A comparative meta-analysis of the efficacy and tolerability of pregabalin versus placebo for the management of fibromyalgia in adults

Background Fibromyalgia (FM) is a multifactorial condition of unknown aetiology. Although it is primarily characterised by chronic diffuse pain, it is also associated with a number of symptoms including: cognitive impairment, sleep problems, fatigue, anxiety and depression. FM patients frequently report of a reduced quality of life, and this often due to the inherent disability associated with these symptoms. Although there is currently no curative treatment for FM, the anti-convulsant drug pregabalin is one of a number of interventions employed to manage this condition. Objectives To assess the efficacy and tolerability of pregabalin for the management of FM in adults compared to a placebo. Search methods Electronic searches were performed using the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2017), MEDLINE accessed through PubMed (1966 to December 2016), and www.clinicaltrials. gov (website of the US National Institute of Health) to December 2016 for unpublished clinical trials. Additionally, searches were performed on the bibliographies of existing reviews to retrieve relevant articles. Selection criteria The studies included in this review investigated the efficacy and tolerability of pregabalin for the management of FM in adults. They were all full journal publications of randomised controlled trials (RCTs) which employed a double-blind experimental procedure and lasted for eight weeks or longer. Data collection and analysis The titles and abstracts of studies were individually scrutinised to determine their eligibility for inclusion. Studies which obviously did not satisfy the basic inclusion criteria (i.e. double-blind, RCT) were excluded outright. Full copies of potential studies were obtained and read in-depth to ascertain their eligibility for inclusion. The risk of bias was determined for each study using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions [Higgins and Green 2011]. Data was then extracted and double-checked for accuracy prior to entry into Review Manager 5 [RevMan, 2014] Main results This review includes eight studies of both classical and enriched enrolment randomised withdrawal (EERW) design. Six studies of classical design (3812 participants) were included in this review. Participants were randomised at the start of the study to receive either: 150, 300, 450 or 600 mg daily pregabalin or placebo for 8 to 13 weeks. All studies used a placebo as the comparator. The studies had a low risk of bias with the exception of the last observation carried forward (LOCF) imputation for missing data which can overestimate or underestimate the magnitude of treatment effect. With regards to pain outcomes, pregabalin was more effective than placebo in reducing mean pain scores (SMD: -0.26; 95% CI; -0.34 to -0.19; P = <0.00001), as well as achieving both ≥30% (RR: 1.38; 95% CI; 1.23 to 1.55; P = 0.00001) and ≥50% reductions in pain intensity (RR: 1.61; 95% CI; 1.35 to 1.93; P = 0.00001); the numbers needed to treat for an additional beneficial (NNTB) outcome by pregabalin over placebo was ≈9 and ≈12 respectively. The overall effect of pregabalin in producing improvements to patient global impression of change (PGIC) was statistically significant (RR: 1.40; 95% CI; 1.25 to 1.58; P = 0.00001); the NNTB by pregabalin over placebo was ≈9. Pregabalin did not substantially reduce fatigue (SMD: -0.17; 95% CI; -0.25 to -0.09; P = <0.0001), anxiety (SMD: -0.13; 95% CI; -0.21 to -0.06; P = <0.0007), depression (SMD: -0.10; 95% CI; -0.18 to -0.02; P=0.01) or health related quality of life (SMD: 0.17; 95% CI; -0.26 to -0.09; P = <0.0001), but produced modest improvements to symptoms of sleep problems (SMD: -0.34; 95% CI; -0.42 to -0.27; P = <0.0001). The incidence of participant withdrawal was higher with pregabalin than placebo (RR: 1.75; 95% CI; 1.42 to 2.15; P = 0.00001); the numbers needed for an additional harmful outcome (NNTH) by pregabalin over placebo was ≈12. Somnolence and dizziness are two of the most common side-effect of pregabalin; both occurred more frequently following treatment with pregabalin as opposed to placebo; (RR: 3.89; 95% CI; 3.16 to 4.78; P = 0.00001) for dizziness and (RR: 3.42; 95% CI; 2.71 to 4.32; P = 0.00001) for somnolence. The NNTH by pregabalin over placebo was ≈3 for dizziness, and ≈7 for somnolence respectively. With regards to the incidence of serious adverse effects, there was no significant difference between pregabalin and placebo (RR: 1.06; 95% CI; 0.73 to 1.53; P = 0.31). Two studies (687 participants) of EERW design were included in this review. They were deemed as having a low risk of bias as there was no missing data and no imputation. The maintenance of therapeutic effect (MTR) was used as the primary efficacy outcome in this review. Of the participants whom entered the double-blind treatment phase, 39.8% of participants receiving pregabalin, and 20.9% of participants receiving placebo achieved MTR. The overall effect of pregabalin on achieving MTR was statistically significant (RR: 1.9; 95% CI; 1.5 to 2.4; P = 0.00001) and the NNTB by pregabalin over placebo was ≈5. As with the studies of classical design, the incidence of adverse effects was higher with pregabalin than placebo. 64.9% of participants experienced at least one adverse effect following treatment with pregabalin, as opposed to 48.7% of those receiving placebo. The overall effect of pregabalin in causing adverse effects was statistically significant (RR: 1.3; 95% CI; 1.2 to 1.5; P = 0.000028), and the NNTH by pregabalin over placebo was ≈6. Author’s conclusions Pregabalin 300 to 600 mg daily has the potential to achieve substantial improvements the symptoms of FM, but this is generally observed in a minority of participants. Although its use can yield small improvements to the symptoms of pain and sleep problems, it is generally less effective in addressing the other symptoms of FM (i.e. fatigue, anxiety). Although the use of pregabalin is not associated with any serious adverse effects, participants typically experience adverse effects (i.e. somnolence and dizziness) more frequently than in the placebo group. Furthermore, the incidence of participant withdrawal due to adverse effects was higher in the pregabalin group. Generally speaking these observations did not follow a dose response relationship.