Nocebo effects in multiple sclerosis trials: a meta-analysis.
OBJECTIVE
To estimate the incidence and severity of nocebo responses in trials of symptomatic treatments (STs) and disease-modifying treatments (DMTs) for multiple sclerosis (MS).


METHODS
We conducted a systematic Medline search for all randomised, placebo-controlled MS trials published between 1989 and 2009. Meta-analysis of the incidence of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited adverse events. Nocebo severity was calculated from the percentage of placebo-treated patients that dropped-out due to drug-related adverse events.


RESULTS
Data were extracted from 56 DMT and 44 ST eligible trials. The pooled incidence of nocebo responses was 74.4% (95% CI: 69.92-88.30) in DMT trials and 25.3% (95% CI: 15.24-36.90) in ST trials and was significantly higher in the former (p < 0.0001). The pooled nocebo severity was 2.1% (95% CI: 1.6-2.67) in DMT and 2.34% (95% CI: 1.54-3.29) in ST trials. Meta-regression analysis revealed a higher nocebo incidence in parallel design ST studies compared to crossover ones (p = 0.013) and a higher nocebo severity in phase II ST studies compared to phase III ones (p = 0.0001). Nocebo severity in DMT trials exhibited an association with the year of study publication (p = 0.011) and the frequency of drug administration (p = 0.0082).


CONCLUSIONS
Nocebo responses in MS trials are substantial and appear to have increased significantly in recent years with important implications for both trial design and clinical practice. Furthermore, nocebo responses exhibit an association with medication and trial-related factors.
Department of Neurology, Athens Naval Hospital, Athens, Greece.
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Papadopoulos
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Mitsikostas
D000328:Adult; D016009:Chi-Square Distribution; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D019317:Evidence-Based Medicine; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy*; D010352:Patient Dropouts; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
D007155:Immunologic Factors