The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl

Abstract

The orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD).Suvorexant (Belsomra TM ) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.

Suvorexant ameliorated sleep disturbance, opioid withdrawal, and craving during a buprenorphine taper

“…Suvorexant improved all three measures of craving during the taper, and suvorexant continued to produce increased avoidance and control during the post-taper period when compared with placebo. Several preclinical studies have demonstrated that orexin 1 and 2 receptor antagonists reduce opioid tolerance, withdrawal, and drug-seeking behaviors (13,14,(27)(28)(29); however, here we suggest that orexin receptor antagonism might affect the human experience of opioid withdrawal and craving. It is noteworthy that a nonopioid medication produced such profound and consistent effects on opioid craving, particularly during a supervised withdrawal treatment paradigm.…”

“…Dual-orexin receptor antagonists (DORAs) improve sleep continuity and duration in humans (7), and orexin receptor antagonists decrease opioid withdrawal symptoms, opioid tolerance, and motivation to seek opioids in rodent models of OUD (8)(9)(10)(11)(12)(13)(14). Suvorexant is a Food and Drug Administration (FDA)-approved DORA used to treat both sleep initiating and maintenance insomnia (15,16) and could be particularly efficacious in persons with OUD who may experience sleep disturbance as a result of increased orexin signaling (17,18).…”

Oxytocin and orexin systems bidirectionally regulate the ability of opioid cues to bias reward seeking

“…or 30 mg/kg (3 ml/kg, i.p.) based on effective doses of other DORAs reported in the literature [47][48][49][50]. Heroin (diamorphine hydrochloride) was dissolved in 0.9% saline (0.04 mg/50 μl infusion per reward).…”

“…These data raise the possibility that compounds that block signaling at both the Ox1R and Ox2R (dual orexin receptor antagonists; DORAs) might have more pronounced therapeutic properties compared to single orexin receptor antagonists [44][45][46]. Indeed, initial preclinical studies indicate that DORAs reduce drug taking and seeking across several classes of drugs of abuse [47][48][49][50], and a preliminary clinical study reported that the DORA suvorexant (marketed by Merck as Belsomra TM ) reduces several relapse-related and self-reported craving indices in patients with cocaine or opioid use disorder [51,52]. Based on the success of these studies, the National Institute on Drug Abuse (NIDA) declared the orexin system a target of high priority for new medication development to tackle the opioid epidemic [53], although additional studies are needed to examine the efficacy of DORAs in preclinical OUD models.…”

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

“…Moreover, based on preclinical studies finding higher efficacy of orexin receptor antagonists in rats with stronger addiction phenotypes Fragale et al, 2019;James et al, 2019a;Mohammadkhani et al, 2019a), it is possible that low, non-sedating doses of suvorexant will be effective at reducing craving. Additionally, evidence indicating that the anti-drug seeking properties of orexin receptor antagonists, including suvorexant, extend beyond their bioavailability (up to 48h) suggests that daily dosing might not be necessary (Brodnik et al, 2020;Mohammadkhani et al, 2019b;O'Connor et al, 2020). Clearly, significant work is required to address these questions around potential clinical use of orexin receptor antagonists for polysubstance use, as well as the more mechanistic questions raised throughout this article.…”