Pharmacokinetic considerations for community-based dosing of nasal naloxone in opioid overdose in adults

ABSTRACT

Introduction

The administration of the opioid antagonist naloxone in the community is a measure to prevent death from opioid overdose. Approved nasal naloxone sprays deliver initial doses of 0.9 to 8 mg. The level of the initial community dose is controversial, as the scientific base is weak.

In this review knowledge of the pharmacokinetics of nasal, both approved and improvised nasal sprays, and intramuscular naloxone will be utilized to evaluate dose-effect relationships in previous studies of opioid overdose outcomes.

Areas covered

The aim was to present scientifically based considerations on the initial nasal naloxone doses currently available, which reasonably balances the effect and adverse outcomes, given that at least two doses are at hand. Also included in these considerations is the challenge by illicitly manufactured fentanyl and analogs.

This paper is based on both peer-reviewed and grey literature identified by several searches, of such as naloxone pharmacokinetics/formulations/outcomes/emergency medical services, in PubMed and Embase.

Expert opinion

There is little scientific evidence that supports the use of initial systemic dosing that exceeds 0.8 mg in the community. Higher doses increase the risk of withdrawal symptoms feared in people who use opioids. Many obstacles may reduce the potential of community-administered naloxone.

KEYWORDS:

• Administration
• intranasal
• narcotic antagonists
• opiate
• heroin
• fentanyl
• antidote
• spray
• harm reduction
• adverse events
• withdrawal symptoms

Article highlights

• The administration of the opioid antagonist naloxone in the community is an important measure to prevent death from opioid overdose.

• The aim is to restore adequate ventilation and not to fully awake the patient.

• The amount of naloxone in the initial dose is controversial as the scientific base is weak.

• Pharmacokinetic knowledge of naloxone in healthy volunteers may be valuable for interpreting the dose–effect relationship in opioid overdose reversal studies after community administration of naloxone.

• The introduction of concentrated nasal naloxone formulations may have led to an unnecessary increase in the general naloxone dose level.

• Given that at least two doses are available, the use of an initial systemic dose exceeding 0.8 mg in the community is not scientifically justified as due to the increased risk of withdrawal.

• Opioid overdose reversal studies using naloxone should be analyzed with reference to the severity of overdose at inclusion, rather than dichotomization to heroin or fentanyl.

• The procedure of approving non-injectable naloxone formulations based on studies in healthy volunteers should be replaced with adequate studies in the target population such as randomized controlled trials.

This box summarizes key points contained in the article.

Acknowledgments

Thanks to Arne Skulberg for feedback and technical support, Rebecca McDonald for input, editing, and proofreading, to Anders Åsberg for supplying Figure 3, and to Phatsawee Jansok for reviewing the paragraphs on excipients. Thanks also to Ida Tylleskär and Arne Skulberg for all inputs to our naloxone projects.

Declaration of interest

NTNU – The Norwegian University of Science and Technology has signed a collaboration and licensing agreement with Dne Pharma to commercialize a nasal spray formulation. Dne pharma has received marketing authorization for a naloxone nasal spray (Ventizolve/Respinal) based on this collaboration. The formulation was invented by O Dale, and the agreements ensure potential royalties for him through NTNU, and NTNU’s opportunity to publish results from its own research on the product. O Dale was the Principal Investigator (no personal honorarium) for dne pharma on a study of naloxone spray in volunteers and has been reimbursed for project-related journeys. O Dale has received honoraria and travel support from dne pharma for presentations on marketing event. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2022.2072728.

Additional information

Funding

This paper was not funded.