Research Points to Promise of Orexin Receptor Antagonists in Stress, AUDs

Aleksey/Adobestock

CONFERENCE REPORTER

Orexin may prove to be another tool to address alcohol disorder, according to research presented at the 63rd Annual Meeting of the American College of Neuropsychopharmacology.¹

Stephanie Gorka, PhD, shared highlights from her research (NCT05656534) on orexin antagonism and its role in alcohol use disorder (AUD), specifically in reducing stress reactivity and subsequent drinking severity.² In addition to investigating the psychopharmacology of suvorexant for this use, Gorka and her team were interested in exploring which types of patients with moderate to severe AUD would benefit from orexin antagonism in modifying brain-behavior stress targets. Gorka, associate professor in the Department of Psychiatry & Behavioral Health Institute for Behavioral Medicine Research at the Ohio State University College of Medicine, launched the first Promising Targets Oral Session at the meeting.

Study participants were aged 18 to 65 years, were in general medical good health, and met the DSM-5 criteria for current moderate to severe AUD. Individuals were randomly assigned to the active treatment group (10 mg oral suvorexant) or placebo. The active treatment and placebo arms were matched in age, biological sex, race/ethnicity, and total score on the Alcohol Use Disorders Identification Test (AUDIT).

Treatments were administered as a drug challenge and then self-administered nightly for 4 weeks. The team used a No Threat-Predictable Threat-Unpredictable Threat task at baseline, after treatment administration, and after the 4 weeks of treatment; startle eyeblink potentiation was used as a measure. Smartphones monitored daily medication adherence, subjective stress levels, alcohol consumption, and any adverse events.

Adherence across the treatment groups was good, she reported, and the agent appeared to be well tolerated. Gorka noted there were no moderate or severe adverse events reported. In addition, mild adverse events were similarly reported in both the placebo and drug treatment groups.

Gorka et al found suvorexant was beneficial for the unexpected threat reactivity both after the initial dose and again after 4 weeks of treatment. Specifically, they found the agent was associated with a 40.2% reduction in unexpected threat reactivity. It also resulted in an overall reduction of drinking for these participants. However, the drug did not have an impact on predicted threat.

Because suvorexant is FDA-approved for sleep issues, the researchers also considered the impact of sleep in the study. The participants were all relatively good sleepers to start, getting 7 to 8 hours per night, Gorka told attendees, and not much changed with drug initiation. Gorka et al concluded any changes in sleep did not account for changes in startle and subjective stress.

The research has greater implications, Gorka explained, as 12% of US adults meet criteria for AUD and alcohol related mortality has doubled in the past 20 years. Meanwhile, there are only a handful of medications that address AUD, and about half of those receiving these medications relapse, she told attendees.

Produced in the hypothalamus, orexins are associated with wakefulness, arousal, energy metabolism, and stress, Gorka said. She was intrigued because orexin receptor 1 and orexin receptor 2 are distributed throughout the brain and in networks involved in stress, fear, and anxiety. She and her team hypothesized orexin antagonism may be effective in disrupting AUD’s negative reinforcement cycle.

“These results extend our initial findings that SUV [suvorexant]selectively and effectively reduces objective reactivity to U-threat [unexpected threat] in humans,” explained Gorka. “These results have significant clinical implications and further highlight the role and importance of the orexin system as a promising target for stress-related drinking and AUD.”1

Based on these findings, Gorka said the next step would be a large scale randomized controlled trial to further investigate the relationship and for whom this treatment works.

References

1. Gorka S. Acute and Chronic Antagonism of the Orexin Receptor System Reduces Stress Reactivity and Drinking Severity in Alcohol Use Disorder. Presented at: 63rd Annual Meeting of the American College of Neuropsychopharmacology. Phoenix, Arizona. December 8 -12, 2024.

2. Gorka SM. Orexin Receptor Antagonists as Modulators of Threat Sensitivity in Individuals With Alcohol Use Disorder. Accessed December 8, 2024. https://clinicaltrials.gov/study/NCT05656534