Patient-controlled dose regimen of methadone for chronic cancer pain.

Säwe, Juliette; Hansen, Jacob J.; Ginman, Claes; Hartvig, Per; Jakobsson, P-J; Nilsson, Magnus; Rane, Anders; Änggård, Erik

doi:10.1136/bmj.282.6266.771

Cited by 100 publications

(18 citation statements)

References 9 publications

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“…Fredheim et al reported that morphine and metabolites were completely eliminated and steady state for methadone reached within 1 week in 12 patients with nonmalignant pain after a 3DS [17]. Only one study describes plasma concentrations of methadone after a switch from oxycodone in cancer patients [19]. The switching strategy in that study was patient controlled, and methadone concentrations were at steady state after 2-3 days.…”

Section: Introductionmentioning

confidence: 96%

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

Moksnes

Kaasa

Paulsen

et al. 2012

Eur J Clin Pharmacol

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Section: Introductionmentioning

confidence: 96%

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

Moksnes

Kaasa

Paulsen

et al. 2012

Eur J Clin Pharmacol

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“…More comprehensive data on methadone kinetics have been collected from other clinical groups including cancer patients receiving i.v. infusions of methadone (5-40 mg ) for the relief of chronic Drug administration pain [16][17][18][19][20], and surgical patients given parenteral metha-…”

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confidence: 99%

The pharmacokinetics of methadone in healthy subjects and opiate users

Wolff¹,

Rostami‐Hodjegan

Shires

et al. 1997

Brit J Clinical Pharma

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Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac‐methadone were given to 13 drug‐naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P‐Pharm software. Results Comparison of kinetic models incorporating mono‐ or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h−1 (5.3±1.2 s.d. l h−1 using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h−1, P<0.001); 95% CI for the difference=−3 to −6 l h−1 and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half‐life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half‐life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).

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“…The pharmacokinetics in non-tolerant ("naive") subjects might differ from those in tolerant subjects [10,11]. Also short-term treatment might give different results from long-term (steady-state) treatment [12,13]. However, it seems that determinations of plasma methadone in outdoor addicts show wider scatters in elimination half-lifes than those performed in closed metabolic wards: 17.8-63.8 h [8] and 18.9-43 h [2], respectively.…”

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confidence: 99%

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

Vos

Geerlings

Brink³

et al. 1995

Eur J Clin Pharmacol

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In a closed metabolic ward the pharmacokinetics of methadone and its primary metabolite (EDDP) were studied in 20 long-term opiate addicts. After administration of the daily oral dose of methadone HC1 (mean 60 rag, range 10-225 rag) blood samples were taken and analysed, using a newly developed high-performance liquid chromatography (HPLC) method. The steady-state plasma concentrations of the 20 subjects varied from 65-630 ng'ml -~ and from 5 to 55 ng'm1-1, whereas the peak concentrations were 124-1255 ng.m1-1 and 10 301 ng'ml -~ for methadone and EDDR respectively. The calculated ratios between the area under the curve (AUC(0_24 h)) for methadone and the AUC(0_24 h) for EDDP varied from 5.9 to 44.6, indicating interindividual differences in metabolic activity. In 19 out of 20 subjects the pharmacokinetics of methadone are best described using a two-compartment model. The mean body clearance was 1.64 ml.min-l.kg -~, whereas the mean elimination rate constant (/~) and plasma half-life (t,/fi) were 0.026'h -1 (range 0.013-0.053"h -~) and 31.2 h (range 13-53 h), respectively. Differences of gender were also found. A poor correlation was found between the methadone dose and the steady-state level. A much better correlation was found between the normalized steady-state level and the body clearance.Since methadone maintenance therapy (MMT) was introduced [1], many studies have been conducted to establish the pharmacokinetics of methadone. Unfortunately they have not led to a general consensus with regard to well-defined dosage schedules related to clinical and therapeutic efficacy. This might be explained in part by the very divergent results of most of the studies performed so far. For example, plasma half-lives of methadone in tolerant subjects under MMT have varied from 19 h [2] to even 75 h [3]. Both studies were performed in closed metabolic wards. The same variability has applied for bioavailability, which has ranged from 36% to 106% (mean 87%) among 12 tolerant opiate addicts [4], also in a closed metabolic ward. Another study revealed a mean bioavailability of 79% (range 41-99%) [5]. Furthermore, there has been no consensus as to whether the disposition of methadone follows a one-[6-8] or a two- [4,5,9] compartment model. However, most of these studies were performed under divergent, hardly comparable circumstances. The pharmacokinetics in non-tolerant ("naive") subjects might differ from those in tolerant subjects [10,11]. Also short-term treatment might give different results from long-term (steady-state) treatment [12,13]. However, it seems that determinations of plasma methadone in outdoor addicts show wider scatters in elimination half-lifes than those performed in closed metabolic wards: 17.8-63.8 h [8] and 18.9-43 h [2], respectively.The metabolism of methadone has been studied intensively. Many metabolites have been traced and identified in human urine [14,15]. Nevertheless essential knowledge about the formation and disposition of the major metabolite of methadone, EDDP (1,5-dimethyl-3,3-diphenyl-2-eth...

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Patient-controlled dose regimen of methadone for chronic cancer pain.

Cited by 100 publications

References 9 publications

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

Serum concentrations of opioids when comparing two switching strategies to methadone for cancer pain

The pharmacokinetics of methadone in healthy subjects and opiate users

Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts

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