The effects of buprenorphine on fentanyl-induced respiratory depression in rats

The opioid antagonists, naloxone and nalmefene, are used clinically to rapidly reverse opioid overdose, but often precipitate withdrawal symptoms in opioid-dependent individuals. This study compared 2 medications used for opioid use disorder, buprenorphine and methadone, to naloxone for reversing fentanyl-induced effects in rats. Buprenorphine alone did not produce significant respiratory depression at 0.5-5.0 mg/kg. Rats were challenged with 0.1 mg/kg fentanyl, which resulted in a significant reduction in oxygen saturation (SpO₂), and naloxone 0.1 mg/kg, buprenorphine 3.0 mg/kg, methadone 2.25 mg/kg, or saline control was given to reverse fentanyl effects. Antinociception and SpO₂ were restored to baseline by 15 minutes after administration of naloxone and buprenorphine. The saline group showed a slow return to baseline SpO₂ within 30 minutes, whereas methadone extended the duration of, but did not enhance, the effects of fentanyl. To determine whether buprenorphine could rapidly (within minutes) reverse fentanyl-induced respiratory depression, rats were given a dose of fentanyl 0.1 mg/kg s.c., followed by saline, naloxone 0.1 mg/kg, or buprenorphine 3.0 mg/kg, and SpO₂ was monitored continuously for 10 minutes. Both naloxone and buprenorphine reversed fentanyl effects within 3.5 minutes, whereas the saline group did not return to baseline levels during the monitoring period. Buprenorphine at 0.3 and 1.0 mg/kg also reversed fentanyl effects, with a slower onset of reversal. In a follow-up study, rats received fentanyl followed by saline, buprenorphine, or methadone for reversal, and blood and brain levels were measured. Fentanyl concentration in the brain was not significantly affected by methadone and buprenorphine treatment, suggesting that differences in SpO₂ were not attributable to pharmacokinetic interactions. These data support repurposing buprenorphine for the treatment of opioid overdose. SIGNIFICANCE STATEMENT: Opioid overdoses cause ∼80,000 annual deaths in the United States. Buprenorphine is an opioid partial agonist used for opioid use disorder. This study used a rat model to compare buprenorphine to naloxone for efficacy in reversing fentanyl-induced respiratory depression.