Do we need a new procedure for the assessment of adverse events in anti-migraine clinical trials?

The large number of randomized controlled clinical trials on migraine have drawn the attention of some authors to the need to improve the design of such trials. In particular, adequate methodology is a critical issue in their planning and execution, as different methodological approaches can translate into different results. The side-effects observed in both the active medication arm and the placebo arm - considering anti-migraine randomized clinical trials - are often influenced by non specific factors. This issue can be quantified by using a systematic review approach to study the rates of adverse events reported in the placebo arms of clinical trials. Such a study requires increased standardization of the methods used to collect adverse data in clinical trials. This focused review article provides a critical re-analysis of the results obtained, by our group, in a recent systematic review of adverse events reported in the placebo groups of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants [Amanzio et al., 2009]. We consider the need for caution in interpreting side-effect profiles of the different placebo groups. In particular, since the side-effects observed in both the active medication and placebo arms of randomized clinical trials are often influenced by patients' and investigators' expectations, the nocebo phenomenon may help to understand the occurrence of (adverse) non-specific side effects observed in these groups. We also discuss the importance of evaluating the role of contributing factors in the results obtained, such as the need for the examiner to be blind to the expected side-effects of the drug being evaluated and a better rationalization of informed consent in order to avoid the occurrence of negative expectations in patients, aimed at preventing negative expectation effects among both investigators and patients. Currently, there is one patented design for investigating reductions in the placebo effect in controlled clinical trials. This paper discusses how these ideas may be helpful in the assessment of adverse events in active and placebo groups.