Clinical studies comparing the response and side effects of various opioids have not been able to... more Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.
Objective. Animal experiments and clinical observations have indicated a different working profil... more Objective. Animal experiments and clinical observations have indicated a different working profile of oxycodone compared to morphine, and it has previously been shown that oxycodone attenuates visceral pain better than morphine. The objective of this study was to test the effects of oxycodone and morphine on experimental pain in patients with pain caused by chronic pancreatitis. Material and methods. Ten patients took part in this blinded, cross-over study. The analgesic effects of morphine (30 mg, oral), oxycodone (15 mg, oral) and placebo were tested against multimodal (mechanical, thermal and electrical) experimental pain in the skin, muscles and oesophagus. Pain was assessed at baseline and 30, 60 and 90 min after drug administration. Results. In the skin and muscles, oxycodone was more effective than placebo and morphine on mechanically (skin: F0/12.4, p B/0.001, muscle: F0/11.0, p B/0.001) and thermally (skin: F0/8.5, p B/0.001) evoked pain. In oesophageal heat pain, the effect of morphine was equal to that of placebo, while oxycodone attenuated pain better than both morphine and placebo (F 0/9.5, p B/0.001). Both morphine and oxycodone were more effective in attenuating mechanical pain in the oesophagus than placebo (F0/8.6, p B/0.001). After electrical stimulation no differences were seen between the opioids and placebo in any tissue studied. Conclusions. Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus.
Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neu... more Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids. On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate rele...
Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreati... more Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP. 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve bl...
Basic & clinical pharmacology & toxicology, Jan 29, 2015
Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is i... more Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 men and 7 women, 24.9 ± 2.6 years) in a randomized, double-blind, placebo-controlled, cross-over study. Painful stimulations were applied to the right forearm using a contact heat evoked potential stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n = 16, p < 0.05). In response to morphine treatment, the spatial extent of these pain-specific areas decreased ...
Human experimental pain studies are of value to study basic pain mechanisms under controlled cond... more Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and rs563649 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.
Pain practice : the official journal of World Institute of Pain, Jan 26, 2015
Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions... more Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions. To study the effect of acupuncture in experimental and clinical studies, a control condition with sham acupuncture is needed. However, as such models have not been established in assessment of acupunctures effect against visceral pain, this study aimed to validate a new method for blinded sham acupuncture in experimental rectal pain. Fifteen subjects underwent a sequence of either sham or real acupuncture in randomized order. In the sham arm, a hollow inner tube with a sharp tip was fitted into an outer tube and subjects were blinded to the stimulations. Before and after the intervention, pain was induced by rectal stimulation with an inflatable balloon distended until the subjects' pain threshold was reached. The resting electroencephalogram (EEG) was quantified by spectral power analysis to explore the central nervous system effects objectively. Additionally, after the second stu...
Background: Experimental investigation of cerebral mechanisms underlying pain and analgesia are i... more Background: Experimental investigation of cerebral mechanisms underlying pain and analgesia are important in the development of methods for diagnosis and treatment of pain. The aim of the current study was to explore brain metabolites in response to pain and treatment with morphine. Methods: Proton magnetic resonance spectroscopy of the anterior cingulate cortex was performed in 20 healthy volunteers (13 males and seven females, aged 24.9±2.6 years) during rest and acute pain before and during treatment with 30 mg of oral morphine or placebo in a randomized, double-blinded, cross-over study design. Pain was evoked by skin stimulation applied to the right upper leg using a contact heat-evoked potential stimulator. Results: Data from 12 subjects were valid for analysis. Painful stimulation induced an increase in N-acetylaspartate/creatine compared with rest (F=5.5, P=0.04). During treatment with morphine, painful stimulation induced decreased glutamate/creatine (F=7.3, P=0.02), myo-inositol/creatine (F=8.38, P=0.02), and N-acetylaspartate/creatine (F=13.8, P=0.004) concentrations, whereas an increase in the pain-evoked N-acetylaspartate/creatine concentration (F=6.1, P=0.04) was seen during treatment with placebo. Conclusion: This explorative study indicates that neuronal metabolites in the anterior cingulate cortex, such as N-acetylaspartate, glutamate, and myo-inositol, could be related to the physiology of pain and treatment with morphine. This experimental method has the potential to enable the study of brain metabolites involved in pain and its treatment, and may in the future be used to provide further insight into these mechanisms.
