title: Tolerability of new antiepileptic drugs: a network meta-analysis.
abstract: OBJECTIVE
  The objective of this study was to perform a comparative assessment of tolerability of all licensed new antiepileptic drugs (AEDs) through a network meta-analysis (NMA) including all placebo-controlled double-blind clinical trials (RCTs) in all conditions in which these drugs have been tested.
  
  
  METHODS
  NMA with a frequentist approach was used to compare proportions of patients withdrawing because of adverse events (AEs). Analyses were conducted for all therapeutic doses pooled and specifically for high therapeutic doses. Patients treated with non-therapeutic doses of each drug were excluded.
  
  
  RESULTS
  A total of 195 RCTs were included in the current analysis, comprising a total of 28,013 patients treated with AEDs and 17,908 patients treated with placebo. RCTs included in the analysis were 8 for brivaracetam; 5 for eslicarbazepine; 22 for gabapentin; 7 for lacosamide; 14 for levetiracetam; 14 for lamotrigine; 6 for oxcarbazepine; 9 for perampanel; 50 for pregabalin; 5 for tiagabine; 36 for topiramate; 7 for zonisamide; 4 for gabapentin-extended formulation (ER); 2 each for levetiracetam-ER, lamotrigine-ER, and topiramate-ER; and 1 each for oxcarbazepine-ER and pregabalin-ER. Brivaracetam, gabapentin, gabapentin-ER, and levetiracetam had a significantly lower withdrawal rate compared to several other AEDs, while eslicarbazepine, lacosamide, oxcarbazepine, and topiramate had a higher withdrawal rate. Perampanel, lamotrigine, pregabalin, tiagabine, and zonisamide showed an intermediate pattern of tolerability. Additional analysis has been conducted through selection of highly recommended doses for each drug. This analysis has roughly confirmed results of head to head comparisons of the all-dose analysis, with some exceptions. A further analysis has been conducted after exclusion of RCTs in which patients were allocated to the therapeutic dose of the experimental drug without titration, and it failed to show clinically important differences.
  
  
  CONCLUSIONS
  Relevant differences in short-term tolerability of AEDs have been observed between AEDs. Brivaracetam, gabapentin, and levetiracetam show the best tolerability profile while other AEDs are at higher risk for intolerable adverse effects.
authors.affiliation: Department of Medicine, Unit of Neurology, Florence Health Authority, Florence, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zaccara
authors.affiliation: Department of Medicine, Unit of Neurology, Florence Health Authority, Florence, Italy. fabio.giovannelli@unifi.it.|Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), University of Florence, Florence, Italy. fabio.giovannelli@unifi.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Giovannelli
authors.affiliation: Section of Neurology, Pisa University Hospital, Pisa, Italy.
authors.forename: Filippo Sean
authors.initials: FS
authors.lastname: Giorgi
authors.affiliation: Department of Internal Medicine and Therapeutics, Division of Clinical and Experimental Pharmacology, University of Pavia, Pavia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Franco
authors.affiliation: Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gasparini
authors.affiliation: School of Clinical Science, Bristol Heart Institute, University of Bristol, Bristol, UK.
authors.forename: Umberto
authors.initials: U
authors.lastname: Benedetto
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D006801:Humans; D016032:Randomized Controlled Trials as Topic
chemical_list: D000927:Anticonvulsants
keywords: Adverse effects; Brivaracetam; Eslicarbazepine; Lacosamide; Meta-analysis; Network meta-analysis; Perampanel; Tolerability of antiepileptic drugs