Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

Rutger van der Schrier, M.D.; Jack D. C. Dahan, B.Sc.; Martijn Boon, M.D., Ph.D.; Elise Sarton, M.D., Ph.D.; Monique van Velzen, Ph.D.; Marieke Niesters, M.D., Ph.D.; Albert Dahan, M.D., Ph.D.


Anesthesiology. 2022;136(4):618-632. 

In This Article

Controlled Substances: Opioids

Buprenorphine, among other drugs, is registered by the U.S. Food and Drug Administration (Silver Spring, Maryland) for treatment of opioid use disorder. Buprenorphine is a long-acting opioid that displaces the abused shorter-acting opioid from the μ-opioid receptor and dampens withdrawal symptoms and craving.[82] Eventually, illicit narcotic use will diminish. The question is whether long-acting opioid treatment also prevents respiratory depression from potent short-acting opioids such as fentanyl, heroin, and oxycodone that rapidly cross the blood–brain barrier. Particularly, the characteristics of buprenorphine are such that it may prevent lethal apneas in individuals with an opioid use disorder who overdose on potent opioids. Buprenorphine is a partial agonist at the μ-opioid receptor, antagonist at the κ-opioid receptor, and agonist at the nociception protein receptor. Partial agonism prevents full development of respiratory depression, while nociception protein receptor (NOP) activation stimulates breathing.[83,84] Both reduce the probability of severe respiratory depression or a fatal apneic event. Moreover, buprenorphine has slow receptor kinetics with high affinity for the μ-opioid receptor.[83] This indicates that buprenorphine will prevent binding of potent opioids to the μ-opioid receptor. We tested this assumption in individuals with an opioid use disorder and observed that buprenorphine at concentration in plasma greater than 2 ng/ml prevented respiratory depression and apnea from intravenous fentanyl, even when administered at high dose, a cumulative dose 1,800 μg in individuals with an opioid use disorder.[85] Simulation studies revealed that the best result is observed at a buprenorphine concentration of 5 ng/ml to prevent respiratory depression at the highest fentanyl dose simulated (5,000 μg), a dose not uncommon in the abuse scene.

Buprenorphine may also be used to treat opioid-induced respiratory depression. In opioid-dependent patients who were brought to the emergency room because of respiratory depression or developed respiratory depression during hospitalization, in the context of an opioid overdose, buprenorphine was superior to a continuous infusion of naloxone in reversal of respiratory depression as measured by blood gas values, intubation, and death.[86] Additionally, buprenorphine precipitated less withdrawal than naloxone, although some withdrawal was seen after high-dose buprenorphine. These results warrant further studies to address the interaction between buprenorphine and potent opioids as one needs to realize that buprenorphine, particularly at high dose, produces respiratory depression by itself, and interactions with potent short-acting opioids and sedatives are not well described in humans.

Finally, other opioid receptor agonists/antagonists have been studied in veterinary medicine to prevent lethal opioid-induced respiratory depression from potent opioids such as etorphine.[87,88] For example, in etorphine-immobilized goats, the partial agonists at the μ-opioid receptor nalbuphine and butorphanol improve respiratory parameters but at the cost of excitatory responses.[80] Given the many side effects that these agents produce, such as sedation, confusion, dizziness, and hallucinations, their use in humans is limited. Another example is diprenorphine,[88] which is used as a veterinary antidote after etorphine or carfentanil immobilization of large animals (e.g., rhinoceros). Its long duration of action, high receptor affinity, and partial agonist activity have prevented its use in humans.