LAUSR

In 2017 the US Department of Health and Human Services declared the epidemic of opioid use disorder (OUD) sweeping the nation a public health emergency. Major aspects of OUD management include detoxification, prevention of overdose, and relapse prevention. The main approach to OUD treatment is opioid substitution therapy (OST) using full (methadone) or partial (buprenorphine) opioid agonists. Drawbacks of this approach include restricted access, risk of overdose, stigma of iatrogenic opioid dependence, and interference with pain management that limit its effectiveness. Clearly, there is an urgent need for the development of new medications that rely on different mechanisms, which could augment OST or serve as an alternative. In 2018, the National Institute on Drug Abuse’s (NIDA) Division of Therapeutics and Medical Consequences named ten mechanisms of action, which NIDA has gauged to have the “highest probability of a path to FDA approval for the treatment of some aspect of OUD in the near term” [1]. Atop this list are antagonists and/or negative allosteric modulators that dampen the signaling of the hypothalamic orexin (hypocretin) neuropeptides. We believe this focus to be well-justified given the 15+ years of preclinical data indicating that orexin signaling, particularly at the orexin-1 receptor (Ox1R), selectively underlies the motivational and craving properties of all drugs of abuse tested [2]. We and others have speculated that a rapid orexin-based approach might be to repurpose the already FDA-approved dual Ox1R/Ox2R antagonist, suvorexant, marketed by Merck as Belsomra for the treatment of insomnia [2–4]. In addition to reducing drug craving (primarily via actions at Ox1R), suvorexant may have the additional benefit of indirectly reducing relapse risk by normalizing sleep disturbances (primarily via Ox2R), which are observed in ~80% of OUD patients. Indeed, the wellknown deficits in executive function that accompany disturbed sleep may contribute to relapse vulnerability in treatmentseeking OUD individuals, as sleep disturbance comorbidity is negatively associated with OST outcomes [5]. Moreover, given the known role for the orexin system in mediating stress and anxiety behaviors [6], including opioid withdrawal syndrome [7], additional therapeutic benefits of suvorexant may come from its ability to treat underlying comorbid disorders. Several clinical trials are currently underway to examine the efficacy of suvorexant in normalizing sleep outcomes, as well as craving, stress, and sleep indices, in OUD and other substance use disorder patients (ClinicalTrials.gov Identifier numbers: NCT03412591, NCT03897062, NCT03789214, NCT03937986, NCT03789214, NCT03657355). These studies represent an important step toward repurposing suvorexant for addiction, and will provide proof-of-principle data to help guide the development of further trials across various substances of abuse. However, as we outline here, preclinical studies examining systemic dual orexin receptor antagonism as a therapeutic for opioid addiction remain nascent, and several key questions are unanswered with respect to the efficacy and safety profile of suvorexant in OUD individuals. Notably, no clinical or preclinical study has yet directly tested the efficacy of suvorexant in reducing opioid use and craving. Indeed, all three studies that explored suvorexant as a treatment for addiction were conducted in rodent models of psychostimulant abuse [8]. This being said, many animal studies now support the efficacy of selective orexin antagonists in reducing a wide range of OUD-related behaviors, including demand and relapse (e.g., see [9]. However, these studies have generally focused on selective Ox1R antagonists, and thus it is unclear whether suvorexant, which has a slightly higher binding affinity for Ox2R (0.35 nM) over Ox1R (0.55 nM) [10], can reduce craving without also causing unwanted sedation or off-target effects. Notably, one study reported that Ox2R antagonism reduced heroin intake following long duration drug self-administration sessions [11], indicating that there may be therapeutic benefit to suvorexant’s actions at both receptors. Key questions also remain regarding the prospective dosing regimen of suvorexant, as the overwhelming majority of studies of selective or dual orexin receptor antagonists have tested their efficacy only when administered acutely. This is important, as one study reported that chronic Ox1R antagonism during cocaine extinction training resulted in enhanced cued reinstatement when tested in a drug-free state [12]. Also, new evidence indicates that a single dose of an Ox1R antagonist can disrupt drug seeking behavior beyond the bioavailability of the compound [13], raising the possibility that daily dosing may not be necessary. It is also unclear what time of day would be best to administer suvorexant; when prescribed for insomnia, suvorexant is administered at bedtime; however, the ~12 h half-life of suvorexant means that this regimen might result in reduced bioavailability during the daytime when opportunity for drug use is high. It is possible that