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Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review


Health-related quality of life of patients with epilepsy is heavily influenced by antiepileptic drug (AED) tolerability. However, an accepted method for precise assessment of AED-induced adverse events (AEs) has not yet been established. Assessment of tolerability and of the frequency of predefined AEs among drug-resistant epilepsy patients through an analysis of placebo-treated patients from randomized controlled studies (RCTs) performed in patients with partial onset epilepsies (POS) and evaluation of factors which may influence the occurrence of AEs in these patients are the objectives of this study. We searched all double-blind, placebo-controlled trials investigating any AED on adult patients with POS and extracted both for patients treated with placebo and for those treated with the active drug, number of patients, number of responders, number of patients withdrawing because of AEs, number of patients with AEs, and number of patients with 11 predefined AEs. We also explored the effect of multiple factors on AEs reporting. Seventy-nine RCTs were included in our study with 12,594 patients, 6,793 of whom randomized to placebo. In placebo-treated patients, overall responder rate was 15.2 %, proportion of placebo-treated patients withdrawing because of AEs was 3.9 %, and proportion of patients with AE was 60.3 %. The four most frequently reported AEs were headache (12.4 %) somnolence (8.6 %), dizziness (8.2 %), and fatigue (7.9 %). Several factors were found to influence these outcomes. Several factors influence AEs’ appearance in RCTs. Among the most important, we found the expectations of patients and doctors and their attitudes on the positive or negative effect of a drug.

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We are grateful to Valentina Franco for her contribution in doing bibliographic search. We also thank Andrea Messori and Dario Maratea for their help in performing statistical analyses. The authors received no funding for this study. FG is supported by a grant by “Ente Cassa di Risparmio di Firenze”.

Conflicts of interest

GZ has received speaker’s or consultancy fees from EISAI, Jansen-Cilag, Sanofi-Aventis, and UCB Pharma. AV received a grant by Viropharm. FG, MC and GL report no disclosures.

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Correspondence to Gaetano Zaccara.

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Zaccara, G., Giovannelli, F., Cincotta, M. et al. Adverse events of placebo-treated, drug-resistant, focal epileptic patients in randomized controlled trials: a systematic review. J Neurol 262, 501–515 (2015).

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  • Antiepileptic drugs
  • Adverse effects
  • Side effects
  • Meta-regression
  • Placebo effects
  • Nocebo effects