Total amount: € 0,00
III MEETING OF PAIN SECTION OF SIAARTI
INTERNATIONAL J. J. BONICA MEMORIAL
Capo Calavà (Messina), September 20-23, 2004
Inturrisi C. E. 1,2
1 Department of Pharmacology Weill Medical College of Cornell University New York, NY, USA
2 The Pain and Palliative Care Service Memorial Sloan-Kettering Cancer Center New York, NY, USA
Methadone is a synthetic opioid analgesic that is used as an alternate to morphine and hydromorphone for patients with severe pain. It is increasingly being used in opioid rotation schedules. Methadone has an asymmetric carbon atom resulting in 2 enantiomeric forms, the d and l isomers. The racemic mixture (dl-methadone) is the form commonly used clinically. Recent studies have revealed the pharmacological activity of the d-methadone isomer. 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 completely prevented by the coadministration of intrathecal d-methadone at 160 µg/rat. In addition, the decrease in thermal paw withdrawal latency induced by the intrathecal administration of 1.64 µg/rat NMDA was completely blocked by pretreatment with 160 µg/rat d-methadone. Thus, the same dose of intrathecal d-methadone that attenuates the development of spinal morphine tolerance blocks NMDA-induced hyperalgesia in rats. These results support the conclusion that d-metha-done affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.