Plasma concentrations of the
narcotic analgesic,
levorphanol, have been determined following i.v., i.m. and
oral administration of therapeutic doses of the
drug to patients with
pain. In two patients who received single i.v. doses of
levorphanol the plasma concentration-time profile in each subject was best described by a triexponential decline of the concentrations with terminal half-lives (t 1/2) of about 11 hr. Following i.m. and
oral administrations, peak plasma concentrations of intact
drug were generally reached after about 0.5 and 1 hr, respectively. Conjugated (
beta-glucuronidase labile)
levorphanol appeared rapidly in plasma following all routes of administration and quickly reached concentrations which were 5 to 10 fold higher than the intact
drug. Effective
analgesic steady-state concentrations of
levorphanol in patients receiving a wide range of chronic oral and i.m. dosages of the
drug ranged from about 10 to 100 ng/ml and these concentrations showed no apparent correlation with either the dose or the subjective
analgesic response achieved. The latter observations are probably a reflection of extensive and variable inter-subject "first-pass" metabolism of the
drug combined with different degrees of pharmacologic tolerance at the receptor level. However, in the non-tolerant patient it appears that a plasma concentration of about 10 ng/ml is associated with a positive
analgesic effect. Furthermore it seems that
analgesia is often maintained within a narrow plasma concentration range for each subject in that relatively small decreases in plasma concentration in some patients may be associated with either mild or severe
pain.
Plasma protein binding at steady-state in 10 patients averaged 40 +/- 2.6%. Concentrations of the
drug in the cerebrospinal fluid of 2 patients studied were 60 to 70% of the corresponding plasma levels of the
drug.