Evidence for the emergence of an opioid-resistant respiratory rhythm following fentanyl overdose.

Breathing resumes within one to two minutes following fentanyl overdose induced apnea in spontaneously breathing rats. As this regular rhythm is produced at a time wherein fentanyl concentrations and receptor occupancy are likely to be extremely high, the mechanisms initiating and sustaining such a respiratory activity remain unclear. Forty-four un-anesthetized adult rats were studied in an open-flow plethysmograph. Regardless of the dose of fentanyl that was used, i.e. 50 μg.kg-1 (n = 8), 100 μg.kg-1 (n = 8) or 300 μg.kg-1 (n = 7), all rats developed an immediate central apnea followed by a depressed regular rhythm that was produced 118, 97 and 81 s (median) later, respectively. Only one rat did not recover. This inspiratory and regular activity consisted of a low frequency and tidal volume pattern with a significant reduction in V̇E/V̇CO2 ratio, which persisted for at least 30 min and that was not different between 100 or 300 μg.kg-1. The time at which this respiratory rhythm emerged, following the highest dose of fentanyl, was not affected by 100 % O2 or 8% CO2/15 % O2. The absolute level of ventilation was however higher in hypercapnic and moderately hypoxic conditions than in hyperoxia. When a second injection of the highest dose of fentanyl (300 μg.kg-1) was performed at 10 min, ventilation was not significantly affected and no apnea was produced in major contrast to the first injection. When a similar injection was performed 30 min after the first injection, in a separate group of rats, an apnea and breathing depression was produced in 30 % of the animals, while in the other rats, ventilation was unaffected. We conclude that the depressed regular respiratory activity emerging during and following fentanyl overdose is uniquely resistant to fentanyl.