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Randomized Controlled Trial
. 2022 Jan 27;17(1):e0256752.
doi: 10.1371/journal.pone.0256752. eCollection 2022.

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients

Laurence M Moss  1   2 , Marijke Hyke Algera  2 , Robert Dobbins  3 , Frank Gray  3 , Stephanie Strafford  3 , Amy Heath  3 , Monique van Velzen  2 , Jules A A C Heuberger  1 , Marieke Niesters  2 , Erik Olofsen  2 , Celine M Laffont  3 , Albert Dahan  2 , Geert Jan Groeneveld  1   2
Affiliations
Randomized Controlled Trial

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients

Laurence M Moss et al. PLoS One. .

Abstract

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 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 opioid-tolerant 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 opioid-tolerant 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 opioid-tolerant 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.

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Conflict of interest statement

The authors have read the journal’s policy and have the following competing interests: RD, FG, SS, AH, and CL are paid employees of Indivior Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Figures

Fig 1
Fig 1. CONSORT flow diagram.
BUP, buprenorphine; PD, pharmacodynamic; PK, pharmacokinetic. aRandomised sequences for Part A were Placebo:BUP N = 5, BUP:Placebo N = 3 for the 0.2 ng/mL group and Placebo:BUP N = 2, BUP:Placebo N = 4 for the 0.5 ng/mL group. bOne volunteer in the lower dose group received the incorrect buprenorphine dose and was excluded from the PD analyses. Data were available for six healthy volunteers in each treatment (placebo and buprenorphine) for the PD analyses in the lower dose group due to two volunteers in the lower dose group who completed only one study period.
Fig 2
Fig 2. Mean buprenorphine plasma concentration-time curves.
Upper panel: Part A, healthy volunteers; Lower panel: Part B, opioid-tolerant patients. In both healthy volunteers and opioid-tolerant patients, a 10-fold higher infusion rate was used over the first 15 minutes to speed attainment of steady-state buprenorphine concentrations at the site of action. Infusions were stopped at 360 min. Steady-state buprenorphine infusion rates are labelled in the graphs.
Fig 3
Fig 3. Mean fentanyl plasma concentration-time curves.
Upper panel: Part A, healthy volunteers; Lower panel: Part B, opioid-tolerant patients. At 120, 180, 240, and 300 minutes after the start of the buprenorphine or placebo infusion, escalating intravenous fentanyl doses were administered over 90 seconds. Planned fentanyl bolus doses are labelled in the graphs. Higher doses were not administered to participants if they did not tolerate lower fentanyl doses.
Fig 4
Fig 4. Example graphs showing the effect of fentanyl on minute ventilation in three opioid-tolerant patients during placebo infusion and buprenorphine infusion.
(1) Placebo infusion (A, C and E) and buprenorphine infusion (B, D, F) at target plasma concentrations of 1 ng/mL (top row), 2 ng/mL (middle row) and 5 ng/mL (lower row). (2) Open spaces in the beginning of graphs A, C, D and E relate to concurrent clinical events such as temporary removal of the facemask. (3) Grey dots are stimulated breaths in case of an apnea episode. (4) The time on the x-axis in the graphs is related to the start time of the ventilation experiment, not the timing of the buprenorphine/placebo infusion and fentanyl injections.
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References

    1. United Nations Office on Drugs and Crime. World Drug Report 2020, (United Nations publication, Sales No. E.20.XI.6).
    1. van Amsterdam J, Philips L, Henderson G, Bell J, Bowden-Jones O, Hammersley R, et al.. Ranking the harm of non-medically used prescription opioids in the UK. Regul Toxicol Pharmacol 2015; 73, 999–1004. doi: 10.1016/j.yrtph.2015.09.014 - DOI - PubMed
    1. Stokes A, Berry KM, Hempstead K, Lundberg DJ, Neogi T. Trends in prescription analgesic use among adults with musculoskeletal conditions in the United States, 1999–2016. JAMA Netw Open 2019; 2: e1917228. doi: 10.1001/jamanetworkopen.2019.17228 - DOI - PMC - PubMed
    1. Dahan A, van der Schrier R, Smith T, Aarts L, van Velzen M, Niesters M. Averting opioid-induced respiratory depression without affecting analgesia. Anesthesiology 2018; 128: 1027–37. doi: 10.1097/ALN.0000000000002184 - DOI - PubMed
    1. Centers for Disease Control and Prevention. 2019 Annual Surveillance Report of Drug-Related Risks and Outcomes—United States Surveillance Special Report. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Published November 1, 2019. https://www.cdc.gov/drugoverdose/pdf/pubs/2019-cdc-drug-surveillance-rep.... Accessed August 25, 2020.

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