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

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.

Efficacy and tolerability of lornoxicam versus tramadol in postoperative pain.

This randomized double-blind study compared the analgesic efficacy and tolerability of intramuscular lornoxicam and tramadol in 76 patients with moderate to unbearable pain following arthroscopic reconstruction of the anterior cruciate ligament using the patella bone-tendon-bone technique. Patients receiving a single dose of lornoxicam 16 mg experienced significantly greater total pain relief than patients receiving tramadol 100 mg over the following 8 hours. Lornoxicam had greater analgesic efficacy than tramadol in patients with moderate baseline pain but was of equivalent efficacy in those with severe/unbearable baseline pain. Fewer patients in the lornoxicam group required rescue medication (58% vs. 77%, respectively). Patients' global impression of efficacy showed lornoxicam to be superior to tramadol with 82% and 49% of patients, respectively, rating treatment as good, very good, or excellent. Following multiple-dose administration of lornoxicam (8 mg tid) or tramadol (100 mg tid) for 3 days, efficacy profiles similar to those following a single dose were obtained. Thus, slightly fewer patients in the lornoxicam group required rescue medication, and patients' global impression of efficacy again favored lornoxicam. Adverse events were reported by 38 of the 76 patients and were mainly mild to moderate in severity. Significantly fewer patients reported one or more adverse events with lornoxicam than with tramadol (14 vs. 24, respectively). Thus, intramuscular lornoxicam offers a useful alternative to tramadol for the treatment of moderate to severe postoperative pain.

Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects.

OBJECTIVE: Codeine O-demethylation to morphine is catalysed by the genetic polymorphic sparteine oxygenase (CYP2D6). The objective of the present study was to assess the analgesic effect of codeine on different types of experimental pain in relation to sparteine phenotype. METHODS: Fourteen extensive (EMs) and 14 poor metabolizers (PMs) of sparteine completed a randomized, double-blind, three-way, cross-over study with a single oral dose of codeine (75 or 100 mg) against morphine (20 or 30 mg) and placebo. Pain tests performed before and 1, 2, 3, and 4 h after medication included the cold pressor test and pain thresholds for heat and pressure stimulation. Adverse effects were rated by a structured interview. RESULTS: After morphine, morphine and morphine-6-glucuronide were present in equal amounts in plasma of PMs and EMs. After codeine, neither morphine nor morphine-6-glucuronide could be detected in 13 of the 14 PMs, whereas at least one of the compounds could be detected in all EMs. Peak pain and discomfort rated on a VAS scale during the cold pressor test were significantly reduced by morphine in both EMs and PMs, with a median peak change of 8.5 and 7.0 mm, respectively, for peak pain, and 11.5 and 15.5 mm, respectively, for discomfort. Codeine only reduced these pain measures significantly in EMs, with a median peak change of 5.5 mm for peak pain and 10.5 mm for discomfort. Pain detection and tolerance thresholds to heat and pressure were not consistently altered by either morphine or codeine. In PMs, adverse effects were significantly more pronounced on morphine than on codeine and only showed a slight difference between codeine and placebo. In EMs, there was no difference between codeine and morphine and more pronounced adverse effects on both drugs as compared to placebo. CONCLUSION: This study confirms that codeine O-demethylation depends on CYP2D6; it shows that the 6-glucuronidation of morphine is independent of CYP2D6; it supports the theory that the analgesic effect of codeine depends on its O-demethylation; and it indicates that this is probably also the case for the adverse effects. The results lend no support to the suggestion of a non-opioid analgesic effect of codeine.

Pharmacokinetics of oral idarubicin in breast cancer patients with reference to antitumor activity and side effects.

The pharmacokinetics of orally administered idarubicin (22.5 mg/m2/week) and idarubicinol were studied for 12 weeks in 14 patients with breast cancer. Plasma concentrations were monitored for 72 hours after the first, fourth, and twelfth doses and trough concentrations after 1, 2, 3, 4, 5, 7, 11, and 12 weeks of treatment. The half-lives of idarubicin and idarubicinol were 19 and 60 hours, respectively. No time-dependent changes or cumulation were observed. The metabolic ratio showed little variation. The plasma AUCs of idarubicin and idarubicinol varied between patients but were fairly constant in individual patients. The sum of the plasma AUCs was lower in patients with rapid progression than in patients who responded to treatment. A correlation between this parameter and the relative decrease in the leukocyte counts was demonstrated (p less than 0.05). No correlation was found between the pharmacokinetic parameters and the time to final progression.

Phase I study of 4-demethoxydaunorubicin by oral route in patients with advanced cancer.

In a phase I trial 4-demethoxydaunorubicin (4-dm DNR) was administered as oral capsules once a week to 51 adults with advanced mainly gastrointestinal solid tumors. No fatal toxicity was observed at doses up to 25.0 mg/m2. Dose-limiting granulocytopenia and non-hematologic toxicity developed at dosages greater than or equal to 22.5 mg/m2. No response to the therapy was observed. The plasma concentrations of 4-dm DNR were measured in 4 of the patients.