Steady-state kinetics and dynamics of morphine in cancer patients: is sedation related to the absorption rate of morphine?

TY - JOUR

T1 - Steady-state kinetics and dynamics of morphine in cancer patients

T2 - is sedation related to the absorption rate of morphine?

AU - Christrup, Lona Louring

AU - Sjøgren, P

AU - Jensen, N H

AU - Banning, A M

AU - Elbaek, K

AU - Ersbøll, A K

PY - 1999/9

Y1 - 1999/9

N2 - Eighteen patients suffering from chronic pain due to cancer completed a balanced, double-blind, double-dummy, two period cross-over trial comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, after administration of morphine given as controlled-release (CR) tablets (every 12 h) and immediate-release (IR) tablets (every 6 h). The same total daily dose of morphine was given in both study periods. Patients received both test formulations for 4 days and on the final day of each period, peripheral venous blood samples for analysis of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were obtained. Pain intensity, sedation, and continuous reaction time (CRT) were assessed. No significant differences could be demonstrated in AUC/dose, Cmin, Cmax or fluctuation index values between the two treatments (IR and CR tablets) for either morphine or its metabolites. Tmax for morphine and its metabolites occurred significantly later after administration of CR tablets than after administration of IR tablets. There were no significant differences between the IR and the CR formulation with respect to analgesia and side effects, and there was no difference in the patients' overall impression of the two treatments. More important, there was no difference between the Tmax and the time to peak sedation after administration of IR tablets (P = 0.63). However, due to the relatively small number of patients and the variability in the data, the statistical power of the test was only 0.074. The risk of a type II error is 0.926. These data demonstrate the PK and PD similarities and differences between CR and IR morphine. They suggest that there may be a relationship between Tmax (determined by absorption rate) and sedation, but further evaluation of this potential relationship is needed.

AB - Eighteen patients suffering from chronic pain due to cancer completed a balanced, double-blind, double-dummy, two period cross-over trial comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, after administration of morphine given as controlled-release (CR) tablets (every 12 h) and immediate-release (IR) tablets (every 6 h). The same total daily dose of morphine was given in both study periods. Patients received both test formulations for 4 days and on the final day of each period, peripheral venous blood samples for analysis of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were obtained. Pain intensity, sedation, and continuous reaction time (CRT) were assessed. No significant differences could be demonstrated in AUC/dose, Cmin, Cmax or fluctuation index values between the two treatments (IR and CR tablets) for either morphine or its metabolites. Tmax for morphine and its metabolites occurred significantly later after administration of CR tablets than after administration of IR tablets. There were no significant differences between the IR and the CR formulation with respect to analgesia and side effects, and there was no difference in the patients' overall impression of the two treatments. More important, there was no difference between the Tmax and the time to peak sedation after administration of IR tablets (P = 0.63). However, due to the relatively small number of patients and the variability in the data, the statistical power of the test was only 0.074. The risk of a type II error is 0.926. These data demonstrate the PK and PD similarities and differences between CR and IR morphine. They suggest that there may be a relationship between Tmax (determined by absorption rate) and sedation, but further evaluation of this potential relationship is needed.

KW - Aged

KW - Analgesics, Opioid

KW - Biotransformation

KW - Cross-Over Studies

KW - Double-Blind Method

KW - Female

KW - Humans

KW - Hypnotics and Sedatives

KW - Male

KW - Middle Aged

KW - Morphine

KW - Neoplasms

KW - Pain, Intractable

KW - Tablets

M3 - Journal article

C2 - 10517037

SN - 0885-3924

VL - 18

SP - 164

EP - 173

JO - Journal of Pain and Symptom Management

JF - Journal of Pain and Symptom Management

IS - 3

ER -