Lemborexant as a safer alternative to GABA agents for long-term treatment of insomnia

Commonly prescribed insomnia medications, such as benzodiazepines and ‘Z-drugs’, which target the gamma-aminobutyric acid (GABA) receptors, are associated with unwanted consequences including next-day impairment, dependence, confusion and falls, especially in older people. Hence, there is an unmet need for safe and effective agents for long-term management of insomnia. In an interview with MIMS Doctor, Professor Motohiro Ozone of the Department of Neuropsychiatry, Kurume University School of Medicine, Fukuoka, Japan, discussed benefits of using the dual orexin receptor antagonist (DORA), lemborexant (Dayvigo®, Eisai), over GABA agents in adults with insomnia.

Insomnia management in clinical practice
Insomnia has a significant impact on patients’ mental and physical health, resulting in poor functioning and impaired quality of life. It is often comorbid with psychiatric disorders, such as depression, and is also a risk factor for dementia. Lack of sleep also increases the risk of accidents and falls, and negatively affects work performance. [Innov Clin Neurosci 2018;15:28-32; BMC Psychiatry 2018;18:38; J Manag Care Spec Pharm 2021;27:1296-1308]

Guidelines recommend cognitive behavioural therapy and pharmacological interventions for treatment of insomnia in adults. Established pharmacological agents include GABA receptor agonists, such as benzodiazepines and other non-benzodiazepine hypnotic drugs (also called Z-drugs). However, these agents are not recommended for longer-term treatment of insomnia due to undesirable side effects, including withdrawal symptoms and dependence. [J Sleep Res 2017;26:675-700]

Lemborexant is a DORA approved for treatment of adults with insomnia characterized by difficulties with sleep onset and/or maintenance. It regulates sleep-wake rhythm through antagonism of dual orexin receptors. [Dayvigo Hong Kong Prescribing Information, 2021]

In the pivotal phase III, randomized, placebo-controlled SUNRISE 1 and SUNRISE 2 trials, Lemborexant significantly improved sleep onset and sleep maintenance endpoints compared with zolpidem tartarte extended release and/or placebo. [JAMA Netw Open 2019;2:e1918254; Sleep 2020;43:1-11] Lemborexant’s effectiveness persisted at 12 months, demonstrating its longer-term benefits. [Sleep Med 2021;80:333-342]

Lemborexant for insomnia treatment
“Lemborexant and GABA agents are generally equally effective at facilitating sleep,” said Ozone. “However, there are differences in terms of their toxicity profiles. GABA agents are associated with physiologic tolerance, risk of abuse or dependence, rebound insomnia upon withdrawal, cognitive decline, and increased risk of falls. Therefore, GABA agents are best avoided in older adults, who are particularly vulnerable to the latter two side effects. Conversely, Lemborexant is not known to cause dependence or withdrawal symptoms.”[Aust Prescr 2015;38:152-155]

In addition, an analysis of nine placebo- or active comparator–controlled clinical studies involving use of lemborexant in healthy individuals and insomnia patients found that lemborexant did not substantially impair next-day functioning, including next-morning postural stability, cognitive performance and impact on driving. (Figure) On the contrary, next morning subjective sleep diary ratings showed significantly greater alertness with lemborexant vs placebo after ≤6 months of treatment. [Postgrad Med 2021;133:71-81]

Following 12 months of continuous lemborexant treatment in SUNRISE 2, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. The most common TEAEs in the lemborexant 5 mg and 10 mg groups vs placebo were somnolence (8.6–13.1 percent vs 1.6 percent), nasopharyngitis (9.2–9.6 percent vs 12.5 percent) and headache (6.7–8.9 percent vs 6.6 percent). [Sleep Med 2021;80:333-342]

“Given the favourable safety profile of lemborexant, I usually prescribe it as first-line therapy for insomnia,” said Ozone. “Dependence on GABA agents can lead to [unnecessary] long-term use of sleep medication. The absence of withdrawal effects allows lemborexant to be administered for a limited period of time to help patients overcome trouble sleeping, and then they can be easily weaned off it.”

