Development and Characterization of a Swine Model of Non-lethal Critical Respiratory Depression Induced by Opioid Overdose

Abstract

This study characterized a swine model of fentanyl- and heroin-induced non-lethal apnea to support development of translational strategies for opioid overdose interventions. Spontaneously breathing, isoflurane-anesthetized Hanford swine (n=18; 4–25 kg) received intravenous fentanyl (n=12) or heroin (n=6) via constant rate infusion (fentanyl: 30 µg/kg/h; heroin: 1 mg/kg/h) until apnea. Fentanyl-treated pigs were either sexually immature (~2 months) or mature (~4 months); heroin-treated pigs were immature. Statistical comparisons used unpaired two-tailed Mann-Whitney and Gehan-Breslow-Wilcoxon tests (p<0.05). Data are median (IQR). Fentanyl doses to induce apnea were 17 (15–36) µg/kg (immature) and 8 (7–10) µg/kg (mature), while heroin dose was 360 (290–502) µg/kg. Serum fentanyl concentrations at apnea were 4 (3–7) and 6 (4–8) ng/mL, with norfentanyl levels of 1.5 (0.8–2.2) and 0.1 (0.1–0.2) ng/mL, respectively. Heroin exposure produced 6-acetylmorphine and morphine levels of 57 (44–91) and 34 (29–61) ng/mL. Return to spontaneous breathing occurred at reduced serum concentrations. In conclusion, this reproducible model enables evaluation of opioid-induced respiratory depression and supports therapeutic development. Sexual maturity, not sex, influenced opioid sensitivity. This model offers a foundation for assessing long-term effects of opioid exposure, including impacts on brain function and clinical treatment strategies.