Elsevier

Drug and Alcohol Dependence

Volume 163, 1 June 2016, Pages 16-23
Drug and Alcohol Dependence

Review
Naloxone without the needle − systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal

https://doi.org/10.1016/j.drugalcdep.2016.02.042Get rights and content

Highlights

  • Deaths from opioid overdose can be prevented by prompt injection of the opiate antagonist naloxone.

  • After 40 years of injection-based naloxone, a concentrated naloxone nasal spray is now approved.

  • Systematic review finds 3 potential injection-free naloxone routes: nasal, sublingual & buccal.

  • Alongside concentrated nasal naloxone, buccal may have distinct advantages as future product.

  • Wider pre-provision of naloxone across the community is essential; all three routes warrant study.

Abstract

Introduction

Deaths from opioid overdose can be prevented through administration of the antagonist naloxone, which has been licensed for injection since the 1970s. To support wider availability of naloxone in community settings, novel non-injectable naloxone formulations are being developed, suitable for emergency use by non-medical personnel.

Objectives

1) Identify candidate routes of injection-free naloxone administration potentially suitable for emergency overdose reversal; 2) consider pathways for developing and evaluating novel naloxone formulations.

Methods

A three-stage analysis of candidate routes of administration was conducted: 1) assessment of all 112 routes of administration identified by FDA against exclusion criteria. 2) Scrutiny of empirical data for identified candidate routes, searching PubMed and WHO International Clinical Trials Registry Platform using search terms “naloxone AND [route of administration]”. 3) Examination of routes for feasibility and against the inclusion criteria.

Results

Only three routes of administration met inclusion criteria: nasal, sublingual and buccal. Products are currently in development and being studied. Pharmacokinetic data exist only for nasal naloxone, for which product development is more advanced, and one concentrated nasal spray was granted licence in the US in 2015. However, buccal naloxone may also be viable and may have different characteristics.

Conclusion

After 40 years of injection-based naloxone treatment, non-injectable routes are finally being developed. Nasal naloxone has recently been approved and will soon be field-tested, buccal naloxone holds promise, and it is unclear what sublingual naloxone will contribute. Development and approval of reliable non-injectable formulations will facilitate wider naloxone provision across the community internationally.

Introduction

Heroin/opioid overdose deaths represent a major international public health concern (UNODC/WHO, 2013). Even in countries with low prevalence of opioid use relative to consumption of other illicit drugs, opioids contribute disproportionately to overdose fatalities (Degenhardt et al., 2011, WHO, 2014). In the United States (US), there has been a greater than fourfold increase in overdose deaths from prescription opioids since 1999, accounting for 16,651 deaths in 2010 alone (CDC, 2012, Volkow et al., 2014), as well as a simultaneous rise in heroin overdose deaths from 2007 onwards (Calcaterra et al., 2013). In the United Kingdom (UK), a 64% rise in heroin/morphine deaths was recorded for England and Wales between 2012 and 2014 (ONS, 2015).

In response, there are increasing calls for wider access to the opioid antagonist naloxone (ACMD, 2012, UNODC/WHO, 2013). The World Health Organization (WHO) launched new guidelines on the prevention of opioid overdose deaths in 2014, recommending that “people likely to witness an opioid overdose should have accesss to naloxone” (p. x) (WHO, 2014).

In the US, the National Institute on Drug Abuse (NIDA) made funding available for the development of novel injection-free naloxone products (Volkow et al., 2014) and, in November 2015, the US Food and Drug Administration (FDA) gave approval to a new nasal spray of concentrated naloxone solution (FDA, 2015), thereby giving the first regulatory product approval worldwide for a non-injectable naloxone product.

The notion of non-injectable formulations of naloxone is attractive: naloxone without needles would have many advantages. Firstly, medications which need to be injected are intimidating for lay persons to use in non-medical settings (Beletsky et al., 2012). Secondly, with use of naloxone by injection, there is the risk of needle-stick injury and contraction of blood-borne diseases (e.g., hepatitis C, HIV), which are highly prevalent among this patient group. Thirdly, non-injectable naloxone could more easily be provided to a much wider intervention workforce (e.g., hostel staff, outreach workers, police, etc.).

New methods of delivery for naloxone need to be suitable for emergency use by non-medical personnel in community-based settings. Furthermore, formulations should be developed with longer shelf-life, especially in view of the pre-placement of these naloxone products to community and families and other non-hospital settings. Naloxone also needs to be absorbed rapidly, given the emergency situation, in quantity sufficient to effect quick reversal of opioid-induced respiratory depression.

