Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily antiepileptic that is converted to eslicarbazepine after oral administration. ESL was approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary generalization. ESL is not approved in the US. Adverse events such as dizziness and somnolence reported in phase 1 3 studies suggest that ESL has detectable central nervous system (CNS) effects in addition to its antiepileptic effects. The aim of this study was to evaluate the abuse potential of ESL compared with alprazolam (ALZ) and placebo (PBO) in recreational CNS sedative users.Methods: In this single dose, randomized, double-blind, PBO- and active-controlled crossover study, 44 healthy recreational sedative users received single oral doses of ESL (800mg, 1600 mg, 2000 mg, and 2400 mg), ALZ (1.5 mg and 3.0 mg) or PBO. Eligible subjects were required to pass a qualification session to ensure they could distinguish and like the effects of 2 mg ALZ. In the main study, subjective effects, including at the moment visual analog scales (VAS) e.g., Drug Liking (primary endpoint), and Addiction Research Center Inventory (ARCI) Morphine-Benzedrine Group (MBG, euphoria), Pentobarbtial Chlorpromazine Alcohol Group (PCAG, sedation) and Lysergic Acid Diethylamide (LSD, dysphoria) scales were evaluated at multiple time points up to 24 hours post dose. Cognitive effects were evaluated using choice reaction time (CRT), divided attention (DAT) and the Hopkins Verbal Learning Task- Revised tests.Results: Peak Drug Liking score was significantly higher for both doses of ALZ versus PBO (p<0.05), validating the study. All doses of ESL demonstrated significantly lower peak Drug Liking scores compared with ALZ (p<0.0001 for both ALZ doses). Peak Drug Liking score for 800 mg ESL (therapeutic dose) was similar to PBO (Least Square (LS) mean difference: 3.6, p=0.19). At the 3 supratherapeutic doses (1600 mg, 2000 mg and 2400 mg), ESL showed greater Drug Liking scores compared with PBO; however, the magnitude of the effect was minimal (LS mean difference: 9.3 13.3 out of 100). Similarly, ESL showed significantly lower effects compared with both ALZ doses on most secondary subjective measures (ie, Good Effects and High VAS, ARCI-MBG, Take Drug Again and Overall Drug Liking VAS and ARCI-PCAG). In general, there was a plateau in the dose-response at the higher ESL doses. Although, significant differences were observed for ESL compared with PBO on some specific CRT and DAT endpoints (ie, reaction time, manual tracking, hit latency), ALZ demonstrated significant and dose-dependent impairment on the majority of cognitive endpoints when compared with PBO and ESL.Conclusions: Drug Liking scores and the majority of secondary endpoints, including assessments of positive and sedative effects and cognitive function were significantly lower with ESL than with ALZ. This study demonstrated that single doses of ESL may have a lower potential for abuse than ALZ in recreational sedative users.