High plasma concentrations of buprenorphine may reduce fentanyl-induced respiratory depression, new research suggests.
The primary endpoint measure in a small “proof of principal” pharmacology study was effect of escalating fentanyl dosing on respiratory depression by way of decreased isohypercapnic minute ventilation (VE) – or volume of gas inhaled or exhaled per minute from the lungs.
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Results showed the maximum decrease in highest-dose fentanyl-induced VE was almost 50% less for opioid-tolerant patients receiving a 2.0 ng/mL concentration of steady-state plasma buprenorphine than when receiving matching placebo.
Risk for apnea requiring stimulation after fentanyl dosing was also significantly lower with buprenorphine.
“Even though the study is small, a lot of data were collected which will allow us to very accurately predict which plasma concentrations, and therefore drug doses, are needed to protect people adequately in practice,” study coinvestigator Geert Jan Groeneveld, MD, PhD, neurologist and clinical pharmacologist at the Centre for Human Drug Research, Leiden, the Netherlands, and professor of clinical neuropharmacology at Leiden University Medical Center, told this news organization.
He added the “beautiful results” were in line with what the researchers expected and although further research is needed, the study provides a lot of useful information for clinicians.
“I think this is an approach that works, and this study makes that clear,” Dr. Groeneveld added.
The findings were published online Jan. 27, 2022, in PLoS One.
High death rate from synthetic opioids
A recent report from the Centers for Disease Control and Prevention noted that, between June 2020 and June 2021, there were more than 100,000 drug overdose deaths in the United States. Of these, more than 73,000 were attributed to opioids and more than 60,000 to synthetic opioids such as fentanyl.
Most opioid-related overdose deaths in the United States are attributable to synthetic opioids “that can unexpectedly cause respiratory depression by being ingested as a substitute for heroin or with [other] drugs,” Indivior noted in a press release.
Buprenorphine is a partial agonist that “binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects,” the investigators wrote.
As reported by this news organization, the Food and Drug Administration approved buprenorphine extended release (Sublocade, Indivior) in 2017 as the first once-monthly injection for the treatment of opioid use disorder.
In the current study, which was conducted in Leiden, the Netherlands, the investigators used continuous intravenous buprenorphine in order to “mimic” the sustained plasma concentrations of the drug that can be delivered with the long-acting injectable, noted Christian Heidbreder, PhD, chief scientific officer at Indivior.
“This was an experimental medicine study, whereby we used intravenous buprenorphine to really understand the interaction with escalating doses of fentanyl” on respiratory depression, he told this news organization.
Two-part, two-period study
In part A, period one of the two-period crossover study, 14 healthy volunteers were randomly assigned to receive for 360 minutes continuous infusion of 0.02 or 0.05 mg/70 kg per hour of buprenorphine to target plasma concentrations of 0.2 or 0.5 ng/mL, respectively, or matching placebo. In the second period, participants received the alternative infusion – either placebo or the active drug.
In part B, eight opioid-tolerant patients who had used high-dose opioids for at least 3 months prior received a higher infusion rate of 0.1, 0.2, or 0.5 mg/70 kg per hour to target plasma concentrations of 1, 2, or 5 ng/mL, respectively.
The 2 ng/mL “is a very important threshold for us” and the result from several previous experiments, Dr. Heidbreder noted. So the investigators targeted that concentration as well as one below and one “much higher” in the current study.
“Because tolerance to opioid effects is poorly characterized in patients receiving long-term opioids, opioid-tolerant participants in part B had a fixed treatment sequence, receiving placebo infusion plus fentanyl challenges in period 1 to optimize the fentanyl dose escalation before buprenorphine and fentanyl were coadministered in period 2,” the investigators reported.
All participants received up to four escalating doses of intravenous fentanyl after reaching target buprenorphine plasma concentrations.
For healthy volunteers, the planned fentanyl doses were 0.075, 0.15, 0.25, and 0.35 mg/70 kg. For the opioid-tolerant patients, the doses were 0.25, 0.35, 0.5, and 0.7 mg/70 kg.
The infusions began after baseline VE had stabilized at 20 plus or minus 2 L/min, which is about four times above normal resting VE.
First clinical evidence?
Results showed fentanyl-induced adverse changes in VE were less at higher concentrations of buprenorphine plasma.
Opioid-tolerant patients receiving the 2.0 ng/mL concentration of buprenorphine had a 33.7% decrease in highest dose fentanyl-induced VE versus an 82.3% decrease when receiving placebo.
In addition, fentanyl reduced VE up to 49% (95% confidence interval, 21%-76%) in opioid-tolerant patients in all buprenorphine concentration groups combined versus reducing VE up to 100% (95% CI, 68%-132%) during placebo infusion (P = .006).
In addition, buprenorphine was associated with a lower risk versus placebo for apnea requiring verbal stimulation after fentanyl dosing (odds ratio, 0.07; P = .001).
For the healthy volunteers, the first fentanyl bolus reduced VE by 26% for those at target buprenorphine concentration of 0.5 ng/mL versus 51% when receiving placebo (P = .001). The second bolus reduced VE by 47% versus 79%, respectively (P < .001).
“Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection,” the investigators reported.
Overall, the findings “provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids,” they added.
Additional research is now “warranted to assess the competitive interaction of buprenorphine and fentanyl (as well as other illicitly manufactured fentanyl analogs) as we continue to deepen our understanding of buprenorphine as an evidence-based treatment for patients struggling with opioid use disorder,” Dr. Heidbreder said in a press release.
It’s unclear whether the study’s findings are generalizable to other populations, said Dr. Heidbreder.
“So and for that we’ll be using [the injectable] Sublocade as the medication of choice,” said Dr. Heidbreder.
“Conceptually, we feel confident about these data, but now we need to demonstrate what is happening in the real world,” he added.
The study was funded by Indivior. Dr. Groeneveld has reported no relevant financial relationships. Dr. Heidbreder is an employee of Indivior.
A version of this article first appeared on Medscape.com.