Combination analgesic development for enhanced clinical efficacy (the CADENCE trial): a double-blind, controlled trial of an alpha-lipoic acid–pregabalin combination for fibromyalgia pain

Drug therapy for fibromyalgia is limited by incomplete efficacy and dose-limiting adverse effects (AEs). Combining agents with complementary analgesic mechanisms-and differing AE profiles-could provide added benefits. We assessed an alpha-lipoic acid (ALA)-pregabalin combination with a randomized, double-blind, 3-period crossover design. Participants received maximally tolerated doses of ALA, pregabalin, and ALA-pregabalin combination for 6 weeks. The primary outcome was daily pain (0-10); secondary outcomes included Fibromyalgia Impact Questionnaire, SF-36 survey, Medical Outcomes Study Sleep Scale, Beck Depression Inventory (BDI-II), adverse events, and other measures. The primary outcome of daily pain (0-10) during ALA (4.9), pregabalin (4.6), and combination (4.5) was not significantly different ( P = 0.54). There were no significant differences between combination and each monotherapy for any secondary outcomes, although combination and pregabalin were both superior to ALA for measures of mood and sleep. Alpha-lipoic acid and pregabalin maximal tolerated doses were similar during combination and monotherapy, and AEs were not frequent with combination therapy. These results do not support any additive benefit of combining ALA with pregabalin for fibromyalgia. The observation of similarly reached maximal tolerated drug doses of these 2 agents (which have differing side-effect profiles) during combination and monotherapy-without increased side effects-provides support for future development of potentially more beneficial combinations with complementary mechanisms and nonoverlapping side effects.