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

J Opioid Manag. 2020 May/Jun;16(3):209-214. doi: 10.5055/jom.2020.0569.


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 tox-icity. 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 tol-erated with no adverse events noted during the trial. The pharmacokinetic results showed that a higher dose of intra-muscular 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 hy-drochloride 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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Analgesics, Opioid* / administration & dosage
  • Analgesics, Opioid* / pharmacokinetics
  • Biological Availability
  • Cross-Over Studies
  • Healthy Volunteers
  • Humans
  • Naloxone* / administration & dosage
  • Naloxone* / pharmacokinetics


  • Analgesics, Opioid
  • Naloxone