ORCID Profile
0000-0001-7465-964X
Current Organisations
Aalborg University Hospital
,
Aalborg University
,
Aalborg Universitet
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Public Library of Science (PLoS)
Date: 30-10-2017
Publisher: Wiley
Date: 17-03-2014
DOI: 10.1111/BCPT.12217
Abstract: The purpose of the study was to investigate placebo and buprenorphine effects on event-related potentials (ERPs) in experimental pain and the potential benefit of population pharmacodynamic modelling in data analysis. Nineteen healthy volunteers received transdermal placebo and buprenorphine in a cross-over study. Drug plasma concentrations and ERPs after electrical stimulation at the median nerve with intensity adjusted to pain detection threshold were recorded until 144 hrs after administration. Placebo and concentration-effect models were fitted to data using non-linear mixed-effects modelling implemented in NONMEM (V7.2.0.). Pharmacodynamic models were developed to adequately describe both placebo and buprenorphine ERP data. Models predicted significant placebo effects, but did not predict significant effects related to buprenorphine concentration. Models revealed that ERPs varied both between subjects and between study occasions. ERPs were found to be reproducible within subjects and occasions as population variance was found to be eight times higher than the unexplained variances. Between-subject variance accounted for more than 75% of the population variance. In conclusion, pharmacodynamic modelling was successfully implemented to allow for placebo and variability correction in ERP of experimental pain. Improved outcome of ERP studies can be expected if variation between subjects and study occasions can be identified and described.
Publisher: Wiley
Date: 29-09-2019
DOI: 10.1111/NMO.13734
Abstract: The 3D-Transit electromagnet tracking system (Motilis Medica, SA, Lausanne, Switzerland) is an emerging tool for the ambulatory assessment of gastrointestinal (GI) transit and motility. Using this tool, we aimed to derive normative values for region-specific colonic and GI transit times and to assess the influence of age, gender, and body mass index (BMI). Regional and total colonic transit times (CTT), gastric emptying (GET), small intestinal (SITT), and whole gut (WGTT) transit times were extracted from 111 healthy volunteers from the United Kingdom and Denmark (58 female median age: 40 years [range: 21-88]). The effects of age, gender, and BMI were assessed using standard statistical methods. The ascending, transverse, descending, and rectosigmoid colon transit times accounted for 32%, 34%, 17%, and 17% of total CTT in females, and 33%, 25%, 14%, and 28% of total CTT in males. CTT and WGTT were seen to cluster at intervals separated by approximately 24 hours, providing further evidence of the non-continuous nature of these measurements. Increasing age was associated with longer CTT (P = .021), WGTT (P < .001) ascending (P = .004), transverse (P < .001), and total right (P < .001) colon transit times, but shorter rectosigmoid (P = .004) transit time. Female gender was significantly associated with longer transverse (P = .049) and descending (P < .001) colon transit times, but shorter rectosigmoid (P < .001) transit time. Increasing BMI was significantly associated with shorter WGTT (P = .012). For the first time, normative reference values for region-specific colonic transit have been presented. Age, gender, and BMI were seen to have an effect on transit times.
Publisher: Wiley
Date: 12-07-2021
DOI: 10.1111/BCPT.13634
Abstract: The physiological changes following Roux‐en‐Y gastric bypass (RYGB) surgery may impact drug release from mechanistically different controlled‐release tablets, making generic substitution inappropriate. This study aimed to characterise the pharmacokinetic‐pharmacodynamic relationships of oxycodone from a lipid‐based and water‐swellable controlled‐release tablet in RYGB patients. Twenty RYGB patients received 10‐mg oral solution oxycodone or 20‐mg controlled‐release (water‐swellable or lipid‐based) oxycodone in a three‐way, randomised, semiblinded and cross‐over study. Blood s ling and pupillary recordings were conducted over a 24‐h period. A previously established pharmacokinetic‐pharmacodynamic model of these three formulations in healthy volunteers was used in the analysis as a reference model. No differences in absorption kinetics were seen between controlled‐release formulations in patients. However, the absorption lag time was 11.5 min in patients vs 14 min in healthy volunteers for controlled‐release tablets ( P 0.001). Furthermore, oral bioavailability was 14.4% higher in patients compared to healthy volunteers regardless of formulation type ( P 0.001). Oxycodone pharmacodynamics were not significantly affected by formulation or patient status. However, baseline pupil diameter was inversely correlated with age ( P 0.001) and plasma concentrations of oxycodone at half‐maximum effect were 31% lower in males compared to females ( P 0.05). Generic substitution of monophasic lipid‐based and water‐swellable controlled‐release oxycodone tablets may be considered safe in RYGB patients.
