Study data supporting the manuscript titled: Effect of buprenorphine on fentanyl-induced respiratory depression

Background: Opioid-induced respiratory depression driven by ligand binding
to mu-opioid receptors is a leading cause of opioid-related fatalities.
Buprenorphine, a partial agonist, binds with high affinity to mu-opioid
receptors but displays partial respiratory depression effects. The authors
examined whether sustained buprenorphine plasma concentrations similar to
those achieved with some extended-release injections used to treat opioid
use disorder could reduce the frequency and magnitude of fentanyl-induced
respiratory depression. Methods: In this two-period crossover,
single-centre study, 14 healthy volunteers (single-blind, randomized) and
eight opioid-tolerant (OT) patients taking daily opioid doses ≥90 mg oral
morphine equivalents (open-label) received continuous intravenous
buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma
concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or
5.0 ng/mL in OT patients. Upon reaching target concentrations,
participants received up to four escalating intravenous doses of fentanyl.
The primary endpoint was change in isohypercapnic minute ventilation (VE).
Additionally, occurrence of apnea was recorded. Results: Fentanyl-induced
changes in VE were smaller at higher buprenorphine plasma concentrations.
In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL,
the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26%
(13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79%
(69-89%) during placebo infusion (p=0.001 and <.001, respectively).
Discontinuations for apnea limited treatment comparisons beyond the second
fentanyl injection. In OT patients, fentanyl reduced VE up to 49% (21-76%)
during buprenorphine infusion (all concentration groups combined) versus
up to 100% (68-132%) during placebo infusion (p=0.006). In OT patients,
the risk of experiencing apnea requiring verbal stimulation following
fentanyl boluses was lower with buprenorphine than with placebo (odds
ratio: 0.07; 95% CI: 0.0 to 0.3; p=0.001). Interpretation: Results from
this proof-of-principle study provide the first clinical evidence that
high sustained plasma concentrations of buprenorphine may protect against
respiratory depression induced by potent opioids like fentanyl.