Toxicology Case Files from the Utah Poison Control Center
Teaching Points
- Buprenorphine may cause significant respiratory depression even as a partial mu-opioid receptor agonist
- Buprenorphine dissociates from mu receptors very slowly and may not respond immediately to naloxone
- Instead, use a bolus of naloxone followed immediately by an infusion while providing respiratory support
- Full reversal of respiratory depression may not occur for 30 minutes
Case
A 3-year-old male presented to the emergency department following ingestion of a parent’s 8 mg buprenorphine tablet. He was sleepy and had small pupils, with mild hypoxia (85% on RA). He received numerous naloxone boluses due to lack of response to an initial 5 mg bolus. He was eventually stabilized on a 6 mg/hr naloxone infusion which was reduced to 4 mg/hr, then 2 mg/hr. The infusion was stopped the next morning, and the patient did well.
Reversal of buprenorphine-induced respiratory depression with naloxone
Buprenorphine is highly lipophilic, has very high affinity for mu opioid receptors, has a prolonged half-life, and has weak efficacy in activating mu receptors (i.e. acts as a partial agonist).
However, other PK/PD parameters beyond receptor affinity and half-life must be understood to successfully manage overdose. In contrast to other high-affinity opioid ligands like fentanyl and naloxone, buprenorphine stays bound to mu-opioid receptors for an extended period of time. It has a mu receptor dissociation half-life of about 40 minutes.1 This means even in the presence of high concentrations of other opioids, such as naloxone, those opioids will not have an opportunity to bind to mu receptors until buprenorphine first dissociates.
This phenomenon was illustrated by a volunteer study assessing buprenorphine-associated respiratory depression and reversal with naloxone.2 A bolus dose of naloxone did not immediately reverse respiratory depression. However, respiratory depression was reversed with the combination of a bolus of naloxone with an infusion.
As naloxone both rapidly reaches the brain and rapidly redistributes back out, a bolus dose may only transiently raise CNS naloxone concentrations without allowing sufficient time for naloxone to be effective. Adding an infusion maintains a steady amount of CNS naloxone, allowing naloxone to remain present while awaiting the very long dissociation half-life of buprenorphine.
Usual management of opioid overdose involves bolus doses of naloxone titrated to reversal of respiratory depression and then a naloxone infusion only if respiratory depression recurs. In instances of buprenorphine respiratory depression, a bolus dose followed immediately by an infusion may be more effective, and full reversal may not be seen for 30 minutes.
References
- Yassen A, Olofsen E, van Dorp E, Sarton E, Teppema L, Danhof M, Dahan A. Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers. Clin Pharmacokinet. 2007;46(11):965-80. doi: 10.2165/00003088-200746110-00004. PMID: 17922561.
- van Dorp E, Yassen A, Sarton E, Romberg R, Olofsen E, Teppema L, Danhof M, Dahan A. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 2006 Jul;105(1):51-7. doi: 10.1097/00000542-200607000-00012. PMID: 16809994.