Comments on Strang et al. (2016): 'Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?'.

Abstract

In the February commentary, ‘Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures?’1, the authors have dismissed more than 10 years of evidence and experience with intranasal naloxone, although much of their own work heavily references studies with nasal naloxone. Four systematic reviews concluded that take-home naloxone—with nasal naloxone featured prominently—is safe and probably effective in preventing fatal overdose 2-5. Dr McDonald's own Bradford Hill analysis showed take-home naloxone satisfying seven of nine causation criteria 6. The interrupted times–series analysis of the impact of layperson-administered nasal naloxone played a key role in her analysis 7. While data on naloxone rescues are mostly observational, the real-world nature of these results warrants considering these data seriously, not discounting them. We were also surprised that the search of US NIH RePORTER did not reference an ongoing clinical trial from which preliminary data were shared at a Food and Drug Administration (FDA) meeting in July 2015 at which Dr Strang was present 8. Off-label use of nasal naloxone first began in the early 2000s by emergency medical technicians in communities where they were not permitted to deliver medication parenterally. It has since become the standard of care in many areas, with positive results 9, 10. The commentary acknowledges that nasal naloxone was as—or nearly as—effective as intramuscular injection in pre-hospital comparison studies. This evidence, along with the acceptability of needleless alternatives, surely contributed to the 28 446 nasal naloxone doses distributed in 2013 in the United States 11. The commentary bases much of its argument on blood bioavailability and pharmacokinetic data. However, blood bioavailability and pharmacokinetics may be the wrong yardstick by which to model nasal drug effects. Naloxone does not act in the blood; it acts at opioid receptors in the brain. Nasal medications may be efficiently absorbed directly into the cerebrospinal fluid through the cribriform plate 12. The real-world success demonstrated in community nasal naloxone programs as well as ambulance studies, despite low blood bioavailability, may be because of direct brain absorption. Given the breadth of the experience with nasal naloxone, the analyses that correlate its use with a reduction in fatal opioid overdoses, and the extent to which the authors have consistently referred to those data to support their own studies, we remain perplexed by the authors’ explicit conclusion that ‘clinicians should prescribe take-home naloxone only as one of its licensed formulations’. If clinicians were to do have done this, there would be substantially less evidence upon which the authors could base their argument. We agree that new products should be tested rigorously in voluntary opioid-dependent groups before being approved. At the same time, we will continue working alongside laypeople to make available whichever naloxone products are acceptable to the range of probable end users, including drug using social networks, in order to reduce opioid overdose fatalities. M.D.S. is a paid and unpaid consultant on several non-profit educational projects that aim to increase access to all currently available naloxone products. C.B.G. served as an unpaid expert witness for governmental committees in 2015. C.S.D. has nothing to declare. T.C.G.’s time was funded, in part, by a grant from the Centers for Disease Control and Prevention (5 RFA CE15-1501) and the Agency for Healthcare Research and Quality [R18 HS024021-01 Green (Principle Investigator)]. The funding organizations had no role in the design and conduct of the letter, in the analysis and interpretation of the content presented or in the preparation, review or approval of the manuscript. In the past 5 years, T.C.G. was an employee of Inflexxion, Inc., a for-profit, small business that conducts research and creates behavior change products for people with substance use disorders under the NIH small business innovative research grant program. T.C.G. has also received a small grant and $3000 salary support from Purdue Pharma to develop overdose prevention education material for active, out-of-treatment drug users. A.Y.W.’s position at Boston Medical Center/Boston University School of Medicine includes working as the medical director for the Opioid Overdose Prevention Pilot Program at Massachusetts Department of Public Health. A.Y.W. created the Prescribe to Prevent online training module that was supported financially by the Substance Abuse Mental Health Services Administration.