Publisher: Wiley
Date: 08-12-2010
DOI: 10.1111/J.1742-7843.2010.00649.X
Abstract: Pharmacokinetic harmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead to more rational treatment regimens of pain. The aim of this study was to investigate the concentration-effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty-two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor-induced muscle soreness and intradermal capsaicin-induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time-course of placebo was described first and was afterwards added to the description of the time-courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or E(max) model concentration-effect relationships. Time-dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time-course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone-associated pain, heat pain, nerve growth factor-induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue-differentiated analgesic effects between buprenorphine and fentanyl was shown.
Publisher: Wiley
Date: 08-2016
DOI: 10.1111/NMO.12881
Publisher: Wiley
Date: 28-10-2019
DOI: 10.1111/BCPT.13330
Abstract: Oral controlled-release formulations are playing an ever-increasing role in opioid therapy however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (k
Publisher: Wiley
Date: 05-2008
Abstract: Analgesia from most opioids is mediated by mu receptors located mainly in the central nervous system. Previous studies have shown a different pharmacological profile of oxycodone in respect to visceral analgesia. This study investigated if morphine and oxycodone have different pharmacokinetic harmacodynamic profiles, in particular with respect to delay between opioid blood concentration and analgesia. Twenty-four healthy subjects had oral morphine (30 mg), oxycodone (15 mg), or placebo. Mechanical, thermal, and electrical pain tests were performed in the skin and viscera. Blood s les and pain measurements were taken at baseline and after 15, 30, 60, 90, and 120 minutes. Pharmacokinetic harmacodynamic profiles were modeled using a 2-stage, nonlinear, mixed-effects approach with an effect compartment to represent the concentration-analgesia delay. Morphine kinetics was best described by a 2-compartment model, whereas oxycodone kinetics was best described with a 1-compartment model. Generally the analgesic effects of morphine were best related to plasma concentration by introducing a delay via an effect compartment. However, for oxycodone, this was only the case for analgesia in the somatic pain measures, whereas the plasma concentration correlated better to the course of the analgesia with no delay in the visceral pain measures. Oxycodone and morphine showed different pharmacodynamic harmacokinetic relationships for the visceral analgesia, whereas relationships were alike for somatic analgesia.
Publisher: Springer Science and Business Media LLC
Date: 12-2010
DOI: 10.2165/11536610-000000000-00000
Abstract: Oxycodone is not as well characterized, with respect to its pharmacokinetic harmacodynamic properties, as other opioids. Moreover, the pharmacodynamic profile of oxycodone can be affected by changes in the pain system, e.g. hyperalgesia. Therefore, the aim of this study was to investigate the pharmacokinetic harmacodynamic profiles of oxycodone in a human experimental pain model of hyperalgesia. Twenty-four healthy subjects received oral oxycodone (15 mg) or placebo. Pharmacodynamics were assessed utilizing a multimodal, multi-tissue paradigm where pain was assessed from skin (heat), muscle (pressure) and viscera (heat and electricity) before and 30, 60 and 90 minutes after induction of generalized hyperalgesia evoked by perfusion of acid and capsaicin in the oesophagus. Venous blood s les were obtained for quantification of oxycodone plasma concentrations before and 5, 10, 15, 30, 45, 60, 90 and 120 minutes after drug administration. Oxycodone blood concentrations could be described by a one-compartment model but, given the necessarily short timescale of the study, the concentrations were represented by linear interpolation for subsequent pharmacodynamic models. Time-dependent changes in the pain measures in the placebo arm of the study were represented by linear or quadratic functions. The time course of the pain measures in the oxycodone arm was taken to be the time course for the placebo arm plus a concentration-effect relationship that was either zero (no drug effect), linear or a maximum effect (E(max)) model. For three of the four pain measures, there was a time-dependent change after administration of placebo (e.g. due to the development of generalized hyperalgesia). There was a measurable effect of oxycodone, compared with placebo, on all pain measures, and a linear concentration-effect relationship without an effect delay was demonstrated. This could indicate an initial peripheral analgesic effect of oxycodone.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2018
DOI: 10.1097/MPA.0000000000001151
