In randomized controlled trials (RCTs), determining the appropriate patient sample size is necessary to avoid exposing patients to potential harm while also demonstrating a true treatment effect. However, researchers have found that, overall, other research design and methodological criteria should be considered. This is according to research published in The Journal of Pain.
An initial secondary data analysis of 23 articles, published between 1999 and 2013, was conducted. In the current study, researchers used mixed-effects metaregression to test the significance of the relationship between average pain intensity (API) standardized effect sizes and worst pain intensity (WPI) standardized effect sizes. Additionally, quadratic models were used to regress API and WPI standardized effect sizes.
Current analyses show that both API and WPI standardized effect sizes increased slightly over a short time; on average, however, these slopes decreased for every additional year after 1999. “The results of these analyses are consistent with previous reports and demonstrate that the average benefit of efficacious analgesic medications shown in recent RCTs is modest,” the researchers noted.
Investigators also noted that antidepressant clinical trials share several methodologic characteristics with analgesic RCTs that may contribute to decreased assay sensitivity, including subjective outcomes, considerable placebo group responses, and substantial missing data.
“It is crucial to plan these trials with realistic treatment effect estimates,” the researchers wrote, adding that in order to detect standardized effect sizes of 0.30 with 80% power in a parallel group trial, at least 175 patients per group would need to be randomly assigned.
Whereas size matters when determining the number of participants for adequate statistical power, it is important to consider other valid strategies for increasing the efficacy of RCTs.
In neuropathic pain RCTs, for example, placebo groups experience a longer time to onset of pain reduction, consistent with the observation that longer trials tend to result in progressive increases in placebo response. Shorter study length may be more effective in identifying meaningful treatment effects.
Researchers can also minimize placebo effects by “neutrally describing” the treatment to not create participant expectations and by limiting interactions between study participants and staff.
Eligibility criteria also appear to increase assay sensitivity, potentially resulting in “increased comfort” in using “somewhat higher [standardized effect sizes] in sample size determination,” according to the authors. Independent validation of study participants in terms of eligibility criteria may also decrease placebo group responses while potentially increasing the response to effective treatments. Additionally, according to the authors, training participants to more accurately report pain intensity should decrease placebo responses and the variability of outcome assessments without also decreasing treatment group responses.
“Although these emerging techniques are largely untested in clinical trials for pain treatments, many of them have been used in other areas of medicine and have been recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT),” the researchers concluded. “Sample size does matter for ensuring adequate assay sensitivity, but it is not everything and other research design and methodological characteristics of RCTs should be considered.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Smith SM, Fava M, Jensen MP, et al. Size does matter, but it isn’t everything: the challenge of modest treatment effects in chronic pain clinical trials [published online September 30, 2019]. J Pain. doi: 10.1016/j.jpain.2019.09.008