The dual orexin receptor antagonist suvorexant in alcohol use disorder and comorbid insomnia: A case report

Key Clinical Message This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse. Abstract Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.


| INTRODUCTION
Substance use disorders, including alcohol use disorder, are notoriously difficult to treat.Effective pharmacotherapeutic treatments are needed to aid behavioral interventions and formulate successful, holistic treatment regimes.2][3][4][5] One key symptom of alcohol use disorder, often critical for preventing subsequent relapse to alcohol use, is insomnia, during both withdrawal and post withdrawal.Persistent disruption in sleep activity is observed in individuals with alcohol use disorder, even after years of abstinence. 6,7Improving sleep disturbance therefore may be a key component in assisting withdrawal and reducing subsequent relapse to drinking.
In 2014, the US Food and Drug Administration (FDA) approved Belsomra® (suvorexant), a dual orexin receptor antagonist, for the treatment of insomnia.Suvorexant has shown efficacy in the treatment of insomnia since its approval. 8While sleep disruptions are a common symptom of alcohol use disorder and suvorexant has shown promise at reducing sleep disturbances, the literature surrounding the effectiveness of suvorexant to treat comorbid alcohol use disorder and insomnia remains limited.We recently reviewed this literature and introduced our clinical trial plan on the use of suvorexant to treat alcohol use disorder with comorbid insomnia. 9,10More recently, a milestone clinical study using suvorexant has reported increased sleep duration and reduced self-reported withdrawal in a group of inpatients with opioid use disorder. 11Here, we report a case of the beneficial effects of suvorexant in the treatment of alcohol use disorder and comorbid insomnia.This case was part of our Phase II, placebo-controlled, double-blind randomized trial which was impacted by the COVID pandemic from 2020 to 2022 (NCT03897062) and ceased before completion.

| CASE PRESENTATION
The information collected for this case report was approved by the Human Research Ethics Committee of St Vincent's Hospital, Melbourne.Participant 020 is a 31-year-old male, currently unemployed, and living in a private residence with his spouse.Participant 020 was admitted to the Drug and Alcohol withdrawal unit at St. Vincent's Hospital, Melbourne, Australia in March 2022.On admission, Participant 020 consumed 16 standard drinks per day and had mildly abnormal liver function (Table 1).He reported his last consumption of alcohol was 1 day prior to admission and his breath alcohol was 0.0% on admission.He was discharged after 7 days to his private residence and consented to remain in the study as an outpatient.

| METHODS
For treatment, Participant 020 received one 20 mg tablet of suvorexant each evening, at around 8 p.m., for 13 weeks after which he was lost to follow-up.The participant and administering personnel were blinded to treatment condition.Other medications during treatment included levetiracetam for epilepsy (500 mg, twice/day), thiamine prophylaxis against Wernicke-Korsakoff syndrome (100 mg three times/day during admission for alcohol withdrawal, 100 mg daily thereafter), Panadol (1 g 6 h for 3 days during Week 9 for symptoms of flu), ibuprofen (200 mg twice daily for 3 days during Week 9 for symptoms of flu), and diazepam for alcohol withdrawal (10-20 mg if Alcohol Withdrawal Score ≥ 10; total diazepam over course of 7 day admission for withdrawal was 145 mg).Participant 020 had not tried pharmacotherapies for alcohol use disorder such as naltrexone or acamprosate.Participant 020 reported daily tobacco use at the time of admission and intermittent use of cannabis (last use was 3 months prior to admission) and methamphetamine (last use was 9 years prior to admission).Alcohol use, psychological and physical health status, quality of life, sleep disturbance, and vital signs were monitored every 4 weeks post discharge.

| Alcohol use outcomes
Participant 020 reported abstinence from alcohol, confirmed by breath alcohol readings of 0.0% at all follow-up visits.Follow-up visits assessed alcohol and other drug use, sleep assessment, and adverse effects from the suvorexant.No other alcohol pharmacotherapies were offered.Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase.

| Sleep disturbance outcomes
Participant 020 experienced an overall improvement in sleep outcomes following suvorexant treatment.Upon admission the Insomnia Severity Index indicated that Participant 020 had severe clinical insomnia (23 out of 28). 15Daytime sleepiness as assessed by the Epworth Sleepiness Scale was mild (12 out of 24). 16The Pittsburgh Sleep Quality Index also demonstrated poor sleep quality on admission by Participant 020 (17 out of 21). 17y Week 13 follow-up, Participant 020 presented with no clinically significant insomnia based on the Insomnia Severity Index (2 out of 28).Daytime sleepiness was reported to be in the normal range (2 out of 24 with normal ranging from 0 to 10) 16 at Week 13 follow-up and sleep quality was reported to have improved substantially (6 out of 21).

| Vital signs
Vital signs did not change over the course of suvorexant treatment (Table 2).
Here, we present a case of an individual with alcohol use disorder and clinically significant comorbid insomnia.Participant 020 responded positively following 13 weeks of double-blinded suvorexant treatment.This included complete abstinence over the treatment period and improvements in self-reported physical and psychological health, as well as alcohol cravings.Sleep measures also improved during this period, with improved sleep quality, reduced daytime sleepiness, and reduced severity of insomnia.
F I G U R E 1 Self-reported psychological distress, health, well-being, and craving after suvorexant treatment in Participant 020 with comorbid alcohol use disorder and insomnia.Psychological and physical health status and quality of life increased over the treatment period (A).Psychological distress improved over the 13-week treatment period (B).Self-reported craving also reduced over the treatment period (C).9][20][21][22][23][24] Thus, it is encouraging to observe the link between preclinical research and the initiation of human clinical trials in this area (NCT03897062, NCT04229095, and NCT05458609).While the case study described above does not allow for treatment recommendations, it does suggest potential for suvorexant in the treatment of comorbid alcohol use disorder and insomnia.Given the cost of alcohol misuse globally, examining the use of suvorexant to treat comorbid alcohol use disorder and insomnia through a fully powered phase II trial is warranted.

| DISCUSSION
Insomnia features strongly in both withdrawal and relapse to alcohol consumption.In this case study, suvorexant was therefore administered during the withdrawal period and continued post withdrawal.Overall, this case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse.Future work with a fully powered and controlled experimental design are needed.

T A B L E 1
Clinical liver function characteristics from Baseline to Week 9 follow-up for Participant 020.

T A B L E 2
Vital signs during the suvorexant treatment period.