard-dose pregabalin. Pain trajectories over time, responder rates defined by at least 30% and at least 50% pain reduction, and patient-reported outcomes, including the Short-Form McGill Pain Questionnaire, the 36-Item Short Form Health Survey, and the Leeds Assessment of Neuropathic Symptoms and Signs scale, showed similar point estimates. However, non-inferiority was not formally demonstrated for these secondary measures. Exploratory post-hoc subgroup analyses suggested numerically greater effects among patients with a body mass index above 25 or disease duration of more than 2 years. In the intention-to-treat safety population, the combination group reported significantly fewer dose-limiting adverse events, particularly dizziness (34% versus 52%) and dry mouth (10% versus 20%), without an increase in serious adverse events. A fixed-dose combination of low-dose pregabalin and thioctic acid is non-inferior to high-dose pregabalin for analgesic efficacy and demonstrates an improved safety profile. These findings support this combination as a safe and better-tolerated treatment alternative for painful diabetic peripheral neuropathy.

Zárate et al. report that a fixed-dose combination of low-dose pregabalin and thioctic acid was non-inferior to standard-dose pregabalin in reducing pain in adults with painful diabetic nerve damage, while improving tolerability. The findings support a dose-sparing combination strategy as a better-tolerated alternative for long-term treatment.

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