Modeling buprenorphine reduction of fentanyl-induced respiratory depression
Erik Olofsen, Marijke Hyke Algera, Laurence Moss, Robert L. Dobbins, Geert J. Groeneveld, Monique van Velzen, Marieke Niesters, Albert Dahan, Celine M. Laffont
Erik Olofsen, Marijke Hyke Algera, Laurence Moss, Robert L. Dobbins, Geert J. Groeneveld, Monique van Velzen, Marieke Niesters, Albert Dahan, Celine M. Laffont
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Clinical Research and Public Health Clinical trials Neuroscience

Modeling buprenorphine reduction of fentanyl-induced respiratory depression

Abstract

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.

Authors

Erik Olofsen, Marijke Hyke Algera, Laurence Moss, Robert L. Dobbins, Geert J. Groeneveld, Monique van Velzen, Marieke Niesters, Albert Dahan, Celine M. Laffont

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Figure 3

Example of data results and analyses of an opioid-naive individual.

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Example of data results and analyses of an opioid-naive individual. Data...
Data fits and predicted receptor occupancy driving the effect of fentanyl (ascending doses of 0.075, 0.15, and 0.25 mg/70 kg) on minute ventilation at the background of placebo infusion (B, D, and F) and high-dose buprenorphine infusion targeting a plasma concentration of 0.5 ng/mL (A, C, E, and G) in an opioid-naive volunteer. (A) Measured buprenorphine plasma concentration (Cp) (gray circles) and data fits (continuous line). (B and C) Measured fentanyl plasma concentration (Cp) (black circles) and data fits (continuous lines). (D and E) Predicted receptor occupancy for fentanyl (broken line, F) and buprenorphine (continuous line, B). (F and G) Measured ventilation (blue circles) and data fit of the model with a Kalman filter (green line) and data fit of the model without a Kalman filter (red line). Acquisition of ventilation data was sometimes interrupted for various reasons (see text); in this case because the individual had to urinate (F and G).