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Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences.
Romberg R, Olofsen E, Sarton E, den Hartigh J, Taschner PE, Dahan A.
Department of Anesthesiology, Leiden University Medical Center, The Netherlands.
BACKGROUND: Morphine-6-glucuronide (M6G) is a metabolite of morphine and a micro-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design. METHODS: Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia. RESULTS: M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency. CONCLUSIONS: A cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset-offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the micro-opioid receptor and placebo-related phenomena, are discussed. The predictive pharmacokinetic-pharmacodynamic model was applied successfully and was used to estimate M6G analgesia after morphine in patients with normal and impaired renal function.
Publication Types:
PMID: 14695733 [PubMed - indexed for MEDLINE]
Self-mutilation and mental retardation: clues to congenital insensitivity to pain with anhidrosis.
Zafeiriou DI, Vargiami E, Economou M, Gombakis N.
1st Pediatric Clinic, Aristotle University of Thessaloniki, 54622 Thessaloniki, Greece.
PMID: 14760280 [PubMed - in process]
Comment on:
Prognostic value of myeloperoxidase in patients with chest pain.
Asselbergs FW, Tervaert JW, Tio RA.
Publication Types:
PMID: 14752891 [PubMed - indexed for MEDLINE]
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Force production parameters in patients with low back pain and healthy control study participants.
Descarreaux M, Blouin JS, Teasdale N.
Faculte de Medecine, Division de Kinesiologie, U. Laval, Canada. martin.descarreaux@kin.msp.ulaval.ca
STUDY DESIGN: A control group study with repeated measures. OBJECTIVE: To compare isometric force production parameters in low back pain and healthy study participants. SUMMARY AND BACKGROUND DATA: Recent evidence suggests that chronic patients with low back pain exhibit deficits in trunk proprioception and motor control. The control of force and its between-trial variability are often taken as critical determinants of performance. We compared various force time characteristics in patients with low back pain and healthy study participants. METHODS: Fifteen control study participants and 16 patients with low back pain participated in this study. Study participants were required to exert 50% and 75% of the maximal trunk flexion and extension. In a learning phase, visual and verbal feedback was provided. Following these learning trials, study participants were asked to perform 10 trials without any feedback. Time to peak force, time to peak force variability, peak force variability, and absolute error in peak force were calculated. Time to peak and peak dF/dt were computed to determine if the first peak of dF/dt could predict the peak force achieved. RESULTS: Two subgroups of patients with low back pain were identified. Controls and patients with low back pain with more pain showed faster time to peak force than patients with low back pain with less pain (331 ms and 341 ms vs. 574 ms, respectively). Linear regressions showed that, for control study participants and low back pain study participants with more pain, peak dF/dt explained 94.0% and 97.0% of the variance observed in peak force while 84.4% was explained for low back pain study participants with less pain. Peak force variability and absolute error in peak force were similar for all groups. CONCLUSIONS: Patients with low back pain were able to produce isometric forces with an accuracy similar to control study participants. The longer time to peak force and the smaller percentage of variance observed for the linear regressions suggest that some patients with low back pain adopted a control mode that was less "open-loop." It is possible that this mode of producing forces results from an adaptation to chronic pain or tissue degeneration.
PMID: 14752355 [PubMed - in process]
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