Can Intranasal Nalmefene Reduce the Number of Opioid Overdose Deaths?

This Journal recently published a paper describing the pharmacokinetics of a recently Food and Drug Administration (FDA) approved device for intranasal administration of the opioid receptor antagonist nalmefene.¹ Parenteral nalmefene was approved in 1995, but was subsequently withdrawn from the market by the manufacturer because of lack of market success. The new formulation (Trade Name Opvee, Indivior Inc., Richmond, VA) is “indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression”. The basis of this approval was nalmefene's high affinity as an antagonist at the mu opioid receptor, the apparent safety of nalmefene in humans, the pharmacokinetic similarity to intramuscular nalmefene, and the demonstration of changes in minute ventilation in an experimental ventilatory model assessed in non-dependent healthy subjects who received an infusion of remifentanil.

Despite the reportedly favorable pharmacokinetic profile of intranasal nalmefene, the likelihood that this new formulation will play a critical role in preventing opioid overdose deaths in the context of the public health opioid epidemic is questionable given the challenges that have confronted the widely known opioid receptor antagonist naloxone.²

Naloxone, a pure opioid receptor antagonist, has been approved since 1971, is widely available, and can safely reverse the opioid induced respiratory depression and prevent deaths in medical and non-medical settings.³ While naloxone is available in intranasal, intravenous, and intramuscular formulations and is effective in preventing opioid overdose death of individuals, the number of opioid overdose deaths continues to rise (about 80,000 per year).⁴ This limited impact is disappointing but not surprising given the many practical obstacles associated with the use of opioid receptor antagonists, including the following: distribution of naloxone to the location of opioid overdose; providing training to first responders; direct and indirect cost of naloxone (in some cases naloxone is more expensive than the street price of opioids and other drugs); bias and prejudice about individuals who have opioid used disorder (OUD); a mismatch of the at-risk population to the available health services for immediate and longer term management of OUD; and a resistance by many opioid users to receive an antagonist and/or enter treatment. These challenges are further exacerbated by pervasive socio-economic factors, wide geographic variation in overdose rates, and uneven access to and cost of healthcare.

Intranasal nalmefene, like naloxone administered by similar routes, is rapidly absorbed. Theoretically the longer half-life of nalmefene (mean 11.3 hours compared to 30-90 minutes for naloxone) might make the drug useful for preventing and protecting against the toxic effects of longer-acting opioids. However, in emergent overdose situations usually the half-life of the opioid taken is not known. The longer half-life of the antagonist may be associated with a greater frequency of opiate withdrawal, which may need to be managed. The paper published in the Journal documents large variation in C_max for intranasal nalmefene (typical coefficient of variation 50%-70%) suggesting that the actual clinical response to the intranasal nalmefene is not easily predicted and could be quite variable. However, measures of nalmefene opioid receptor occupancy and reversal of morphine-induced respiratory depression suggest quite prolonged effects, perhaps as long as 4-6 hours.^{5, 6}

Approval of the new intranasal formulation was based on the exposure equivalency of the intranasal to intramuscular route and not based on any actual patient data. Ideally, such data should be gathered as part of a postapproval monitoring, research or safety program. Three other factors may also limit clinical use of the new product: first, cost, which is expected to be greater than generic naloxone; second, the new formulation contains only a single dose, decreasing the flexibility of cost-effective repeat dosing if needed; and finally, lack of familiarity of physicians, first responders, and health facilities with “nalmefene”.

In our opinion, the new formulation and availability of intranasal nalmefene will save the lives of individuals who receive the drug; it is far less clear whether it will have a significant impact on overall rates of opioid-related overdose deaths and the public health crisis of OUD.

E.M.S. and M.K.R. have provided psychopharmacology consultant advice to pharmaceutical companies for which they received an hourly consultant fee. Neither E.M.S. nor M.K.R. has any equity or other compensation arrangements with any pharmaceutical company related to product development success or funding. None of the authors received any compensation for preparation of this Letter to the Editor.