The reference for any candidate non-injectable routes is injectable naloxone, administered by the licensed intramuscular (IM), intravenous (IV), and subcutaneous (S/C) routes (WHO, 2014). When administered by the IM or S/C routes, naloxone typically reverses opioid action within 3–7 min; whereas the effect from IV administration has an onset typically within 2 min (UNODC/WHO, 2013). With long-standing approval for, and experience with, naloxone in injectable form, this sets the standard against which possible non-injectable formulations need to be measured (Hertz, 2012). In this review, we examine the options for non-injectable naloxone with potential application for wider community-based opioid overdose reversal.

Section snippets

Material and methods

A three-stage approach has been taken (see Fig. 1). The first stage was an examination of all 112 routes of drug administration listed by the US Food and Drug Administration (FDA, 1992) updated 2014). For each of the 112 possible routes of administration, we considered the potential applicability as a viable non-injectable route for emergency naloxone delivery by non-medical personnel (see Supplementary Material). We thus identified routes as unsuitable according to five exclusion criteria:

  • i)

    If

Shortlisting potential non-injectable routes from analysis of all routes of administration

From examination of all 112 listed routes of administration (FDA, 1992), four were excluded on the basis that they held no analytic relevance (‘unassigned’, ‘unknown’, ‘other’ and ‘not applicable’). From the remaining 108 categories, a further 102 were excluded according to the criteria listed in ‘Method’ (see determination in Supplementary Material). For instance, enteral delivery (through the gastro-intestinal mucosa) was excluded because of insufficient systemic absorption, since naloxone is

Discussion

The development of non-injectable formulations of naloxone is of major importance because of the potential for administration by non-medical people in emergency situations. Injectable routes work well and are fit for purpose for use by medical staff in hospital settings or by ambulance personnel attending a community emergency overdose scenario. However, the consideration is different for emergency administration by the general public (i.e. without medical training). While family members can be

Author contributions

JS and RM drafted the manuscript. RM conducted the database analyses. AA, BF, DT, and PR contributed to the overall work and further development of the manuscript. All authors approved of the final draft of the manuscript.

Funding

No specific funding was sought or secured for the study reported in this paper.

Declaration of interests

JS declares that he is a researcher and clinician who has worked with a range of types of treatment and rehabilitation service-providers. JS is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King's College London. He has also worked with a range of governmental and non-governmental organisations, and with pharmaceutical companies to seek to identify new or improved treatments

References (52)

  • A.Y. Walley et al.

    Opioid overdose prevention with intranasal naloxone among people who take methadone

    J. Subst. Abuse Treat.

    (2013)
  • ACMD

    Consideration of Naloxone

    (2012)
  • Alqurshi, A., Kumar, Z., McDonald, R., Strang, J., Buanz, A., Ahmed, S., Allen, E., Cameron, P., Rickard, J., Sandhu,...
  • L. Beletsky et al.

    Prevention of fatal opioid overdose

    JAMA

    (2012)
  • D. Belz et al.

    Naloxone use in a tiered-response emergency medical services system

    Prehosp. Emerg. Care

    (2006)
  • CDC

    CDC grand rounds: prescription drug overdoses — a U.S epidemic

    MMWR

    (2012)
  • O. Dale et al.

    Intranasal midazolam: a comparison of two delivery devices in human volunteers

    J. Pharm. Pharmacol.

    (2006)
  • L. Degenhardt et al.

    Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies

    Addiction

    (2011)
  • P.G. Djupesland et al.

    The nasal approach to delivering treatment for brain diseases: an anatomic physiologic, and delivery technology overview

    Ther. Deliv.

    (2014)
  • M. Doe-Simkins et al.

    Saved by the nose: bystander-administered intranasal naloxone hydrochloride for opioid overdose

    Am. J. Public Health

    (2009)
  • J. Dowling et al.

    Population pharmacokinetics of intravenous intramuscular, and intranasal naloxone in human volunteers

    Ther. Drug Monit.

    (2008)
  • K. Dwyer et al.

    Opioid education and nasal naloxone rescue kits in the emergency department

    West. J. Emerg. Med.

    (2015)
  • J.D. Ehrick et al.

    Considerations for the development of nasal dosage forms

  • FDA

    Route of Administration

    (1992)
  • FDA

    FDA Moves Quickly to Approve Easy-to-use Nasal Spray to Treat Opioid Overdose

    (2015)
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