Open Access Open Access  Restricted Access Subscription or Fee Access

An open-label, randomized, single-dose, two-period, two-treatment crossover bioavailability study comparing 5 mg/0.5 mL of intramuscular naloxone hydrochloride to 2 mg/0.4 mL intramuscular naloxone hydrochloride autoinjector in healthy subjects

Ronald B. Moss, MD, Fiona Carleton, PhD, Charles P. Lollo, PhD, Dennis J. Carlo, PhD

Abstract


Naloxone is an opioid antagonist used for the acute treatment of opioid overdoses. There has been a dramatic increase of deaths due to synthetic opioids such as fentanyl, some requiring multiple doses of naloxone for reversal of opioid toxicity. Fentanyl appears to differ from other opiates as having a very rapid onset and transport in and out of the central nervous system (CNS). Fentanyl is therefore widely distributed in the CNS. Furthermore, a high range of systemic levels of fentanyl have been observed in overdose victims. Taken together, we believe it is very likely that higher doses of naloxone are needed to combat this new era of overdoses. We examined the bioavailability of an investigational 5 mg intramuscular naloxone in a prefilled syringe (PFS) compared to 2 mg intramuscular naloxone in an autoinjector (AI) at the current approved dose in a crossover design which included 14 healthy subjects. Overall, both doses were well tolerated with no adverse events noted during the trial. The pharmacokinetic results showed that a higher dose of intramuscular naloxone hydrochloride increases Cmax, AUC, and t1/2; however, Tmax was similar for both treatments. Statistical analysis indicated that there were statistical differences between the test and reference treatments for Cmax, AUCs, and t1/2 with ratios of test to reference for Cmax of 337.1 percent (CI: 263.3 percent, 431.5 percent), AUC0-t of 277.5 percent (CI: 260.4 percent, 295.7 percent), AUC0-inf of 273.4 percent (CI: 255.6 percent, 292.4 percent), and t1/2 of 110.5 percent (CI: 95.5, 127.9). These results are consistent with the study rationale that indicated higher doses of intramuscular naloxone hydrochloride would result in higher Cmax and AUCs. These PK characteristics may be desirable for reversing opioid toxicity caused by the higher, more potent synthetic opioids.


Keywords


naloxone, high dose, pharmacokinetics, opioid over-dose

Full Text:

PDF

References


Understanding the Epidemic, Centers for Disease Control and Prevention: Available at https://www.cdc.gov/drugoverdose/epidemic/index.html. Accessed June 16, 2019.

Provisional Drug Overdose Death Counts, Centers for Disease Control and Prevention: Available at https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. Accessed June 16, 2019.

Schumann H, Erickson T, Trevonne M, et al.: Fentanyl epidemic in Chicago, Illinois and surrounding Cook County. Clin Toxicol. 2008; 46:6, 501-506.

Bell A, Bennett A, Jones TS, et al.: Amount of naloxone used to reverse opioid overdoses outside of medical practice in a city with increasing illicitly manufactured fentanyl in illicit drug supply. Subst Abus. 2018; 40(1): 52-55. DOI:10.1080/08897077.2018.1449053.

Somerville NJ, O’Donnell J, Gladden RM, et al.: Morb Mortal Wkly Rep. 2017; 66(14): 382-386.

Moss RB, Carlo DJ: Higher doses of naloxone are needed in the synthetic opioid era. Subst Abus Treat Prev Policy. 2019; 14: 6.

Taylor DR: The pharmacology of fentanyl and its impact on the management of pain. Medscape Neurol. 2005; 7(2): Available at https://www.medscape.org/viewarticle/518441. Accessed June 16, 2019.

Fogarty MF, Papsun DM, Logan BK: Analysis of fentanyl and 18 novel fentanyl analogs and metabolites by lc-ms-ms, and report of fatalities associated with methoxyacetylfentanyl and cyclopropylfentanyl. J Anal Toxicol, 2018; 42(9): 592-604.

Wong B, Perkins MW, Tressler J, et al.: Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone. Inhalation Toxicol. 2017; 29(2): 65-74.

Johansson J, Hirvonen J, Lovró Z, et al.: Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects. Neuropsychopharmacology. 2019; 44(9): 1667-1673. doi:10.1038/s41386-019-0368-x

Lynn RR, Galinkin JL: Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018; 9(1): 63-88.




DOI: https://doi.org/10.5055/jom.2020.0569

Refbacks

  • There are currently no refbacks.