1521-0103/371/2/409–415$35.00 https://doi.org/10.1124/jpet.118.256115 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 371:409–415, November 2019 U.S. Government work not protected by U.S. copyright Special Section on The Opioid Crisis Fighting Fire with Fire: Development of Intranasal Nalmefene to Treat Synthetic Opioid Overdose Philip Krieter, Shwe Gyaw, Roger Crystal, and Phil Skolnick National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland (P.K., S.G.) and Opiant Pharmaceuticals, Santa Monica, California (R.C., P.S.) Downloaded from Received January 2, 2019; accepted March 27, 2019 ABSTRACT The dramatic rise in overdose deaths linked to synthetic opioids Encinitas, CA) reduced Tmax to 0.25 hour and increased Cmax by (e.g., fentanyl, carfentanil) may require more potent, longer- ∼2.2-fold. The pharmacokinetic properties of IN nalmefene jpet.aspetjournals.org duration opiate antagonists than naloxone. Both the high affinity (3 mg) formulated with dodecyl maltoside has characteristics of nalmefene at m opiate receptors and its long half-life led us to consistent with an effective rescue medication: its onset of examine the feasibility of developing an intranasal (IN) formula- action is comparable to an i.m. injection of nalmefene (1.5 mg) tion as a rescue medication that could be especially useful in previously approved to treat opioid overdose. Furthermore, treating synthetic opioid overdose. In this study, the pharmaco- the Cmax following IN administration was ∼3-fold higher than kinetic properties of IN nalmefene were compared with an following i.m. dosing, comparable to previously reported plasma intramuscular (i.m.) injection in a cohort of healthy volunteers. concentrations of nalmefene observed 5 minutes following a Nalmefene was absorbed slowly following IN administration, 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life at ASPET Journals on September 25, 2021 with a median time to reach Cmax (Tmax) of 2 hours. Addition of the (.7 hours) of IN nalmefene present distinct advantages as a rescue absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., medication, particularly against longer-lived synthetic opioids. Introduction and prescription opioids [reviewed by Skolnick (2018)]. Fur- thermore, the piperidine-based structure of fentanyl is highly A Government Accountability Office report released in mutable. More than 1400 fentanyl analogs have been de- October 2018 declared the opioid crisis a public health scribed in the patent and scientific literature, and a dozen or emergency (https://www.gao.gov/products/GAO-18-685R). more are available on the illicit market (Misailidi et al., 2018), The most visible manifestation of this crisis is the rising adding another layer of complexity for both detection and number of opioid overdose deaths and the dramatic spike in interdiction by law enforcement. fatalities linked to fentanyl and related synthetic opioids. Naloxone is currently the only Food and Drug Administra- Thus, based on 2017 estimates (https://www.drugabuse.gov/ tion (FDA)–approved treatment for suspected or confirmed related-topics/trends-statistics/overdose-death-rates), syn- opioid overdose. The efficacy of naloxone at reversing the thetic opioids (“synthetics”) were linked to more than half of pharmacological actions of opioids, including synthetics such the estimated 49,000 opioid-related deaths, far surpassing as fentanyl, has been well established in both the emergency fatalities attributed to either heroin or prescription opioids. department and operating room [Glass et al., 1994; Kaplan et al., There are multiple factors responsible for the dangers posed 1999; reviewed by Boyer (2012)]. There are two FDA-approved by synthetics, including very high potencies, rapid onset of naloxone products (an autoinjector and a nasal spray) that are action, long half-lives, and ease of synthesis; this latter primarily used by first responders (e.g., police, emergency property translates to a low cost of goods relative to heroin medical service technicians, bystanders) to treat overdose victims (Skolnick, 2018). However, both anecdotal reports (https://www.bloomberg.com/news/articles/2017-08-16/heroin- P.S. and R.C. are employees of Opiant Pharmaceuticals, Inc. P.K. and S.G. are employees of the National Institutes of Health. era-antidotes-can-t-handle-overdoses-in-age-of-synthetics; The work was conducted under a Clinical Trial Agreement supported in part https://www.washingtonpost.com/amphtml/news/post-nation/ by Opiant Pharmaceuticals and National Institute on Drug Abuse contracts N01DA-12-8905, N01DA-13-8920, and N01DA-14-8914. wp/2018/04/10/study-despite-decline-in-prescriptions-opioid- https://doi.org/10.1124/jpet.118.256115. deaths-skyrocketing-due-to-heroin-and-synthetic-drugs/) and ABBREVIATIONS: AE, adverse event; AUC0–t, area under the concentration time curve from time zero to the last measurable concentration; CI, confidence interval; DDM, dodecyl maltoside; FDA, Food and