Nocebo in motor neuron disease: systematic review and meta-analysis of placebo-controlled clinical trials

Introduction: Nocebo is very prevalent among neurological disorders, resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in placebo-controlled randomised clinical trials (RCTs) for motor neuron disease (MND). Methods: After a systematic literature search for RCTs for MND pharmacotherapy treatments, we assessed the number of discontinuations because of placebo intolerance. Results: Data were extracted from 12 RCTs fulfilling our search criteria. Approximately eight in 10 placebo-treated patients (78.3%, 95% CI 74.3-82.0%) reported at least one AE and approximately one in 12 placebo-treated patients discontinued placebo treatment because of AEs (8.4%, 95% CI 6.7-10.4%). All patients participating in the MND trials reported similar AEs independently of the study arm to which they belonged. Conclusion: Our study indicates significant nocebo in trials for MND treatment, adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial design.