The putative effects of orexin receptor antagonists on pain and sleep in humans: A systematic review.

OBJECTIVE

Orexin antagonists are newer medications for management of insomnia, a condition frequently associated to chronic pain. This systematic review evaluates the effects of orexin receptor antagonists on pain perception and pain-related outcomes in humans, considering their role in both sleep regulation and pain modulation.

METHODS

A search was conducted in PubMed, Web of Science, Scopus, CINAHL, PsycINFO, and ClinicalTrials.gov, following PRISMA guidelines. Eligible studies included human participants with acute or chronic pain who received orexin receptor antagonists (e.g., suvorexant, lemborexant, daridorexant, filorexant) with pain intensity, pain thresholds, sleep disturbances, and functional outcomes as primary measures. Risk of bias was assessed using RoB 2 for randomized controlled trials (RCTs) and ROBINS-E for observational studies, while the GRADE approach was applied to assess the overall certainty of evidence.

RESULTS

Out of 488 identified records, four studies met the inclusion criteria (three RCTs, one observational study), totaling 331 participants. No significant improvements in pain intensity were found, though one study observed increased pain sensitivity thresholds in fibromyalgia patients. Conversely, orexin receptor antagonists consistently improved sleep parameters, including total sleep time and sleep onset latency. Evidence certainty was moderate for RCTs and low for the observational study, with imprecision and publication bias as key concerns.

CONCLUSION

Orexin receptor antagonists improve sleep, but due to the very limited number of studies and small sample sizes, evidence regarding analgesic effects in humans remains inconclusive. The lack of receptor-selective interventions, short treatment durations, and pain condition variability may contribute to these findings. Future trials should investigate mechanistic analgesic effects, receptor-specific therapies, and explore orexin's role in pain phenotypes.