Pharmacokinetic-Pharmacodynamic Modelling of the Analgesic and Antihyperalgesic Effects of Morphine after Intravenous Infusion in Human Volunteers

Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and antihyperalgesic effects of morphine differ; (ii) investigate the influence of demographic, pain sensitivity and genetic (OPRM1) variables on between-subject variability of morphine pharmacokinetics and pharmacodynamics in human experimental pain models. The study was a randomized, double-blind, 5-arm, cross-over, placebo-controlled study. The psychophysical cutaneous pain tests, electrical pain tolerance (EPTo) and secondary hyperalgesia areas (2HA) were studied in 28 healthy individuals (15 males). The subjects were chosen based on a previous trial where 100 subjects rated (VAS) their pain during a heat injury (47°C, 7 min., 12.5 cm²). The 33% lowest- and highest pain-sensitive subjects were offered participation in the present study. A two-compartment linear model with allometric scaling for weight provided the best description of the plasma concentration-time profile of morphine. Changes in the EPTo and 2HA responses with time during the placebo treatment were best described by a linear model and a quadratic model, respectively. The model discrimination process showed clear evidence for adding between-occasion variability (BOV) on baseline and the placebo slope for EPTo and 2HA, respectively. The sensitivity covariate was significant on baseline EPTo values and genetics as a covariate on the placebo slope for 2HA. The analgesic and antihyperalgesic effects of morphine were pharmacologically distinct as the models had different effect site equilibration half-lives and different covariate effects. Morphine had negligible effect on 2HA, but significant effect on EPTo.Pernille Ravn, David J.R. Foster, Mads Kreilgaard, Lona Christrup, Mads U. Werner, Erik L. Secher, Ulrik Skram and Richard Upto

Indicators for the Data Usage Index (DUI): an incentive for publishing primary biodiversity data through global information infrastructure

<p>Abstract</p> <p>Background</p> <p>A professional recognition mechanism is required to encourage expedited publishing of an adequate volume of 'fit-for-use' biodiversity data. As a component of such a recognition mechanism, we propose the development of the Data Usage Index (DUI) to demonstrate to data publishers that their efforts of creating biodiversity datasets have impact by being accessed and used by a wide spectrum of user communities.</p> <p>Discussion</p> <p>We propose and give examples of a range of 14 absolute and normalized biodiversity dataset usage indicators for the development of a DUI based on search events and dataset download instances. The DUI is proposed to include relative as well as species profile weighted comparative indicators.</p> <p>Conclusions</p> <p>We believe that in addition to the recognition to the data publisher and all players involved in the data life cycle, a DUI will also provide much needed yet novel insight into how users use primary biodiversity data. A DUI consisting of a range of usage indicators obtained from the GBIF network and other relevant access points is within reach. The usage of biodiversity datasets leads to the development of a family of indicators in line with well known citation-based measurements of recognition.</p

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation

Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model: a double-blind, randomized, placebo-controlled, five-arm crossover study

Pernille Ravn,1 Erik L Secher,2 Ulrik Skram,3 Trine Therkildsen,1 Lona L Christrup,1 Mads U Werner41Department of Drug Design and Pharmacology, University of Copenhagen, 2Department of Anesthesiology, Juliane Marie Center, Rigshospitalet, Copenhagen University Hospitals, 3Department of Intensive Care, Gentofte Hospital, Copenhagen University Hospitals, 4Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, DenmarkPurpose: Opioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain. It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than &amp;micro;-opioid receptor agonists. The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers. The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia, antihyperalgesia, and descending pain modulation.Subjects and methods: Twenty-eight healthy subjects were included. The study was a double-blind, randomized, placebo-controlled, five-arm crossover study with a multimodal (electrical, mechanical, and thermal stimuli) testing technique. After baseline assessments, intravenous infusions of morphine (10/20 mg), buprenorphine (0.3/0.6 mg), or placebo (normal saline) were administered over a 210-minute period, during which a cold pressor test, heat injury (47&amp;deg;C, 7 minutes, 12.5 cm2), and the first postburn assessment were done. After completion of the drug infusions, two additional postburn assessments were done. The subjects were monitored during each 8-hour session by an anesthesiologist.Results: For nearly all tested variables, significant dose-dependent analgesic effects were demonstrated. The median antihyperalgesia/analgesia ratio (secondary hyperalgesia/heat injury relative to placebo) for low-dose morphine was 0.01 (interquartile range: &amp;minus;6.2; 9.9), 0.00 (&amp;minus;2.4; 2.1) for high-dose morphine, 0.03 (&amp;minus;1.8; 2.1) for low-dose buprenorphine, and 0.00 (&amp;minus;3.2; 1.1) for high-dose buprenorphine (P &amp;gt; 0.466). There were no significant differences in opioid responses between high and low pain-sensitive subjects (P &amp;gt; 0.286). High-dose buprenorphine, compared to placebo, was associated with a significantly enhanced action of the descending inhibitory pain control system (P = 0.004).Conclusion: The present study, using multimodal testing technique, could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia. Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system.Keywords: analgesia, antihyperalgesia, experimental pain, opioid, pain sensitivity, randomized tria

