Suvorexant enhances oxycodone-induced respiratory depression in male rats

• Published in: Drug and alcohol dependence 2024-11, Vol.264, p.112434, Article 112434
• Main Authors: Moreira-Junior, Eliseu D.C., Rowlett, James K., Berro, Lais F.
• Format: Article
• Language: English
• Subjects: Analgesics, Opioid - pharmacology; Animals; Azepines - pharmacology; Azepines - therapeutic use; Dose-Response Relationship, Drug; Drug Synergism; Male; Orexin; Orexin Receptor Antagonists - pharmacology; Oxycodone; Oxycodone - pharmacology; Rats; Rats, Sprague-Dawley; Respiration; Respiratory depression; Respiratory Insufficiency - chemically induced; Suvorexant; Triazoles - pharmacology
• ISSN: 0376-8716; 1879-0046; 1879-0046
• DOI: 10.1016/j.drugalcdep.2024.112434

Recent studies have proposed the use of dual orexin receptor antagonists, such as suvorexant, for the treatment of opioid use disorder (OUD) and opioid-related sleep disturbances because of orexin’s role in sleep-wake regulation and addiction. Accumulating evidence suggests that orexin is also an important modulator of respiratory function, raising the possibility of adverse respiratory events when combining orexin antagonists and opioids. The aim of the present study was to investigate the effects of suvorexant, alone or in combination with the opioid oxycodone, on pulmonary ventilation in male rats. Adult, male Sprague Dawley rats received treatments with vehicle, oxycodone (3 and 10mg/kg, i.p.) or suvorexant (10 and 18mg/kg, i.p.), and respiratory measures were obtained using whole-body plethysmography. We then tested the effects of a combination of suvorexant (10 and 18mg/kg, i.p.) and the highest dose of oxycodone that did not suppress respiration alone (3mg/kg, i.p). Oxycodone induced respiratory depression at 10mg/kg, but not 3.0mg/kg; as evident by significant decreases in minute volume (mls/min) and tidal volume (mls). Suvorexant alone did not alter any respiratory measures at the doses tested. When combined, 18mg/kg (but not 10mg/kg) suvorexant plus an ineffective dose of oxycodone significantly decreased minute and tidal volume compared with vehicle and either drug alone, whereas respiratory frequency was significantly decreased compared with vehicle. Our findings show that suvorexant, at a dose associated with sleep promotion and blockade of oxycodone self-administration, robustly enhanced oxycodone-induced respiratory depression in male rats. •Oxycodone induces a dose-dependent decrease in respiration.•Suvorexant does not affect respiratory function at therapeutically-relevant doses.•Suvorexant can enhance the respiratory depressant effects of oxycodone.•Orexin antagonists may worsen the respiratory-depressant effects of opioids.•Caution is needed in use of these drugs in combination with opioids.