LONG-TERM EFFECTS AND TOLERANCE OF LEMVOREXANT

Abstract Background Insomnia is not only a night-time sleep problem, but also a daytime symptom, increasing the risk of fatigue, general malaise, mood disorders, agitation, cognitive dysfunction, gastrointestinal disorders, headache, depression and other psychiatric disorders in severe cases, traffic accidents and industrial accidents. Lemborexant (LEM), which was newly developed in 2020, is expected to be a highly useful sleep medication with few side effects and a low risk of abuse. However, there are few reports on long-term administration of LEM. Furthermore, there are no reports on the long-term effects of converting GABA-BZ receptor agonists to LEM, nor are there any reports comparing successful and unsuccessful conversion. Objective This study aimed to examine the patient factors associated with successful conversion to lemborexant (LEM) and evaluate its long-term use, focusing on hypnotic effects and tolerance. Methods Patients (n=53) taking benzodiazepines (BZD) and non-BZD (Z) drugs were divided into two those prescribed LEM (modified group; n=31) and those with no regime change (non- modified group; n=22) and evaluated over 48 weeks. Results Athens Insomnia Scale scores or diazepam equivalence did not significantly differ between two groups. No serious adverse effects were observed in the LEM conversion group; in the modified group, 23 patients who continued taking LEM for 48 weeks were classified into the continuation group and 8 patients who discontinued LEM within 48 weeks were classified into the discontinuation group. No differences in demographic characteristics were observed between the two subgroups. The continuation group had no significant difference in the LEM dose after 12 and 48 weeks. Discussion & Conclusions After prolonged continuous use of BZD and Z drugs, the body gradually develops tolerance to their effects. Tolerance reduces the drug's efficacy and requires higher doses or multiple doses of BZD and Z drugs. Although a clinical trial, no resistance was identified in a 48- week study of LEM, and drug resistance in healthcare settings is rarely reported. In this study, there was no significant difference in LEM doses after 12 and 48 weeks. Therefore, it is considered that resistance does not occur after 48 weeks of continuous LEM administration. LEM may also be a potential alternative to BZD and Z drugs, as the conversion to LEM did not worsen sleep or cause significant side-effects. LEM can potentially be substituted for BZD and Z drugs without worsening sleep or causing notable adverse effects. The ease of transitioning from BZD and Z drugs to LEM varied across individuals but was not specifically characterized. LEM maintained its hypnotic effect and did not lead to tolerance over 48 weeks. The fact that no serious side effects occurred suggests that LEM may be an alternative for patients on long-term BZD and Z drugs, as it is a promising replacement drug. However, factors other than drugs may be involved in the improvement of sleep disturbances, and further studies are needed to investigate the direct effects of LEM. References American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine., 2014:726-731. Itani O, Jike M, Watanabe N, et al. Short sleep duration and health outcomes: a systematic review, meta- analysis, and metaregression. Sleep Med 2017; 32: 246–256. Yardley J, Kä rppä M, Inoue Y, et al. Long-term effectiveness and safety of lemborexant in adults with insomnia disorder: results from a phase 3 randomized clinical trial. Sleep Med. 2021;80:333-342. Burman RJ, Rosch RE, Wilmshurst JM, et al. Why won't it stop? The dynamics of benzodiazepine resistance in status epilepticus. Nat Rev Neurol. 2022 Jul;18(7):428-441.