Morphine- and buprenorphine-induced analgesia and antihyperalgesia in a human inflammatory pain model:a double-blind, randomized, placebo-controlled, five-arm crossover study

PURPOSE: Opioid therapy is associated with the development of tolerance and paradoxically increased sensitivity to pain. It has been suggested that buprenorphine is associated with a higher antihyperalgesia/analgesia ratio than μ-opioid receptor agonists. The primary outcome of this study was therefore to investigate relative differences in antihyperalgesia and analgesia effects between morphine and buprenorphine in an inflammatory pain model in volunteers. The secondary outcome was to examine the relationship between pain sensitivity and opioid-induced effects on analgesia, antihyperalgesia, and descending pain modulation. SUBJECTS AND METHODS: Twenty-eight healthy subjects were included. The study was a double-blind, randomized, placebo-controlled, five-arm crossover study with a multimodal (electrical, mechanical, and thermal stimuli) testing technique. After baseline assessments, intravenous infusions of morphine (10/20 mg), buprenorphine (0.3/0.6 mg), or placebo (normal saline) were administered over a 210-minute period, during which a cold pressor test, heat injury (47°C, 7 minutes, 12.5 cm(2)), and the first postburn assessment were done. After completion of the drug infusions, two additional postburn assessments were done. The subjects were monitored during each 8-hour session by an anesthesiologist. RESULTS: For nearly all tested variables, significant dose-dependent analgesic effects were demonstrated. The median antihyperalgesia/analgesia ratio (secondary hyperalgesia/heat injury relative to placebo) for low-dose morphine was 0.01 (interquartile range: −6.2; 9.9), 0.00 (−2.4; 2.1) for high-dose morphine, 0.03 (−1.8; 2.1) for low-dose buprenorphine, and 0.00 (−3.2; 1.1) for high-dose buprenorphine (P > 0.466). There were no significant differences in opioid responses between high and low pain-sensitive subjects (P > 0.286). High-dose buprenorphine, compared to placebo, was associated with a significantly enhanced action of the descending inhibitory pain control system (P = 0.004). CONCLUSION: The present study, using multimodal testing technique, could not demonstrate any significant differences between morphine and buprenorphine in the profiles of antihyperalgesia and analgesia. Only high-dose buprenorphine was associated with a significant effect on the descending inhibitory pain control system

Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

© Springer-Verlag 2007Objective: The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only. Methods: Twenty-three healthy male volunteers aged 21–40 years received 0.6 mg buprenorphine by means of an i.v. infusion over a 150-min period. The plasma concentration–time profiles up to 24 h post-administration of the infusion were subjected to population pharmacokinetic modelling using NONMEM software. Results: A three-compartment model best described the plasma concentration–time course. Body weight was found to be a significant covariate for elimination clearance in a linear fashion. Inter-individual variability (coefficient of variation) was estimable for apparent clearance (CL, 23.5%), central distribution volume (V₁, 81.8%), peripheral distribution volume 1 (V₂, 23.7%) and inter-compartmental clearances between V₁ and V₂ (Q₂, 34.8%). Models using parameters derived from previous published data obtained after an i.v. bolus of buprenorphine were found to overestimate the measured buprenorphine concentrations during the course of the i.v. infusion and to underpredict those following the end of the infusion. Conclusion: Most parameters describing the disposition of buprenorphine in the volunteers showed only moderate inter-subject variability. However, the parameters differed from those previously reported for i.v. bolus administration. We conclude that pharmacokinetic parameter estimates obtained from the appropriate study in accordance to the mode of administration should be used in the design of dose regimens of buprenorphine.Mette L. Jensen, David J. R. Foster, Richard N. Upton, Kim Kristensen, Steen H. Hansen, Niels-Henrik Jensen, Bettina N. Nielsen, Ulrik Skram, Hanne H. Villesen and Lona Christru