World Journal of Gastrointestinal Pathophysiology, 2014
Intense abdominal pain is the most common symptom in chronic pancreatitis, but the underlying mec... more Intense abdominal pain is the most common symptom in chronic pancreatitis, but the underlying mechanisms are not completely understood and pain management remains a significant clinical challenge. The focus of pain origin in chronic pancreatitis traditionally has been on the pancreatic gland, assuming pain to originate in the pancreas or its surrounding organs. However, research in the last decade points to abnormal central nervous system pain processing. For this reason, electroencephalography has been receiving increasing attention. In contrast to imaging methods such as functional magnetic resonance imaging and positron emission tomography, electroencephalogram has excellent temporal resolution making it possible to investigate central processing of pain on a millisecond time scale. Moreover, continuously advancing methodology made it possible to explore brain sources responsible for generation of evoked potentials and hence to study brain reorganization due to pain in chronic pancreatitis. The aim of this review is to give an overview of the current methods and findings in electroencephalography as a tool to unravel the origin of pancreatic pain.
Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindivid... more Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.
British journal of clinical pharmacology, Jan 31, 2014
The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (... more The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (CHEPs) may be altered by morphine. However, previous studies have averaged CHEPs over multiple stimuli, which is confounded by jitter between sweeps. Thus, the aim was to assess single-sweep characteristics to identify alterations induced by morphine. In a cross-over study 15 single-sweep CHEPs were analysed from 62 electroencephalography electrodes in 26 healthy volunteers before and after administration of morphine or placebo. Each sweep was decomposed by a continuous wavelet transform to obtain normalised spectral indices in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-80 Hz) bands. The average distribution over all sweeps and channels was calculated for the four recordings for each volunteer, and the two recordings before treatments were assessed for reproducibility. Baseline corrected spectral indices after morphine and placebo treatments were...
Variability in patients' postoperative pain experience and response to treatment challenges e... more Variability in patients' postoperative pain experience and response to treatment challenges effective pain management. Variability in pain reflects individual differences in inhibitory pain modulation and psychological sensitivity, which in turn may be clinically relevant for the disposition to acquire pain. The aim of this study was to investigate the effects of conditioned pain modulation and situational pain catastrophizing on postoperative pain and pain persistency. Preoperatively, 42 healthy males undergoing funnel chest surgery completed the Spielberger's State-Trait Anxiety Inventory and Beck's Depression Inventory before undergoing a sequential conditioned pain modulation paradigm. Subsequently, the Pain Catastrophizing Scale was introduced and patients were instructed to reference the conditioning pain while answering. Ratings of movement-evoked pain and consumption of morphine equivalents were obtained during postoperative days 2-5. Pain was reevaluated at six ...
The current study aimed to refine the conventional distension model in the human rectum by measur... more The current study aimed to refine the conventional distension model in the human rectum by measuring the cross-sectional area with a ramp-controlled impedance planimetric system. After preconditioning, the rectum in seven volunteers was distended 56 times with infusion rates of 50, 100 and 200 ml/min and at 100 ml/min during relaxation of the smooth muscle with glucagon. The pump was reversed at maximal tolerated pain. The subjects tolerated a higher volume and pressure with a more reliable sensory rating after preconditioning of the tissue. The three distension rates resulted in different pressure and tension at the maximal pain intensity (P < 0.02 and P < 0.05) with a decrease after relaxation of the smooth muscle with glucagon (P < 0.05). On the other hand, the cross-sectional area and volume were robust, did not show strain-rate dependency, and were not affected by muscle relaxation. Since the cross-sectional area is directly related to the deformation of the gut wall a...
World journal of gastroenterology : WJG, Jan 28, 2005
Sensitization most likely plays an important role in chronic pain disorders, and such sensitizati... more Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization. Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine. The sensitization resul...
