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

Abstract

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.

Fibromyalgia: one year in review 2024

“…A randomised trial investigated efficacy and safety of an alpha-lipoic acid (ALA)-PGB combination. However, this association was not supported by the results of this study (28). Also, an integration of nutraceuticals to drug therapy may show some benefits.…”

“…• Cyclobenzaprine represents an area of interest, especially in its sublingual formulation (TNX-102 SL) (27). • Nutraceuticals and drugs combinations can apport some benefits in treatment strategy (28,29).…”

PRECISE trial (Pain RElief Combination Intervention StratEgies): protocol for the clinical trial of a pregabalin–melatonin combination for fibromyalgia

“…30 41 42 Safety and efficacy of PGB have been evaluated in dozens of high-quality RCTs 31 including studies from our group. [43][44][45][46] A recent meta-analysis of PGB reported on 19 RCTs involving 7003 participants with postherpetic neuralgia, DPN, central neuropathic pain, and fibromyalgia. 31 Relevant to this proposal, review of sleep outcomes in PGB trials support a positive effect of PGB on disturbed sleep through a direct positive effect on sleep maintenance.…”