Fentanyl Disposition in Cerebrospinal Fluid and Plasma and Its Relationship to Ventilatory Depression in the Dog

Abstract

Although fentanyl is a short-acting narcotic analgesic, unexpected respiratory depression has been seen in the postanesthetic period several h after the last dose. The pharmacokinetic characteristics of fentanyl in CSF of the dog were defined and their relationships to ventilatory depression were determined. 3H-fentanyl citrate (10 .mu.g/kg) was injected i.v. in dogs anesthetized with enflurane-O2. Arterial plasma and cisternal CSF were analyzed for concentration of unchanged [3H]-fentanyl [F] and for total radioactivity (3H). Maximum [F] in CSF occurred 2-10 min after injection and declined at the same rate as [F] in plasma. Values of [F] in CSF averaged approximately 46% of those in plasma and reflected the binding of fentanyl to plasma proteins. There was a dose-dependent decrease in minute ventilation and end-tidal CO2 increased. The extent of ventilatory depression correlated closely with the log [F] in arterial plasma and in cisternal CSF (i.e., .DELTA. PETCO2 [end tidal CO2] vs. log [F]CSF, r [correlation coefficient] = 0.97, P < 0.01). An early phase in the recovery of ventilation paralleled the initial, rapid elimination of fentanyl from CSF and plasma. Complete recovery was protracted, and the terminal elimination phases of fentanyl from both CSF and plasma were prolonged (t1/2 [half-life] = 171 .+-. 8 and 201 .+-. 25 min, respectively). Fentanyl, a highly lipophilic drug, equilibrated rapidly between plasma and CSF, there was a close correlation between the concentrations of fentanyl in plasma and CSF and the intensity of respiratory depression. Recovery from the ventilatory effects of fentanyl paralleled the initially rapid elimination of the unchanged drug from CSF and plasma. Low levels of ventilatory depression and of [F] persisted. Repeated injections of the narcotic analgesic led to the accumulation of fentanyl and increased ventilatory depression.