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Does High-Dose Buprenorphine Cause Respiratory Depression?

Possible Mechanisms and Therapeutic Consequences

  • Review Article
  • Published:
Toxicological Reviews

Abstract

Buprenorphine is an opioid agonist-antagonist with a ‘ceiling effect’ for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.

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Acknowledgements

The authors would like to acknowledge Dr Rebeca Gracia, PharmD, DABAT, from the North Texas Poison Center, Dallas, USA for her helpful review of this manuscript.

No source of funds was used to assist in the preparation of this manuscript. The authors are not aware of any potential conflicts of interest directly relevant to the content of this review.

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Authors and Affiliations

  1. Université Paris 7, Université Paris 5, Hôpital Fernand Widal, INSERM U705, CNRS, UMR 7157, Paris, France

    Bruno Mégarbane, Raymond Hreiche, Stéphane Pirnay, Nicolas Marie & Frédéric J. Baud

  2. Réanimation Médicale et Toxicologique, Université Paris 7, Assistance Publique - Hôpitaux de Paris, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010, Paris, France

    Bruno Mégarbane & Frédéric J. Baud

  3. Laboratoire de Toxicologie de la Préfecture de Police, Paris, France

    Stéphane Pirnay

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  1. Bruno Mégarbane
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  2. Raymond Hreiche
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Correspondence to Bruno Mégarbane.

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Mégarbane, B., Hreiche, R., Pirnay, S. et al. Does High-Dose Buprenorphine Cause Respiratory Depression?. Toxicol Rev 25, 79–85 (2006). https://doi.org/10.2165/00139709-200625020-00002

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