Background Pregabalin is a drug used to treat neuropathic pain, and its use has increased substantially since 2007. Early trials found a strong treatment effect on pain for post-herpetic neuralgia and diabetic neuropathy. However more recent studies have failed to replicate these results. Methods This meta-epidemiological study aimed to assess change in the reported effectiveness of pregabalin in neuropathic pain trials over time, and if a change is present, determine any associated factors. Data sources We performed electronic searches for published trials in Medline, Embase and Cochrane Central Register of Controlled Trials databases; and unpublished trials on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australia New Zealand Clinical Trials Registry with no restrictions. Study selection We included randomized, placebo-controlled trials of pregabalin for treatment of neuropathic pain in adults. Data extraction and synthesis Two authors independently extracted study data: sample size and mean baseline, end-point and change in pain scores with measures of variance, trial end year, publication year, clinical indication, funding source, country of study, treatment duration, treatment dose, mean age and percentage male. Primary outcome measure We defined treatment effect as the mean difference in pain scores between pregabalin and placebo groups at trial end-point and assessed for change over time using a random-effects meta-regression, adjusted for sample size, indication, treatment duration (weeks) and treatment dose. Results We included 38 randomized published trials (9038 participants) and found that between 2003 and 2020, the reported treatment effect of pregabalin decreased by 0.4 points (95% CI: 0.3 to 0.6; p<0.001) on an 11-point pain scale per 5-year interval, from 1.3 points (95% CI: 1.0 to 1.5) in trials conducted in 2001–2005, to 0.3 (95% CI: -0.1 to 0.7) in trials conducted in 2016–2020. The reported treatment effect was lower than the minimal clinically important difference (MCID) of 1.7 points across all time periods, doses and most indications and was not found to be associated with study characteristics. Conclusions The reported treatment effect or analgesic efficacy of pregabalin from clinical trials has diminished over time. Clinical recommendations may need to be re-evaluated to account for recent evidence and to consider whether pregabalin therapy is indicated.
Background Before and after studies allow for the investigation of population-level health interventions and are a valuable study design in situations where randomisation is not feasible. The before and after study design involves measuring an outcome both before and after an intervention and comparing the outcome rates in both time periods to determine the effectiveness of the intervention. These studies do not involve a contemporaneous control group and must therefore take into account any underlying secular trends in order to separate the effect of the intervention from any pre-existing trend. Neglecting this important step can lead to spurious results.Methods To illustrate the importance of accounting for underlying trends, we performed a before and after study assessing 30-day mortality in hip fracture patients without any actual intervention, and instead designated an arbitrarily-chosen time-point as our ‘intervention’. We did this to ensure that we were basing our results exclusively on the underlying trend throughout the studied period and also to enable us to show that even an intervention of nothing may be spuriously interpreted to have an effect if the before and after study is incorrectly analysed. Results We found a secular trend in our data showing improving 30-day mortality in hip fracture patients in our institution. We then demonstrated that disregarding this underlying trend showed that our intervention of nothing ‘resulted’ in a significant decrease in mortality, from 6.7% in the ‘before’ period to 3.1% in the ‘after’ period (p<0.0008). This apparent impact on mortality disappeared when we accounted for the underlying trend in our analysis (IRR of 0.75, 95% CI 0.32 – 1.78; p=0.5). In the context of declining 30-day mortality following hip fracture, failure to consider the existing underlying trend lead us to believe that it was our ‘intervention’ that ‘caused’ the decrease in mortality in the ’after’ period compared to the ‘before’ period when our results clearly show that mortality was decreasing irrespective of any intervention.Conclusion Our study highlights the importance of appropriate measurement and consideration of underlying trends when analysing data from before and after studies and illustrates what can happen should researchers neglect this important step.
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