Nalbuphine Potentiates Reversal of Fentanyl Overdose by Naloxone

Abstract

Developing an effective antidote for fentanyl-induced overdose to achieve timely reversal is an unmet public health need. Previously, we found that naloxone derivative NX90 with mild κ-opioid agonistic properties was three-fold more effective than the parent naloxone in reversing a fentanyl overdose in rats. To investigate whether κ-agonistic properties could indeed augment the robustness of overdose reversal, we evaluated a κ-agonist/µ-antagonist nalbuphine (NB) as well as its combinations with naloxone (NX) in a fentanyl overdose model in rodents. An administration of either NB or NX as single agents at 0.1 mg/kg doses produced a full recovery in 90 ± 9.9 min and 11.4 ± 2.7 min, respectively. A higher dose of NX at 0.2 mg/kg reversed an overdose within 4.8 ± 1.0 min. In contrast to that, the coadministration of NB and NX at 0.1 mg/kg each produced a synergistic effect, with overdose reversal in 3.4 ± 0.2 min. The coadministration of NX and NB at sub-therapeutic doses of 0.05 mg/kg each was also 1.2-fold more effective than NX at 0.2 mg/kg. We further found that co-administration of NB at different doses (0.025, 0.05, 0.1 mg/kg) and ratios (1:4 and 1:1) with NX had differential effects on overdose reversal, cardiorespiratory liabilities, and analgesia.

Keywords: fentanyl; nalbuphine; naloxone; overdose reversal; withdrawal.

Figure 1

(A) Total number of deaths from overdose and rates of non-fatal opioid overdose per 100,000 population in the US (2018–2022). (B) Chemical structures of fentanyl, naloxone, and nalbuphine.

Figure 2

(A) Design of the experiment: vitals and reflexes monitored: RR—respiratory rate, HR—heart rate, BT—body temperature, AN—alertness (if the rat responded to acoustic and painful stimuli at the skin level), AT—astasia (if the rat showed locomotor imbalance or stopped moving), CR—corneal reflex (closure of eyelids in response to irritation of the cornea by touching with a sterile cotton applicator), PRT—pinch reflex tail (tail flick when pinching the tail), PRToe—pinch reflex toe (toe flinch when pinching the toe), Rref—righting reflex (the lack of the righting reflex from the decubitus position), ST—sternal recumbency (the rat has no tendency to rise from the sternal recumbency position, in a support position on the 4 limbs). T-20 NOC—nociception pretest 20 min prior to fentanyl administration, T + 40 nociception test 40 min after fentanyl administration. (B) The Bonferroni test was used to compare differences of mean time to all reflexes restored (* p < 0.05; *** p < 0.005).

Figure 3

(A) Mean heart rate (RR) as a percentage of the resting rate for all treated groups. (B) Cumulative measure of respiratory activity for all treated groups (* p < 0.05). (C) Mean heart rate (HR) as a percentage of the resting rate for all treated groups. (D) Cumulative measure of heart rate for all treated groups. The Bonferroni test was used to compare treated groups to NX standard dose (0.1 mg/kg) (* p < 0.05; ** p < 0.01; *** p < 0.005). (E) Analgesia as a percentage of the maximum possible effect for all treated groups. The Bonferroni test was used to compare treated groups to NX standard dose (0.1 mg/kg) (* p < 0.05; ** p < 0.01; *** p < 0.005). (F) Rank order of OD reversal (mean time to all reflexes restored), HR AUC, RR AUC, and analgesia for all interventions. Error bars on the graphs denote standard error.

Figure 3

(A) Mean heart rate (RR) as a percentage of the resting rate for all treated groups. (B) Cumulative measure of respiratory activity for all treated groups (* p < 0.05). (C) Mean heart rate (HR) as a percentage of the resting rate for all treated groups. (D) Cumulative measure of heart rate for all treated groups. The Bonferroni test was used to compare treated groups to NX standard dose (0.1 mg/kg) (* p < 0.05; ** p < 0.01; *** p < 0.005). (E) Analgesia as a percentage of the maximum possible effect for all treated groups. The Bonferroni test was used to compare treated groups to NX standard dose (0.1 mg/kg) (* p < 0.05; ** p < 0.01; *** p < 0.005). (F) Rank order of OD reversal (mean time to all reflexes restored), HR AUC, RR AUC, and analgesia for all interventions. Error bars on the graphs denote standard error.