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

Huhn, Andrew S.; Finan, Patrick H.; Gamaldo, Charlene E.; Hammond, Alexis S.; Umbricht, Annie; Bergeria, Cecilia L.; Strain, Eric C.; Dunn, Kelly E.

doi:10.1126/scitranslmed.abn8238

Cited by 44 publications

(26 citation statements)

References 44 publications

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“…Investigators have hypothesized that an orexin-based approach might directly reduce drug cravings (particularly via actions at Ox1R) and indirectly reduce relapse risk by normalizing sleep disturbances (primarily via Ox2R) . Results from a recently published study support this potential as subjects with opioid use disorder demonstrated increased total sleep time and decreased withdrawal symptoms with SUV versus placebo during a buprenorphine/naloxone taper (Huhn et al 2022). Similar studies, albeit primarily in animals, also suggest a potential therapeutic role for orexin receptor antagonists in cocaine use disorder (James et al 2021;Simmons and Gentile 2020).…”

Section: Factor 3: the State Of Current Scientific Knowledge Regardin...mentioning

confidence: 79%

The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act

et al. 2023

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Rationale Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health. Objectives This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act. Results LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks. Conclusions LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.

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Section: Factor 3: the State Of Current Scientific Knowledge Regardin...mentioning

confidence: 79%

The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act

et al. 2023

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“…Alternative DORAs (i.e., almorexant and DORA-1) have been reported to reduce alcohol intake ( Anderson et al, 2014 ; Srinivasan et al, 2012 ), interfere with the expression of cocaine- and amphetamine-induced conditioned place preference (CPP; Steiner et al, 2013 ), reduce nicotine conditioned reinstatement ( Winrow et al, 2010 ), and attenuate morphine-induced locomotor sensitization ( Steiner et al, 2013 ), although these compounds have yet to obtain FDA-approval. The acute administration of SUV, however, reduced stimulant ( Simmons et al, 2017 ; Gentile et al, 2018 ) and alcohol intake in rats ( Flores-Ramirez et al, 2022 ) and reduced opioid withdrawal and craving in patients who were undergoing buprenorphine taper ( Huhn et al, 2022 ). Therefore, SUV may indirectly reduce the risk to opioid relapse by reducing drug craving (primarily via OX 1 receptor) and normalizing sleep disturbances (primarily via OX 2 receptor) commonly observed in OUD patients ( Peles et al, 2006 ; Hartwell et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

et al. 2023

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Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse.Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i. v., 8 h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0–20 mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20 mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD.Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20 mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females.Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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As opioid-related fatalities continue to rise, the need for novel opioid use disorder (OUD) treatments could not be more urgent. Two separate hypothalamic neuropeptide systems have shown promise in preclinical OUD models. The oxytocin system, originating in the paraventricular nucleus (PVN), may protect against OUD severity. By contrast, the orexin system, originating in the lateral hypothalamus (LH), may exacerbate OUD severity. Thus, activating the oxytocin system or inhibiting the orexin system are potential therapeutic strategies. The specific role of these systems with regard to specific OUD outcomes, however, is not fully understood. Here, we probed the therapeutic efficacy of pharmacological interventions targeting the orexin or oxytocin system on two distinct metrics of OUD severity in rats—heroin choice (versus choice for natural reward, i.e., food) and cued reward seeking. Using a preclinical model that generates approximately equal choice between heroin and food reward, we examined the impact of exogenously administered oxytocin, an oxytocin receptor antagonist (L-368,899), and a dual orexin receptor antagonist (DORA-12) on opioid choice. Whereas these agents did not alter heroin choice when rewards (heroin and food) were available, oxytocin and DORA-12 each significantly reduced heroin seeking in the presence of competing reward cues when no rewards were available. In addition, the number of LH orexin neurons and PVN oxytocin neurons correlated with specific behavioral economic variables indicative of heroin versus food motivation. These data identify a novel bidirectional role of the oxytocin and orexin systems in the ability of opioid-related cues to bias reward seeking.

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

Cited by 44 publications

References 44 publications

The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act

The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

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

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