Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial

Aims: In this study, monotherapy with alpha-lipoic acid (ALA) or pregabalin was compared to the combination for peripheral neuropathic pain.

Methods: This trial was a randomized, controlled, 3-period crossover trial evaluating monotherapy with ALA or pregabalin to combination therapy with ALA and pregabalin for neuropathic pain. In this trial, N=54 participants with neuropathic pain (based on DN4 ≥4 plus daily pain for 3 months and an average weekly pain intensity ≥3/10 on a pain diary) were randomized to 1 of 6 sequences of ALA, pregabalin or the combination. Once randomized, participants completed three 6-week treatment periods of medication initiation and titration to maximum tolerated dose. The primary outcome was average daily pain based on a numerical rating scale (NRS)] on max tolerated dose. The secondary outcomes included quality of life, sleep, depression, anxiety, adverse effects and study medication doses.

Results: Of the initial 54 participants randomized, the mean age was 70 years, 63% were male, 100% Caucasian, 37% had diabetic peripheral neuropathy, and 44 completed all 3 treatment periods. For the primary outcome, pain scores based on NRS were 5.32, 3.96, 3.25, and 3.16 for baseline, ALA, pregabalin and combination, respectively. The percent change in pain intensity for each treatment was 18.6%, 33.5%, and 33% for the ALA, pregabalin, and combination arms, respectively. There was a statistically significant reduction in pain scores in the pregabalin and combination arms compared to ALA (P<0.01). Similar results were found in the subgroup analysis of diabetic peripheral neuropathy where pain scores were 3.53, 2.72, and 2.64 in the ALA, pregabalin and combination arms, respectively, with statistically significant reductions in the pregabalin and combination arms compared to ALA (P<0.01). For the secondary outcomes, improvements in quality of life and sleep were seen in the pregabalin and combination arms compared to ALA (P<0.05). There were no differences in adverse effects or drug doses.

Conclusions: In this 3-arm crossover trial, all treatments (ALA, pregabalin, and combination) reduced pain scores at 6 weeks though pregabalin was superior to ALA for both the primary and secondary outcomes. There was no additional benefit to adding ALA to pregabalin for neuropathic pain.

Comments. Prior studies have suggested benefits of combination anticonvulsant and antidepressant pharmacotherapy for the treatment of painful diabetic neuropathy (Tesfaye S et al Pain 2013;154:2616-2625; Tesfaye S et al Lancet 2022;400:680-690). However, combination studies with antioxidant (ALA) therapy have not been done. In this current study, combination therapy with anticonvulsant and antioxidant medications was evaluated for treatment of neuropathic pain. Based on this trial, there is no additional benefit to adding ALA to pregabalin for neuropathic pain. One caveat may be that this current study included a shorter treatment duration of 6 weeks compared to the prior combination studies. Further studies combining ALA with other agents should be done for a longer period for more definitive conclusions.

Kara Mizokami-Stout

Reference. Gilron I, Robb S, Tu D, Holden RR, Jackson AC, Duggan S, Milev R. Randomized, double-blind, controlled trial of a combination of alpha-lipoic acid and pregabalin for neuropathic pain: the PAIN-CARE trial. Pain. 2024 Feb 1;165(2):461-469. doi: 10.1097/j.pain.0000000000003038. Epub 2023 Sep 7. PMID: 37678556.

https://journals.lww.com/pain/abstract/2024/02000/randomized,_double_blind,_controlled_trial_of_a.21.aspx