The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act

Abstract

Rationale Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health. Objectives This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act. Results LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks. Conclusions LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.

Abuse Potential of Lemborexant, a Dual Orexin Receptor Antagonist, Compared With Zolpidem and Suvorexant in Recreational Sedative Users

“…In studies with rhesus monkeys, no active self-administration or gross behavioral changes that suppressed lever pressing were observed during the self-administration period with LEM, and LEM had no reinforcing effect on intravenous self-administration. In a drug discrimination study in rats, LEM, at doses up to 1000 mg/kg, did not cross-generalize to the ZOL (3 mg/kg) training stimulus, whereas SUV demonstrated partial generalization to ZOL as previously reported 2,7,9 …”

“…When adjusted by duration of exposure, overall incidence and rates (subjects per patient-year) of TEAEs related to abuse potential were 0.2, 0.3, and 0.4 for PBO, LEM5, and LEM10, respectively. When adjusted by duration of exposure, the overall rates (events per patient-year) of TEAEs related to abuse potential were 0.3, 0.5, and 0.6 for PBO, LEM5, and LEM10, respectively, with overall rates higher for LEM5 and LEM10 compared with PBO 7 …”

“…In addition, LEM tablets are not readily manipulated for the purposes of intravenous administration (data on file) owing to limited solubility in water. In a pooled analysis of the 2 pivotal phase 3 studies, there was no evidence of abuse or diversion of study medication during clinical development 4,6,7 …”

“…In a pooled analysis of the 2 pivotal phase 3 studies, there was no evidence of abuse or diversion of study medication during clinical development. 4,6,7 In nonclinical testing, LEM was not associated with physical dependence, reinforcing effects, or cross-generalization to zolpidem (ZOL). 7,8 No evidence of physical dependence was observed in Sprague-Dawley rats following 28-day dosing with LEM at doses of up to 600 mg/kg per day.…”

“…4,6,7 In nonclinical testing, LEM was not associated with physical dependence, reinforcing effects, or cross-generalization to zolpidem (ZOL). 7,8 No evidence of physical dependence was observed in Sprague-Dawley rats following 28-day dosing with LEM at doses of up to 600 mg/kg per day. In studies with rhesus monkeys, no active self-administration or gross behavioral changes that suppressed lever pressing were observed during the self-administration period with LEM, and LEM had no reinforcing effect on intravenous selfadministration.…”