Modeling buprenorphine reduction of fentanyl-induced respiratory depression

BACKGROUND: Potent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression. METHODS: To characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075–0.35 mg/70 kg (opioid naive) and 0.25–0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2–3 background doses of buprenorphine (target plasma concentrations range: 0.2–5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models. RESULTS: Buprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding–dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed. CONCLUSION: Overall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine. TRIAL REGISTRATION: Trialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028) FUNDING: Indivior Inc., North Chesterfield, Virginia, USA.