BACKGROUNDPotent 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.METHODSTo 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.RESULTSBuprenorphine 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.CONCLUSIONOverall, 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 REGISTRATIONTrialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028)FUNDINGIndivior Inc., North Chesterfield, Virginia, USA.