Drug Administration; IN, intranasal; LC-MS/MS, liquid chromatography–tandem mass spectrometry; Tmax, time to reach Cmax;t1/2, elimination phase half-life. 409 410 Krieter et al. clinical case studies (Sutter et al., 2017; Uddayasankar, et al., alcohol from admission to the end of the last blood draw of the study, 2018) indicate overdose with synthetics such as fentanyl and from nicotine and from caffeine-containing products and food for at least carfentanil often requires more naloxone than the standard 1 hour prior to and 2 hours after dose administration, and from caffeine- unit doses [2 mg i.m./4 mg intranasal (IN)] generally available containing products and food from midnight the day prior to and 4 hours ’ to first responders. Some authors (Li et al., 2018) have recom- after nalmefene dosing. On days of dosing, a subject s vital signs were required to be within the normal range before receiving nalmefene mended parenteral naloxone doses of up to 12–15 mg to (systolic blood pressure .90 and #140 mm Hg, diastolic blood pressure .55 successfully reverse a synthetic overdose. While each overdose and #90 mm Hg, resting heart rate .40 and #100 beats per minute, situation is unique (Skolnick, 2018), the current National and respiratory rate .8 and #20 respirations per minute). Institute on Drug Abuse position states that “Overdoses of Study Design. The study was an inpatient, double-blind (for fentanyl should be treated immediately with naloxone and IN administration), randomized, four-period, four-treatment, six- may require higher doses to successfully reverse the overdose” sequence crossover. Subjects were randomly assigned to one of six (https://www.drugabuse.gov/publications/drugfacts/fentanyl). sequences to ensure at least two subjects in each sequence. On the day Moreover, the short half-life of naloxone (t1/2 1.3–2.4 hours) after clinic admission, participants were administered the study drug (Ryan and Dunne, 2018) can complicate the management of in randomized order with a 4-day washout period between doses. overdose with long-lived synthetics, including fentanyl (Ahonen Subjects remained at the clinic for 17 days until all four treatments – et al., 2000; Kharasch, 2015). were administered. They were contacted 3 5 days after discharge by a follow-up telephone call. Subjects fasted overnight before each dosing In response to the increasing number of overdose deaths day and received one of the following four treatments: Downloaded from linked to synthetics, National Institutes of Health leadership recently called for the development of “…stronger, longer- Treatment A: 3 mg IN (one 0.1-ml spray of a 30-mg/ml acting formulations of antagonists” (Volkow and Collins, nalmefene solution in one nostril). 2017). At face value, the opiate antagonist nalmefene fulfills Treatment B: 3 mg plus 0.25% dodecyl maltoside (DDM; Intravail) IN (one 0.1-ml spray of a 30-mg/ml nalmefene these criteria. Thus, multiple studies (Emmerson et al., 1994; solution containing 0.25% DDM in one nostril). Toll et al., 1998; Cassel et al., 2005) have demonstrated that Treatment C: 1.5 mg IN (one 0.1-ml spray of a 15-mg/ml the affinity of nalmefene is ∼5Â higher than naloxone at both nalmefene solution in one nostril). jpet.aspetjournals.org native and recombinant m opioid receptors. The half-life (t1/2) Treatment D: 1.5 mg i.m. (1.5 ml of a 1.0-mg/ml nalmefene solution). of parenterally administered nalmefene is ∼8.2–8.9 hours The IN treatments were randomized while the intramuscular dose (Dixon et al., 1986), comparable to the half-lives of synthetics was the last treatment of all subjects. The high dose (3 mg) of – such as fentanyl (7 to 8 hours) and sufentanil (6 9 hours) nalmefene was selected based on the relative bioavailability (∼50%) (Ahonen et al., 2000; Kharasch, 2015). In addition, the efficacy of the structurally related molecule, naloxone (Krieter et al., 2016), of nalmefene in treating opioid overdose has been established. and the FDA guidance on parenteral dosing of nalmefene that Thus, parenteral nalmefene was FDA approved (1995) to treat produces a maximum reversal of a suspected opioid overdose (https:// at ASPET Journals on September 25, 2021 opioid overdose was but withdrawn from the market in 2008 www.accessdata.fda.gov/drugsatfda_docs/label/2006/020459s006lbl.pdf). due to low sales, with no significant safety issues (https:// In phase I studies, intravenous doses of up to 24 mg have been well www.federalregister.gov/documents/2017/11/03/2017-23952/ tolerated in normal volunteers (Dixon et al., 1986). determination-that-revex-nalmefene-hydrochloride-injection-01- Study Details. IN devices were coded so neither the staff nor the milligram-basemilliliter-and-10). Here, we describe a pilot study subjects knew the treatment administered. IN nalmefene was admin- istered in the supine position, and subjects remained in this position in healthy volunteers demonstrating the feasibility of developing for approximately 1 hour after dosing.