B. T. Gufford,1 G. R. Ainslie,2 J. M. Padowski,3 M. E. Layton,3 J. R. White,1 M. F. Paine1; 1College of Pharmacy, Washington State University, Spokane, WA, 2Curriculum in Toxicology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 3College of Medical Sciences, Washington State University, Spokane, WA

BACKGROUND: Deaths due to opioid overdose are burgeoning. Methods to assess opioid effects and reversal in humans are invasive and costly. A novel intranasal (IN) naloxone formulation was evaluated as a non-invasive, inexpensive method to assess reversal of opioid effects in healthy subjects.
METHODS: Six subjects received naloxone IV, IM, or IN (2 mg) in a 3-phase sequential study; plasma was collected (0-4 h) and analyzed by LC/MS/MS. Six more subjects received alfentanil PO (4 mg) followed by naloxone IN or IM (2 mg), in the absence or presence of grapefruit juice (GFJ), in a 6-phase sequential study; pupil diameter was measured (0-6 h). Pharmacokinetic and effect outcomes were obtained by non-compartmental methods.
RESULTS: Geometric mean [90% CI] bioavailability, AUC0-4h, and mean (SE) MAT of IM vs. IN naloxone, respectively, was 55 [43-70] vs. 41 [27-62] %, 5.8 [5.2-6.5] vs. 4.4 [3.2-6.2] ng*h/mL, and 75 (8.8) vs. 6.7 (4.9) min. Versus water, GFJ enhanced miosis (AUEC0-6h, 61 [38-98] vs. 84 [53-130] h*%). AUEC0-6h after IM vs. IN naloxone in the absence and presence of GFJ, respectively, was 39 [27-57] vs. 41 [33-52] h*% and 43 [19-100] vs. 50 [28-89] h*%.
CONCLUSION: A novel IN naloxone formulation showed favorable pharmacokinetics and reversed miosis, providing a human model to non-invasively assess reversal of opioid effects.