Breathing rhythm stability is higher after intravenous injection of codeine relative to fentanyl in cats.

Codeine is one of the opioids of abuse that is available by prescription, and fentanyl is the leading opioid drug of abuse. Both codeine and fentanyl are µ-opioid agonists that are strong respiratory depressants. However, unlike fentanyl, codeine also binds to nicotinic receptors. We hypothesized that influence of these drugs on the stability of breathing would differ due to the relative non-specificity of codeine. Ten anesthetized, spontaneously breathing adult cats were tracheotomized, and EMG activity was recorded from inspiratory muscles. Dose responses to codeine (n=5, 0.1 - 10 mg/kg, i.v.) or fentanyl (n=5, 0.1 - 10 ng/kg, i.v.) were performed in separate groups of animals. Total breathing cycle time (Ttot) was measured for 30 breaths at each dose. Measurements of Ttot were taken more than 5 minutes following administration of the drugs. Poincaré plots were constructed for Ttot, where an ellipse was fit to the data (Ɵ=45°). The ratio (SD1/SD2) was computed at each dose, where SD1 was the length the ellipse perpendicular to the line of identity, and SD2 was the length along the line of identity. SD1 is associated with short-term variability and SD2 with long-term variability of the data. The dose response relationships showed similar increases in Ttot from vehicle to the highest dose between codeine and fentanyl (codeine: 2.4 ± 0.2 s to 4.4 ± 1.0 s; fentanyl: 2.5 ± 0.4 s to 5.4 ± 0.5 s). Transient apnea (< 60 s) was commonly observed immediately following doses of codeine that were larger than 1 mg/kg, but was not observed after any dose of fentanyl. SD1/SD2 differed between the two drugs, where SD1/SD2 did not change across doses for codeine, and SD1/SD2 decreased significantly in a dose-dependent manner from 0.3 ng/kg (0.77 ± 0.10) to the 3 ng/kg dose (0.32 ± 0.7) for fentanyl. The shift in the SD1/SD2 ratio after fentanyl was driven more by changes in SD2 (81% compared to vehicle) rather than SD1 (-17% compared to vehicle). We conclude that codeine induces relatively similar changes of short and long-term variability of Ttot, whereas fentanyl preferentially reduces long-term variability of Ttot. Alterations in long-term variability are more consistent with a potential for network reconfiguration rather than the respiratory network correcting for breath-to-breath requirements. Our data suggest that a Poincaré plot may be a sensitive metric of the disruption of respiratory control dynamics for the µ-receptor selective fentanyl relative to the µ-opioid agonist/nicotinic ligand codeine.