Combination Analgesic Development for Enhanced Clinical Efficacy (CADENCE Trial): Study Protocol for a Double-Blind, Randomized, Placebo-Controlled Crossover Trial of an Alpha-Lipoic Acid - Pregabalin Combination for the Treatment of Fibromyalgia Pain.

Background: Fibromyalgia is a clinical disorder commonly presenting with chronic widespread pain as well as sleep disturbance, fatigue, depression, and cognitive dysfunction. There is an urgent need for treatment strategies that provide better pain relief and fewer adverse effects (AEs). Efforts to develop rational combinations of specific fibromyalgia treatments have demonstrated potential for measurable improvements in pain relief, quality of life, and health care utilization. More than half of fibromyalgia patients receive 2 or more analgesics but current combination use is based on limited evidence. As an early proof-of-concept project from the Canadian Institutes of Health Research-Strategy on Patient-Oriented Research Chronic Pain Network, this trial protocol is expected to advance the field by rigorously evaluating a new treatment combination for fibromyalgia.

Objective: We will test the hypothesis that analgesic combinations containing at least one nonsedating agent would be as safe but more effective than either monotherapy because of additive pain relief without increasing overall AEs. Pregabalin (PGB), a sedating anticonvulsant, is proven effective for fibromyalgia, and the antioxidant, alpha-lipoic acid (ALA), one of the only nonsedating systemic agents proven effective for neuropathic pain, is currently being evaluated in fibromyalgia. Thus, we will conduct a clinical trial to compare a PGB+ALA combination to each monotherapy for fibromyalgia.

Methods: Using a double-blind, double-dummy, crossover design, 54 adults with fibromyalgia will be randomly allocated to 1 of 6 sequences of treatment with PGB, ALA, and PGB+ALA combination. During each of 3 different treatment periods, participants will take 2 sets of capsules containing (1) ALA (or placebo) and (2) PGB (or placebo) for 31 days, followed by an 11-day taper/washout period. The primary outcome will be mean daily pain intensity (0 to 10 scale) at maximal tolerated doses (MTDs) during each period. Secondary outcomes, assessed at MTD, will include global improvement, adverse events, mood, and quality of life.

Results: This trial attained ethics approval March 6, 2017 (Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board protocol number ANAE-313-17), and recruitment is set to start in August 2017.

Conclusions: This trial will provide rigorous evidence comparing the efficacy of a PGB-ALA combination to PGB alone and ALA alone in the treatment of fibromyalgia.

Trial Registration: International Standard Randomized Controlled Trial Number ISRCTN14939460; https://www.isrctn.com/ ISRCTN1493946 (Archived by WebCite at http://www.webcitation.org/6sFqAjxkt).