Clinical eftects and pharmacokinetics of racemic methadone and its optical isomers

The respiratory and pupillary effects of oral l‐, d‐, and d,l‐methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half‐life of drug in blood was 22 hr for racemic methadone, 24 hr for 1‐methadone, and 25 hr for d‐methadone. The effects of d‐methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l‐methadone and 15 mg of d,l‐methadone induced intense and sustained respiratory depression and miosis. The changes induced by l‐methadone were of longer duration than those of d,l‐methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated weil with respiratory depression and miosis for 1‐ and d,l‐methadone. The potency ratio of l‐methadone to d,l‐methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l‐methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l‐Methadone administeredfrequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.