Opioid substitution treatment for dependence may alter sensitivity to pain. Previous studies on pain sensitivity in methadone maintenance patients have yielded contradictory results. This study compared nociceptive responses between 16 patients on stable, once daily, doses of methadone and 16 matched control subjects. Two types of nociceptive stimuli were used: (1) electrical stimulation; and (2) a cold pressor test. Two parameters were measured: detection for onset of pain, and pain tolerance. Methadone patients were tested over an inter-dosing period: at the time of trough plasma methadone concentration (0 h), and 3 h after their daily dose. Control subjects were tested twice 3 h apart. Blood samples were collected to determine plasma methadone concentration. In methadone patients, trough to peak increases in mean R-(-)- and S-(+)-methadone concentrations (118 and 138 ng/ml to 185 and 259 ng/ml, respectively) resulted in significant increases in pain detection and tolerance values for both nociceptive stimuli. Using electrical stimulation, methadone patients' pain tolerance values were lower than controls at 0 h, but higher than controls at 3 h; no significant differences in pain detection values were found. For the cold pressor test, methadone patients detected pain significantly earlier than controls at 0 h, and were also substantially less pain tolerant than controls at both 0 and 3 h. There were no significant differences in pain detection values between the two groups at 3 h. Pain tolerance to pain detection ratios for methadone patients were significantly lower than controls for the cold pressor test at 0 and 3 h, and for electrical stimulation at 0 h only. In summary, the relative pain sensitivity of methadone maintenance patients is determined by the nature of the nociceptive stimulus (e.g. cold pressor test versus electrical stimulation), the plasma methadone concentration (trough versus peak plasma concentration), and whether thresholds are determined for detection of pain or pain tolerance. Although responding to changes in plasma methadone concentration, maintenance patients are markedly hyperalgesic to pain induced by the cold pressor test.

1 To determine whether cimetidine altered the renal handling of metformin, seven subjects took 0.25 g metformin daily with and without cimetidine 0.4 g twice daily. Blood and urine samples were collected and assayed for metformin, cimetidine and creatinine by h.p.l.c. 2 Cimetidine significantly increased the area under the plasma metformin concentrationtime curve by an average of 50% and reduced its renal clearance over 24 h by 27% (P < 0.008). There was no alteration in the total urinary recovery of metformin when cimetidine was co-administered. 3 The effect of cimetidine on the renal clearance of metformin was time dependent, being significantly reduced up to 6 h following cimetidine. These results appeared to be consistent with competitive inhibition of renal tubular secretion. 4 Cimetidine had no effect on the renal clearance of creatinine, but time-dependent variations in both metformin and creatinine renal clearance were observed. Metformin had no effect on cimetidine disposition. 5 It is concluded that cimetidine inhibits the renal tubular secretion of metformin in man, resulting in higher circulating plasma concentrations. Because of its propensity for causing dose and concentration-dependent adverse effects, the dose of metformin should be reduced when cimetidine is co-prescribed.

Aims To investigate the kinetics of CYP-mediated N-demethylation of methadone in human liver microsomes, and examine the role of stereoselectivity and CYP isoforms involved. Methods The kinetics of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) formation via N-demethylation of rac-, (R)-and (S)-methadone in human liver microsomes prepared from six liver samples were determined by h.p.l.c., and inhibition of metabolic function was studied using isoform-specific chemical inhibitors and monoclonal antibodies. Microsomes containing expressed CYP3A4, CYP2D6 and CYP2C19 were also used to examine the formation of EDDP. 25%). There were no statistically significant differences in the inhibition observed between the three substrates. Selective inhibitors of CYP1A2 (furafylline), CYP2A6 (coumarin), CYP2C19 ((S)-mephenytoin), CYP2D6 (quinidine) and CYP2E1 (diethyldithiocarbamic acid sodium salt and monoclonal human CYP2E1 antibodies) had no significant ( P >0.05) effect. Conclusions The N-demethylation of methadone in human liver microsomes is not markedly stereoselective, and is mediated mainly by CYP3A4 with the possible involvement of CYP2C9 and CYP2C19. Thus, the large interindividual variation reported for methadone pharmacokinetics may be due to variability in the expression of these CYP isoforms, and the reported stereoselectivity in the systemic clearance of methadone in vivo is not due to stereoselectivity in N-demethylation. ResultsKeywords: CYP3A4, EDDP formation, human liver microsomes, methadone Ndemethylation, stereoselectivity molecule ( Figure 1) of (R)-and (S)-enantiomeric forms Introduction in which (R)-methadone has a 10-fold higher affinity at m and d opioid receptors [1] and possesses up to 50 times Rac-methadone is commonly used in the management of chronic pain and as maintenance therapy for the pharmacothe analgesic activity of (S)-methadone in human and animal models of pain [2]. (R)-methadone has also been logical treatment of opioid dependence. Rac-methadone (6-dimethylamino-4,4-diphenyl-3-heptanone) is a chiral shown to prevent the occurrence of opioid withdrawal symptoms, while (S)-methadone is ineffective [3]. Despite this high eudismic ratio, methadone is used as the significantly in their disposition in humans, with

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Aims To investigate the steady-state pharmacokinetics of (R)-and (S)-methadone in a methadone maintenance population. Methods Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultra®ltration, and plasma a 1 -acid glycoprotein concentrations were quanti®ed by radial immunoassay. Results (R)-methadone had a signi®cantly (P<0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were signi®cantly (P<0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were signi®cantly (P<0.01) lower than for (S)-methadone, while AUC ss q u (167%) was signi®cantly (P<0.001) greater. There were no signi®cant (P>0.2) differences between the methadone enantiomers for AUC ss q , steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted signi®cantly (P<0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coef®cients of variation of up to 70%. Conclusions Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a signi®cant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokineticpharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.