ReviewNaloxone without the needle − systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal
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
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These authors contributed equally to this manuscript and should be considered joint first authors.