Abstract: Temporal information about the structural brain changes in chronic pancreatitis (CP) and its relation to the clinical manifestations is lacking. This study investigated changes in morphological brain parameters over 7 years in painful CP patients, compared with controls. In this 7-year longitudinal magnetic resonance imaging study, we included 23 CP patients and 14 controls. Gray matter volume (GMV) and cortical thickness were examined using voxel-based and surface-based morphometry. In addition, patients completed pain questionnaires and diary. At baseline, patients had reduced GMV and cortical thickness in widespread brain areas compared with controls. After 7 years of follow-up, the GMV loss was more pronounced in patients compared with controls, particularly in precentral gyrus and putamen. Moreover, an increase in pain scores was associated with a less reduction of thalamic GMV ( P = 0.046), whereas an increase in brief pain inventory score was associated with more reduction in cortical thickness of precentral ( P = 0.005) and superior temporal gyri ( P = 0.019), indicating that brain morphological alterations are associated with the pain. Chronic pancreatitis pain is associated with morphological brain changes over time in several areas, reflecting that brain plasticity may be a consequence of repeated long-term nociceptive signaling.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.EJPS.2016.02.021
Abstract: Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the ersity in clinical response. The aim of the analysis was to model the exposure-response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs. The population pharmacokinetic-pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters. None of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P 50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability. A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.EJPS.2014.10.003
Abstract: The aim of this study was to develop population pharmacokinetic-pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics. In a randomised, double-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin and muscle. Baseline pain metrics varied between in iduals and occasions, and were described with interin idual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model with interin idual variability on drug effect slope and linked to an effect compartment for muscle pressure. The models indicate that a steady-state morphine concentration of 21ng/ml causes 33% and 0.84% increases in stimulus intensity from baseline for muscle pressure and skin heat, respectively. The population pharmacokinetic-pharmacodynamic models developed in this study indicate that mechanical stimulation of muscle is a more clinically relevant pain stimulus for the assessment of morphine pharmacodynamics than thermal stimulation of skin.
Publisher: Wiley
Date: 29-07-2016
DOI: 10.1002/EJP.921
Abstract: Opioids are often used for pain treatment, but the response is often insufficient and dependent on e.g. the pain condition, genetic factors and drug class. Thus, there is an urgent need to identify biomarkers to enable selection of the appropriate drug for the in idual patient, a concept known as personalized medicine. Quantitative sensory testing (QST) and clinical parameters can provide some guidance for response, but better and more objective biomarkers are urgently warranted. Electroencephalography (EEG) may be suitable since it assesses the central nervous system where opioids mediate their effects. Clinical parameters, QST and EEG (during rest and tonic pain) was recorded from patients the day prior to total hip replacement surgery. Postoperative pain treatment was performed using oxycodone and piritramide as patient-controlled analgesia. Patients were stratified into responders and non-responders based on pain ratings 24 h post-surgery. Parameters were analysed using conventional group-wise statistical methods. Furthermore, EEG was analysed by machine learning to predict in idual response. Eighty-one patients were included, of which 51 responded to postoperative opioid treatment (30 non-responders). Conventional statistics showed that more severe pre-existing chronic pain was prevalent among non-responders to opioid treatment (p = 0.04). Preoperative EEG analysis was able to predict responders with an accuracy of 65% (p = 0.009), but only during tonic pain. Chronic pain grade before surgery is associated with the outcome of postoperative pain treatment. Furthermore, EEG shows potential as an objective biomarker and might be used to predict postoperative opioid analgesia. The current clinical study demonstrates the viability of EEG as a biomarker and with results consistent with previous experimental results. The combined method of machine learning and electroencephalography offers promising results for future developments of personalized pain treatment.
No related grants have been discovered for Asbjørn Drewes.