Elsevier

Brain Research

Volume 1728, 1 February 2020, 146597
Brain Research

Review
Suvorexant to treat alcohol use disorder and comorbid insomnia: Plan for a phase II trial

https://doi.org/10.1016/j.brainres.2019.146597Get rights and content

Highlights

  • Orexin modulates emotional dysregulation during withdrawal from alcohol use.

  • We highlight the role of orexin in sleep-wake regulation and alcohol use disorder.

  • We discuss our plan for a trial examining suvorexant in comorbid insomnia and AUD.

Abstract

Alcohol use disorder (AUD) is a complex neuropsychiatric disease state in which currently approved pharmacotherapeutics are of relatively low effect at a population level. One reason for this may be that current pharmacotherapeutics focus on the reward pathway in relapse prevention, rather than addressing AUD from a holistic perspective. Importantly, one often overlooked symptom of AUD is sleep disruption. In recent years, an efficient, relatively low risk and economic strategy that has proven successful in other disorders is the repositioning or repurposing of drugs approved for the treatment of other indications. Suvorexant, a dual orexin receptor antagonist, has been licensed for the treatment of insomnia in the USA, Australia and Japan. The orexin system also plays a role in the emotional dysregulation that occurs during withdrawal from alcohol use and in alcohol-seeking behaviours. These two factors prompted the planning of a clinical trial into the use of suvorexant to treat insomnia in alcohol dependent individuals during and 24 weeks post-acute alcohol withdrawal. In this review we outline the comorbid nature of AUD and sleep disruptions. We then highlight the role of the orexin system in both sleep-wake regulation and AUD. Finally, we discuss our plan for a Phase II double blind placebo controlled trial examining the effectiveness of suvorexant for the treatment of comorbid insomnia and AUD.

Section snippets

Alcohol use disorder (AUD) and sleep disruptions

AUD is a multifaceted neuropsychiatric disorder with a wide array of physical and psychological symptoms. It is a chronic, relapsing disorder and treatments for AUD need to provide a holistic intervention, targeting not only craving and withdrawal symptoms but also comorbid mood-related disorders (NIDA, 2012). One common, but often overlooked symptom of AUD is altered sleep cycles. Insomnia occurs in ~ 30–70% of people with AUD (Brower, 2003). Indeed, altered sleep architecture is found

Orexin and sleep-wake regulation

The orexins (hypocretins) are two neuropeptides found exclusively in the lateral hypothalamus of the brain (de Lecea et al., 1998, Sakurai et al., 1998). Orexin A and orexin B have two G-protein coupled receptors as binding targets, orexin-1 and orexin-2 receptors (de Lecea et al., 1998, Sakurai et al., 1998). Orexin A binds to orexin-1 and orexin-2 receptors with equal affinity whereas orexin B is more selective for orexin-2 receptors (Ammoun et al., 2003, Sakurai et al., 1998). Initial

Orexin and AUD

The orexin system is integrated within the reward circuitry, having widespread projections throughout the neuraxis particularly to downstream ventral tegmental area dopamine neurons (Korotkova et al., 2003, Nakamura et al., 2000). Due to these widespread projections, orexin is known to be involved in several physiological functions such as the behavioural response to different drugs of abuse, including alcohol. An involvement of the orexin system in alcohol-seeking was first discovered in rats

Clinical trial proposal for the treatment of AUD and comorbid sleep disorders

Our lab presented the first preclinical evidence for a role of the orexin system in AUD (Lawrence et al., 2006). 13 years on, we now present our clinical trial plan to evaluate the efficacy of suvorexant in the treatment of insomnia in clients with comorbid AUD during acute inpatient alcohol withdrawal and up to six months post inpatient withdrawal. We have obtained ethics approval through St Vincent’s Hospital, Melbourne and we are embarking on a Phase II trial of suvorexant (Belsomra, 20 mg)

Summary

Current pharmacotherapeutic treatments for AUD do not take into account the entire symptomatology of AUD, potentially limiting their success. From the outset, our goal is to develop and conduct a trial that meets international standards of best practice. This will be the first placebo-controlled, double-blind randomised trial of suvorexant in the treatment of comorbid insomnia and AUD. We will investigate improvements in sleep-related outcomes and alcohol use-related outcomes. Targeting common,

Funding and disclosure

This work is supported by a Perpetual IMPACT philanthropic grant to AJL and EJC via the Percy Baxter Charitable Trust and a Victoria Medical Research Acceleration Fund 2 grant from the Victorian State Government. AJL is a NHMRC Principal Fellow (1116930) and we acknowledge the Victorian State Government Operational Infrastructure Scheme. Suvorexant and matched placebo tablets are provided gratis by Merck.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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