ReviewSuvorexant to treat alcohol use disorder and comorbid insomnia: Plan for a phase II trial
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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Cited by (17)
Repurposing drugs for treatment of alcohol use disorder
2024, International Review of NeurobiologyInsomnia due to drug or substance abuse and dependence
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionOrexin Reserve: A Mechanistic Framework for the Role of Orexins (Hypocretins) in Addiction
2022, Biological PsychiatryCitation Excerpt :Moreover, the dual orexin receptor antagonist suvorexant, a compound that is Food and Drug Administration–approved for the treatment of insomnia and could readily be repurposed for addiction, can be used in low, nonsedating doses to reduce drug craving in rats (46,60). Indeed, we note that several clinical trials are currently underway to further characterize the potential utility of such compounds for the management of substance use disorders (57,58,61–65). Data linking the number of orexin neurons with addiction behaviors following drug exposure (state differences) also raise the interesting possibility that individual baseline differences in orexin levels (trait differences) may underlie propensity to abuse drugs.
The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse
2021, NeuropharmacologyCitation Excerpt :To this end, the FDA-approved DORA suvorexant (Belsomra™) represents an attractive therapeutic option with the possibility of being readily repurposed. Indeed, we note that several clinical trials are currently underway examining the efficacy of suvorexant in CUD and AUD populations (ClinicalTrials.gov; and Campbell et al., 2020b; James et al., 2020); it is not clear to what extent these studies will include polydrug use as a key outcome measure. Notably, suvorexant and another recently approved DORA (lemborexant) are hypnotics designed to promote sleep in an insomnia indication (Kishi et al., 2020), thus any studies examining their repurposing for addiction must consider whether the soporific effects of these compounds might be enhanced by concomitant drug use.