Modeling buprenorphine reduction of fentanyl-induced respiratory depression
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...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-05-01
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| Series: | JCI Insight |
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| Online Access: | https://doi.org/10.1172/jci.insight.156973 |
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| author | Erik Olofsen Marijke Hyke Algera Laurence Moss Robert L. Dobbins Geert J. Groeneveld Monique van Velzen Marieke Niesters Albert Dahan Celine M. Laffont |
| author_facet | Erik Olofsen Marijke Hyke Algera Laurence Moss Robert L. Dobbins Geert J. Groeneveld Monique van Velzen Marieke Niesters Albert Dahan Celine M. Laffont |
| author_sort | Erik Olofsen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:33:41Z |
| format | Article |
| id | doaj.art-faf5c86fc2f348318525716d62bbc243 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T12:33:41Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-faf5c86fc2f348318525716d62bbc2432022-12-22T03:32:57ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-05-0179Modeling buprenorphine reduction of fentanyl-induced respiratory depressionErik OlofsenMarijke Hyke AlgeraLaurence MossRobert L. DobbinsGeert J. GroeneveldMonique van VelzenMarieke NiestersAlbert DahanCeline M. LaffontBACKGROUND 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.https://doi.org/10.1172/jci.insight.156973Clinical trialsNeuroscience |
| spellingShingle | Erik Olofsen Marijke Hyke Algera Laurence Moss Robert L. Dobbins Geert J. Groeneveld Monique van Velzen Marieke Niesters Albert Dahan Celine M. Laffont Modeling buprenorphine reduction of fentanyl-induced respiratory depression JCI Insight Clinical trials Neuroscience |
| title | Modeling buprenorphine reduction of fentanyl-induced respiratory depression |
| title_full | Modeling buprenorphine reduction of fentanyl-induced respiratory depression |
| title_fullStr | Modeling buprenorphine reduction of fentanyl-induced respiratory depression |
| title_full_unstemmed | Modeling buprenorphine reduction of fentanyl-induced respiratory depression |
| title_short | Modeling buprenorphine reduction of fentanyl-induced respiratory depression |
| title_sort | modeling buprenorphine reduction of fentanyl induced respiratory depression |
| topic | Clinical trials Neuroscience |
| url | https://doi.org/10.1172/jci.insight.156973 |
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