Pharmacology of methadone and its isomers.

Methadone is a synthetic opioid analgesic that is used as an alternate to morphine and hydro- morphone for patients with severe pain. It is increasingly being used in opioid rotation schedules. Methadone has an asymmetric car- bon atom resulting in 2 enantiomeric forms, the d and l isomers. The racemic mixture (dl- methadone) is the form commonly used clin- ically. Recent studies have revealed the phar- macological activity of the d-methadone iso- mer. We found that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity both in vitro and in vivo. Studies were designed to examine the ability of d-methadone to attenuate the development of morphine tolerance and to modify NMDA- induced hyperalgesia in rats. Repeated dosing with intrathecal morphine produced a 38-fold increase in the morphine ED50 value. This decrease in the potency of morphine was com- pletely prevented by the coadministration of intrathecal d-methadone at 160 µg/rat. In addi- tion, the decrease in thermal paw withdrawal latency induced by the intrathecal administra- tion of 1.64 µg/rat NMDA was completely blocked by pretreatment with 160 µg/rat d- methadone. Thus, the same dose of intrathe- cal d-methadone that attenuates the develop- ment of spinal morphine tolerance blocks NMDA-induced hyperalgesia in rats. These results support the conclusion that d-metha-