Dataset Information

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.

ABSTRACT:

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).

SUBMITTER: Gilron I

PROVIDER: S-EPMC5705061 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Gilron Ian I Tu Dongsheng D Holden Ronald R Towheed Tanveer T Vandenkerkhof Elizabeth E Milev Roumen R

JMIR research protocols 20170804 8

<h4>Background</h4>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 ...[more]

PMID: 28778847

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Project description:IntroductionFibromyalgia is a chronic disorder characterized by widespread pain and tenderness. Prior trials have demonstrated the efficacy of pregabalin for the relief of fibromyalgia symptoms, and it is approved for the treatment of fibromyalgia in the United States. However, prior to this study, there has not been a large-scale efficacy trial in patients with fibromyalgia in Japan.MethodsThis randomized, double-blind, multicenter, placebo-controlled trial was conducted at 44 centers in Japan to assess the efficacy and safety of pregabalin for the symptomatic relief of pain in fibromyalgia patients. Patients aged ≥18 years who had met the criteria for fibromyalgia were randomized to receive either pregabalin, starting at 150 mg/day and increasing to a maintenance dose of 300 or 450 mg/day, or placebo, for 15 weeks. The primary efficacy endpoint was mean pain score at final assessment. Secondary endpoints included Patient Global Impression of Change (PGIC) together with measures of sleep, physical functioning and quality of life.ResultsA total of 498 patients (89% female) were randomized to receive either pregabalin (n = 250) or placebo (n = 248). Pregabalin significantly reduced mean pain score at final assessment (difference in mean change from baseline, compared with placebo -0.44; P = 0.0046) and at every week during the study (P <0.025). Key secondary endpoints were also significantly improved with pregabalin treatment compared with placebo, including PGIC (percentage reporting symptoms "very much improved" or "much improved", 38.6% vs 26.7% with placebo; P = 0.0078); pain visual analog scale (difference in mean change from baseline, compared with placebo -6.19; P = 0.0013); Fibromyalgia Impact Questionnaire total score (-3.33; P = 0.0144); and quality of sleep score (-0.73; P <0.0001). Treatment was generally well tolerated, with somnolence and dizziness the most frequently reported adverse events.ConclusionsThis trial demonstrated that pregabalin, at doses of up to 450 mg/day, was effective for the symptomatic relief of pain in Japanese patients with fibromyalgia. Pregabalin also improved measures of sleep and functioning and was well tolerated. These data indicate that pregabalin is an effective treatment option for the relief of pain and sleep problems in Japanese patients with fibromyalgia.Trial registrationClinicalTrials.gov: NCT00830167.

Project description:BACKGROUND: Folklore remedies for pain and inflammation in rheumatoid arthritis include the application of magnets and copper to the skin. Despite the popular use of devices containing magnets or copper for this purpose, little research has been conducted to evaluate the efficacy of such treatments. OBJECTIVE: To investigate whether the practice of wearing magnetic wrists straps, or copper bracelets, offers any specific therapeutic benefit for patients with rheumatoid arthritis. DESIGN: Randomised double-blind placebo-controlled crossover trial. METHODS: 70 patients, aged 33 to 79 years and predominantly female (n = 52), with painful rheumatoid arthritis were recruited from general practices within Yorkshire. Participants were randomly allocated to wear four devices in a different order. Devices tested were: a standard (1502 to 2365 gauss) magnetic wrist strap, a demagnetised (<20 gauss) wrist strap, an attenuated (250 to 350 gauss) magnetic wrist strap, and a copper bracelet. Devices were each worn for five weeks, with treatment phases being separated by one week wash-out periods. The primary outcome measured was pain using a 100 mm visual analogue scale. Secondary pain measures were the McGill Pain Questionnaire and tender joint count. Inflammation was assessed using C-reactive protein and plasma viscosity blood tests and by swollen joint count. Physical function was assessed using the Health Assessment Questionnaire (Disability Index). Disease activity and medication use was also measured. RESULTS: 65 participants provided complete self-report outcome data for all devices, four participants provided partial data. Analysis of treatment outcomes did not reveal any statistically significant differences (P>0.05) between the four devices in terms of their effects on pain, inflammation, physical function, disease activity, or medication use. CONCLUSIONS: Wearing a magnetic wrist strap or a copper bracelet did not appear to have any meaningful therapeutic effect, beyond that of a placebo, for alleviating symptoms and combating disease activity in rheumatoid arthritis. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN51459023 ISRCTN51459023.

Project description:Background: The fibromyalgia (FM) physiopathology involves an intracortical excitability/inhibition imbalance as measured by transcranial magnetic stimulation measures (TMS). TMS measures provide an index that can help to understand how the basal neuronal plasticity state (i.e., levels of the serum neurotrophins brain-derived neurotrophic factor (BDNF) and S100-B protein) could predict the effect of therapeutic approaches on the cortical circuitries. We used an experimental paradigm to evaluate if pregabalin could be more effective than a placebo, to improve the disinhibition in the cortical circuitries in FM patients, than in healthy subjects (HS). We compared the acute intragroup effect of pregabalin with the placebo in FM patients and healthy subjects (HS) on the current silent period (CSP) and short intracortical inhibition (SICI), which were the primary outcomes. Pain scores and the pain pressure threshold (PPT) were secondary outcomes. Methods: This study included 27 women (17 FM and 10 HS), with ages ranging from 19 to 65 years. In a blinded, placebo-controlled clinical trial, participants were randomized to receive, in a cross-over manner, oral pregabalin of 150 mg or a placebo. The cortical excitability pain measures were assessed before and 90 min after receiving the medication. Results: A generalized estimating equation (GEE) model revealed that in FM, pregabalin increased the CSP by 14.34% [confidence interval (CI) 95%; 4.02 to 21.63] and the placebo reduced the CSP by 1.58% (CI 95%; -57 to 25.9) (P = 0.00). Pregabalin reduced the SICI by 8.82% (CI 95%, -26 to 46.00) and the placebo increased it by 19.56% (CI 95%; 8.10 to 59.45; P = 0.02). Pregabalin also improved the pain measures. In the treatment group, the BDNF-adjusted index was positively correlated and the serum S100-B negatively correlated with the CSP, respectively. However, in the HS, pregabalin and the placebo did not induce a statistically significant effect in either intracortical excitability or pain measures. Conclusion: These results suggest that pregabalin's effect on cortical neural networks occurs, particularly under basal neuronal hyperexcitability, because its impact on the cortical excitability and the pain measures was observed only in the FM group. This indicates that pregabalin increased the CSP to induce inhibition in specific neural networks, while it increased the SICI to improve the excitability in other neurobiological systems. Trial registration in clinicaltrials.gov Identifier: NCT02639533.

Dataset Information

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

Objective

Methods

Results

Conclusions

Trial registration

Publications

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.

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