title: Adverse events, placebo and nocebo effects in placebo-treated paediatric patients with refractory focal epilepsies. Analysis of double-blind studies.
abstract: OBJECTIVE
  Assessment of placebo and nocebo effects and evaluation of background incidence of some predefined adverse effects (AEs) of antiepileptic drugs (AEDs) in placebo-treated paediatric patients recruited in randomized controlled studies (RCTs) of refractory focal epilepsies.
  
  
  METHODS
  We searched all add-on, double-blind, placebo-controlled trials investigating any AED in paediatric patients with focal epilepsies and extracted both for patients treated with placebo and for those treated with the active drug, number of patients, number of responders (≥50% reduction of seizure frequency) number of patients withdrawing because of AEs, number of patients with AEs, and number of patients with 11 predefined AEs. The association between placebo and active treatment AEs was also explored.
  
  
  RESULTS
  Seven RCTs were included in our study with a total of 668 children treated with the experimental drug and 634 with placebo. In placebo-treated patients, overall responder rate was 19.7% [(95% CI), (16.0, 23.4)], proportion of placebo-treated patients withdrawing because of AEs was 3.6% (2.1, 5.1%), and proportions of patients with any AE was 81.3% (68.5, 94.1%). The three most frequently reported AEs were headache (PR=11.4%, 6.4,16.3%) somnolence (PR=9.6%, 4.9, 14.3%), and ataxia (PR=4.6, -1.1, 10.2). A significant correlation between placebo-treated patients and those treated with the active drug was found for the outcome measure any AE and the AEs somnolence, headache and fatigue.
  
  
  CONCLUSIONS
  Both placebo and nocebo effects assessed in this paediatric population did not differ from findings reported in adults. This is in partial contrast to what has been previously reported and with observations in other diseases. Also specific AEs, which are at least in part, caused by the background treatment, failed to show significant differences from what previously observed in adult RCTs.
authors.affiliation: Unit of Neurology, Department of Medicine, Florence Health Authority, Firenze, Italy. Electronic address: gaetano.zaccara@asf.toscana.it.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zaccara
authors.affiliation: Unit of Neurology, Department of Medicine, Florence Health Authority, Firenze, Italy; Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Firenze, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Giovannelli
authors.affiliation: Clinical and Experimental Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Franco
authors.affiliation: Unit of Neurology, Department of Medicine, Florence Health Authority, Firenze, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cincotta
authors.affiliation: Unit of Neurology, Department of Medicine, Florence Health Authority, Firenze, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Tramacere
authors.affiliation: Department of Pediatrics, University of Perugia, Perugia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Verrotti
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use; D002648:Child; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000188:drug therapy* / Q000523:psychology*; D006801:Humans; D064786:Nocebo Effect; D016032:Randomized Controlled Trials as Topic
chemical_list: D000927:Anticonvulsants
keywords: Adverse effects; Antiepileptic drugs; Epilepsy; Nocebo effects; Placebo effects; Side effects