title: Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant.
abstract: Suvorexant (Belsomra®) is a dual orexin receptor antagonist approved for the treatment of insomnia. Because of its pharmacology within the central nervous system, intended therapeutic indication, and first-in-class status, an assessment of suvorexant abuse liability potential was required prior to marketing approval. The nonclinical abuse liability potential studies for suvorexant included: 1) rat drug-dependence model to assess physical dependence following abrupt cessation; 2) rat drug-discrimination model to examine the potential similarity of the interoceptive or subjective effects of suvorexant to those elicited by zolpidem and morphine; 3) self-administration model to assess the relative reinforcing efficacy of suvorexant in rhesus monkeys conditioned to self-administer methohexital. No significant signs of spontaneous drug withdrawal or 'discontinuation syndrome' were observed in rats following abrupt discontinuation of suvorexant. Suvorexant did not elicit complete cross-generalization to either a zolpidem or morphine training/reference stimuli in rats, and suvorexant was devoid of behavioral evidence of positive reinforcing efficacy in monkeys. These nonclinical findings suggested that suvorexant will have low abuse potential in humans. In the final regulatory risk assessment, suvorexant was placed into Schedule IV, likely due to its first-in-class status, its sedative properties, and the outcome of the clinical abuse potential assessment.
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA. Electronic address: stephanie_born@merck.com.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Born
authors.affiliation: MPI Research, Inc., Mattawan, MI, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Gauvin
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Briscoe
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008253:Macaca mulatta; D000068796:Orexin Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D000068776:Sleep Aids, Pharmaceutical / Q000494:pharmacology*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy; D019966:Substance-Related Disorders / Q000209:etiology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001381:Azepines; D006993:Hypnotics and Sedatives; D000068796:Orexin Receptor Antagonists; D000068776:Sleep Aids, Pharmaceutical; D014230:Triazoles; C551624:suvorexant
keywords: Abuse potential; Drug dependence; Drug discrimination; MK-4305; Methods; Orexin receptor antagonist; Preclinical drug development; Self-administration; Suvorexant; Withdrawal