Stereoselective Pharmacokinetics of Methadone in Chronic Pain Patients

Abstract

Ten patients with chronic pain were randomized to an open, balanced, crossover study. Each patients received two different preparations of racemic methadone, i.e., tablets and intravenous infusion. The pharmacokinetic parameters of the R- and S-enantiomers of the racemate are reported. The analgesically active R-methadone has a significantly longer mean elimination half-life than the optical antipode S-methadone (t1/2 = 37.5 and 28.6 h, respectively). The mean total volume of distribution is 496.6 L for R-methadone and 289.1 L for S-methadone. Significant differences in the mean clearance between R- and S-methadone are seen (0.158 and 0.129 L/min, respectively). However, the lagtime after oral administration and the bioavailability did not show differences between the isomers. The data suggest that both enantiomers of methadone should be measured if correlations between pharmacodynamics and kinetics are made due to the stereoselective differences in half-life, total volume of distribution, and clearance.

O uso de opióides no tratamento da dor crônica não oncológica: o papel da metadona

“…É um agonista dos receptores opióides Mµ, Delta e Kappa. A metadona também é um antagonista do receptor NMDA e parece bloquear a recaptação de serotonina e noradrenalina 22,23,26,27 . A absorção após administração oral de metadona em solução ou comprimidos é rápida e quase completa.…”

“…Metadona não é removida pela hemodiálise. Também está presente no leite materno em concentrações que teoricamente não impedem a amamentação, porém cruza a barreira placentária em concentração que pode causar síndrome de abstinência no recém-nascido de mães que usam metadona 22,23,25,27,28,[31][32][33] . A metadona produz menos náusea, constipação e sedação do que a morfina.…”

“…It is a Mµ, Kappa and Delta opioid receptors agonist. Methadone is also an NMDA receptor antagonist and seems to block serotonin and norepinephrine reuptake 22,23,26,27 .…”

“…Methadone is removed by hemodialysis. It is also present in maternal milk in concentrations which, in theory, do not prevent breast-feeding, but crosses blood-brain barrier in concentrations able to cause withdrawal syndrome in neonates of mothers under methadone 22,23,25,27,28,[31][32][33] . Methadone causes less nausea, constipation and sedation than morphine.…”

Bioavailabilities of rectal and oral methadone in healthy subjects

“…Studies in chronic pain and opioid replacement patients have shown different pharmacokinetic characteristics of the enantiomers. However, the bioavailabilities and AUCs of the latter did not differ in any of these studies [28,29]. Thus, our data on racemic bioavailability probably reflects those of the respective enantiomers.…”