Is pregabalin alone sufficient for painful diabetic neuropathy?
Aims: The OPTIMUM study assessed the efficacy and safety of alpha-lipoic acid (ALA), pregabalin, and their combination in patients with painful diabetic peripheral neuropathy (DPN) and type 2 diabetes. The main hypothesis was that pregabalin monotherapy would be non-inferior to combination therapy in reducing neuropathic pain.
Methods: This 12-week, randomized, active-controlled, open-label, multicenter phase IV trial included 151 patients with painful DPN, randomized 1:1:1 to ALA 480 mg/day, pregabalin 150 mg/day, or their combination. Pregabalin could be increased to 300 mg/day at week 6 according to response and tolerability. The primary endpoint was the change in pain intensity from baseline to week 12, assessed by visual analogue scale (VAS). Secondary outcomes included pain questionnaires, quality of life, inflammatory biomarkers, lipid profile and oxidative stress markers. A post hoc cluster analysis grouped patients according to DPN duration and DN4 score, identifying three clusters with short (1), intermediate (2) and long-standing DPN (3).
Results: At week 12, pregabalin reduced VAS pain score by −19.73 ± 18.94 mm, while combination therapy reduced it by −23.28 ± 18.15 mm. The least-square mean difference was 3.46 mm (95% CI −4.94 to 11.87), confirming the non-inferiority of pregabalin monotherapy. Overall, no significant differences were observed among treatment groups, and safety outcomes were comparable.
Cluster analysis provided an exploratory stratified perspective. DPN duration was 8.68 ± 10.78 months in cluster 1, 63.52 ± 14.27 months in cluster 2, and 122.38 ± 20.69 months in cluster 3. Only cluster 1, characterized by shorter DPN duration, showed significant treatment differences. In this subgroup, combination therapy was superior to pregabalin monotherapy at week 12, producing an additional reduction of 14.79 points on the VAS pain scale compared with pregabalin alone (95% CI 4.59–24.99; p = 0.0055). Clusters 2 and 3 showed no significant differences between treatments.
Conclusions: Pregabalin monotherapy was non-inferior to pregabalin plus ALA in the overall population. However, patients with a shorter duration of diabetic peripheral neuropathy may benefit more from combination therapy, which suggests a potential role in the early stage of the DPN.
Comments: This study addresses the clinically relevant question of whether combination therapy adds benefit over pregabalin alone. Its findings are broadly consistent with the PAIN-CARE trial (Gilron I et al Pain. 2024;165:461-469), which also found no clear overall advantage of combining ALA with pregabalin compared with monotherapy. However, OPTIMUM adds a more DPN-specific perspective, including only patients with painful DPN and exploring treatment response through cluster analysis. The possible greater benefit of combination therapy in patients with shorter DPN duration is clinically interesting. Strengths include the randomized multicenter design and clinically meaningful endpoints. Limitations include the open-label design, short follow-up, conservative dosing, small cluster sample sizes and lack of correction for multiple comparisons. Therefore, the cluster findings should be considered hypothesis-generating.
Fabiana Picconi
Reference. Oh TJ, Kim SS, Lee SH, Kwon HS, Kim ES, Rhee EJ, Yoo HJ, Jang HN, Lee WJ, Kim ES, Kim SY, Koh G, Hong EG, Park TS, Won JC. Efficacy and Safety of Pregabalin and Alpha-Lipoic Acid Combination in Patients With Painful Diabetic Peripheral Neuropathy: A Randomized, Open-Label, Non-Inferiority, Phase IV Clinical Trial and Subgroup Analysis (OPTIMUM Study). Diabetes Obes Metab. 2026 Jul;28(7):6172-6183. doi: 10.1111/dom.70795. Epub 2026 Apr 29. PMID: 42056717; PMCID: PMC13243964.
