Opioid Overdose: Limitations of Naloxone

Abstract and Introduction

Abstract

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression.

However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the μ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, the authors examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest.

Authors and Disclosures

Table 1. μ-Opioid Receptor Affinities and Receptor Dissociation Constants of Different Opioids ^6,15,17–19
	Receptor Affinities (nM)	Receptor Dissociation Constants (s⁻¹)
Codeine	734
Meperidine	450
Oxycodone	25.9
Methadone	3.38
Fentanyl	1.35	0.004
Morphine	1.17	0.002
Hydromorphone	0.37
Buprenorphine	0.22	0.0002
Sufentanil	0.14	0.001
Carfentanil	0.05	0.00025
Naloxone	1.1	0.040

Maarten van Lemmen, B.Sc.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Jeffrey Florian, Ph.D.
Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.

Zhihua Li, Ph.D.
Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.

Monique van Velzen, Ph.D.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Eveline van Dorp, M.D., Ph.D.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Marieke Niesters, M.D., Ph.D.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Elise Sarton, M.D., Ph.D.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Erik Olofsen, Ph.D.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

Rutger van der Schrier, M.D.
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.

David G. Strauss, M.D., Ph.D.
Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.

Address correspondence to
Dr. Dahan: Department of Anesthesiology, Anesthesia & Pain Research Unit, Leiden University Medical Center, H5-022, 2300 RC Leiden, The Netherlands. a.dahan@lumc.nl. ANESTHESIOLOGY's articles are made freely accessible to all readers on www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.

Competing Interests
In the last 36 months, Dr. Dahan received consultancy fees from Enalare Therapeutics Inc. (Princeton, New Jersey), Trevena Inc. (Chesterbroom, New Jersey), Cessation Therapeutics Inc. (Chapel Hill, North Carolina), and Takeda Pharmaceuticals International AG (Switzerland) and awards or grants from the U.S. Food and Drug Administration (Silver Spring, Maryland), the Netherlands Organization for Health Research and Development (ZonMW, The Hague, The Netherlands) in the framework of GGG (Good Use of Medication; project No. 848120001), and from the Dutch Research Council (NWO, The Hague, The Netherlands) in the framework of the Nederlandse Wetenschaps Agenda-Onderzoek op Routes door Consortia (NWA-ORC) Call for research project TAPTOE, Tackling and preventing the opioid epidemic (NWA.1160.18.300). Dr. Dahan holds Enalare stock options. The other authors declare no competing interests.

Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest

Abstract and Introduction

Abstract

Tables

References

Authors and Disclosures

Authors and Disclosures

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