However, apart from SUNRISE 1, data on direct comparisons between lemborexant and other agents in insomnia patients are lacking. “Head-to-head trials are needed to better understand their similarities and differences in long-term treatment of insomnia,” remarked Ozone.

A systematic review and network meta-analysis (involving 154 randomized controlled trials) of various pharmacological agents for acute and long-term treatment of insomnia found that lemborexant had one of the best profiles in terms of efficacy, acceptability, and tolerability. [Lancet 2022;400:170-184]

“Lemborexant is suitable for a wide variety of patients, including the elderly and first-time sleeping pill users,” commented Ozone. “Lemborexant has a potent sleep onset effect, which is particularly useful for treatment-naïve patients who often cite difficulty falling asleep as their primary concern. Furthermore, given that most hypnotics are prescribed for <1 month, lemborexant is a good choice for first-time users due to its non-addictive nature.”

“It is also appropriate for individuals with cognitive deficits [eg, older hospitalized patients] in whom administration of GABA agents could trigger delirium. The only contraindication is narcolepsy,” added Ozone. [J Am Geriatr Soc 2019;67:674-694; Dayvigo Hong Kong Prescribing Information, 2021]

Practical guidance on switching from GABA agents to Lemborexant
A multicentre open-label pilot study showed that adults with insomnia can successfully transition directly from zolpidem to lemborexant. Among 53 patients enrolled in the study, 43 (81 percent) transitioned to Lemborexant at the end of the 2-week titration period. Of these, 41 continued treatment with lemborexant during the 12-week extension period, and 38 (92.7 percent) successfully completed treatment. Lemborexant was generally well tolerated. [Sleep 2021;44(Suppl 2):A134, abstract 335]

Another phase IV, multicentre, open-label study is ongoing to evaluate the efficacy and safety of transitioning from four different drug regimens (including GABA agents) to Lemborexant in Japanese patients with insomnia. [NCT04742699]

“To prevent withdrawal symptoms, dosage of the GABA agent can be gradually tapered while transitioning to lemborexant,” explained Ozone. “Sometimes, patients can be fearful or hesitant to make rapid changes in their medication. In such patients, a gentle approach is recommended and the switch may take several weeks.”

“Patient education is also important to ease any concerns,” he added. “We have created a patient education video on sleep hygiene. Patients have to feel empowered that they possess an innate ability to sleep, and understand that medication just helps to activate it.” [Sleep Biol Rhythms 2023;doi:10.1007/s41105-023-00446-4]

“Transition from GABA agents to lemborexant can be recommended for many elderly patients, especially those with comorbid dementia, who may be concerned about further impact of GABA agents on their cognitive function as well as dependence,” continued Ozone. “Switching can also be recommended for younger patients who are dependent on GABA agents and experience GABA-specific side effects, such as sedation and morning somnolence. Another point worth considering is that while doctors are aware of the residual side effects of GABAs, the patients are relatively indifferent to the side effects, such as dizziness and falls, which may lead to bone fractures, and which are especially important for elderly patients.”

Conclusion
Over the past 50 years, GABA agents have been the predominant treatment for insomnia in adults. However, they are associated with numerous side effects, such as increased risk of falls and, in some cases, delirium, which make them particularly unsuitable for older patients. Furthermore, long-term use of GABA agents is not recommended because it can lead to tolerance, dependence and withdrawal symptoms.

Lemborexant’s alternative mechanism of action offers a breakthrough and a safer alternative with equivalent efficacy in initiation and maintenance of sleep. Use of lemborexant as a first-line agent and switching to it from other treatments is feasible, safe and effective, including in older patients. Importantly, treatment with Lemborexant can be easily discontinued without fear of rebound insomnia.