Introduction and aimPain sensitivity has been linked to the melanocortin-1 receptor (MC1R) gene. ... more Introduction and aimPain sensitivity has been linked to the melanocortin-1 receptor (MC1R) gene. A mutation in MC1R can result in pale skin and red hair in humans and may modulate pain responses in general. Human studies have shown that women with non-functional MC1R&amp;#x27;s were sensitive to experimental induced cold and heat pain. A study demonstrated that females with red hair
Background: Normal upper endoscopy may be a marker of ischemic heart disease in patients with une... more Background: Normal upper endoscopy may be a marker of ischemic heart disease in patients with unexplained chest/epigastric pain.
World journal of gastroenterology : WJG, Jan 7, 2015
Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., in... more Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including qu...
To explore changes in current source density locations after remifentanil infusion in healthy vol... more To explore changes in current source density locations after remifentanil infusion in healthy volunteers using source localization of the electroencephalography (EEG). EEG data was collected from 21 males using a 62-electrode system. Additionally, cognitive performance was evaluated by a continuous reaction time paradigm, and pain scores were obtained for experimental bone and heat stimuli. Data were recorded before and during treatment with remifentanil and placebo. Source localization was performed by sLORETA at delta (1-3.9Hz), theta (4-7.9Hz), alpha (8-12Hz), beta1 (12.1-18Hz), and beta2 (18.1-30Hz) frequency bands. Pre-treatment recordings demonstrated reproducible source characteristics. The alterations (i.e., pre- versus post-treatment) due to remifentanil were significantly and robustly different from placebo infusions. The results indicated that neurons in several brain areas including inferior frontal gyrus and insula at frontal lobe oscillated more strongly after remifentanil infusion compared to placebo. Furthermore, the source activity at delta band was correlated with continuous reaction time index. These results indicate that alterations in brain oscillations during remifentanil are mostly localized to frontal, fronto-temporal and fronto-central lobes and related to cognitive function. The approach offers the potential to be used for understanding the underlying mechanism of action of remifentanil on brain activity.
Introduction: Opioid analgesia can be explored with quantitative sensory testing, but most invest... more Introduction: Opioid analgesia can be explored with quantitative sensory testing, but most investigations have used models of phasic pain, and such brief stimuli may be limited in the ability to faithfully simulate natural and clinical painful experiences. Therefore, identification of appropriate experimental pain models is critical for our understanding of opioid effects with the potential to improve treatment. Objectives: The aim was to explore and compare various pain models to morphine analgesia in healthy volunteers.
Clinical studies comparing the response and side effects of various opioids have not been able to... more Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.
Objective. Animal experiments and clinical observations have indicated a different working profil... more Objective. Animal experiments and clinical observations have indicated a different working profile of oxycodone compared to morphine, and it has previously been shown that oxycodone attenuates visceral pain better than morphine. The objective of this study was to test the effects of oxycodone and morphine on experimental pain in patients with pain caused by chronic pancreatitis. Material and methods. Ten patients took part in this blinded, cross-over study. The analgesic effects of morphine (30 mg, oral), oxycodone (15 mg, oral) and placebo were tested against multimodal (mechanical, thermal and electrical) experimental pain in the skin, muscles and oesophagus. Pain was assessed at baseline and 30, 60 and 90 min after drug administration. Results. In the skin and muscles, oxycodone was more effective than placebo and morphine on mechanically (skin: F0/12.4, p B/0.001, muscle: F0/11.0, p B/0.001) and thermally (skin: F0/8.5, p B/0.001) evoked pain. In oesophageal heat pain, the effect of morphine was equal to that of placebo, while oxycodone attenuated pain better than both morphine and placebo (F 0/9.5, p B/0.001). Both morphine and oxycodone were more effective in attenuating mechanical pain in the oesophagus than placebo (F0/8.6, p B/0.001). After electrical stimulation no differences were seen between the opioids and placebo in any tissue studied. Conclusions. Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus.
Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neu... more Modulatory descending pathways, originating at supraspinal sites that converge at dorsal horn neurons, influence pain perception in humans. Defects in descending pain control are linked to chronic pain states and its restoration may be a valuable analgesic tool. Conditioned pain modulation (CPM) is a surrogate marker of descending inhibition that reduces the perception of pain from a primary test stimulus during application of a conditioning stimulus. Here the effects of the analgesics tapentadol, a combined mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and morphine, a strong mu-opioid receptor agonist, were tested on CPM in a randomized, double-blind, placebo-controlled crossover trial in 12 healthy pain-free volunteers, to understand possible differences in mechanism of action between these opioids. On three occasions CPM responses were obtained 60-90 and 120-150 min following intake of tapentadol (100 mg immediate release tablet), morphine (40 mg immediate rele...
Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreati... more Chronic pancreatitis (CP) is an inflammatory disease that causes irreversible damage to pancreatic tissue. Pain is its most prominent symptom. In the absence of pathology suitable for endoscopic or surgical interventions, pain treatment usually includes opioids. However, opioids often have limited efficacy. Moreover, side effects are common and bothersome. Hence, novel approaches to control pain associated with CP are highly desirable. Sensitisation of the central nervous system is reported to play a key role in pain generation and chronification. Fundamental to the process of central sensitisation is abnormal activation of the N-methyl-D-aspartate receptor, which can be antagonised by S-ketamine. The RESET trial is investigating the analgaesic and antihyperalgesic effect of S-ketamine in patients with CP. 40 patients with CP will be enrolled. Patients are randomised to receive 8 h of intravenous S-ketamine followed by oral S-ketamine, or matching placebo, for 4 weeks. To improve bl...
Basic & clinical pharmacology & toxicology, Jan 29, 2015
Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is i... more Knowledge about cerebral mechanisms underlying pain perception and effect of analgesic drugs is important for developing methods for diagnosis and treatment of pain. The aim was to explore altered brain activation before and after morphine treatment using functional magnetic resonance imaging recorded during experimental painful heat stimulation. Functional magnetic resonance imaging data were recorded and analysed in 20 healthy volunteers (13 men and 7 women, 24.9 ± 2.6 years) in a randomized, double-blind, placebo-controlled, cross-over study. Painful stimulations were applied to the right forearm using a contact heat evoked potential stimulator (CHEPS) before and after treatment with 30 mg oral morphine and placebo. CHEPS stimulations before treatment induced activation in the anterior cingulate cortex, secondary somatosensory cortex/insula, thalamus and cerebellum (n = 16, p < 0.05). In response to morphine treatment, the spatial extent of these pain-specific areas decreased ...
Human experimental pain studies are of value to study basic pain mechanisms under controlled cond... more Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and rs563649 (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.
Pain practice : the official journal of World Institute of Pain, Jan 26, 2015
Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions... more Acupuncture is increasingly used as an alternative to medical therapy for various pain conditions. To study the effect of acupuncture in experimental and clinical studies, a control condition with sham acupuncture is needed. However, as such models have not been established in assessment of acupunctures effect against visceral pain, this study aimed to validate a new method for blinded sham acupuncture in experimental rectal pain. Fifteen subjects underwent a sequence of either sham or real acupuncture in randomized order. In the sham arm, a hollow inner tube with a sharp tip was fitted into an outer tube and subjects were blinded to the stimulations. Before and after the intervention, pain was induced by rectal stimulation with an inflatable balloon distended until the subjects' pain threshold was reached. The resting electroencephalogram (EEG) was quantified by spectral power analysis to explore the central nervous system effects objectively. Additionally, after the second stu...
Background: Experimental investigation of cerebral mechanisms underlying pain and analgesia are i... more Background: Experimental investigation of cerebral mechanisms underlying pain and analgesia are important in the development of methods for diagnosis and treatment of pain. The aim of the current study was to explore brain metabolites in response to pain and treatment with morphine. Methods: Proton magnetic resonance spectroscopy of the anterior cingulate cortex was performed in 20 healthy volunteers (13 males and seven females, aged 24.9±2.6 years) during rest and acute pain before and during treatment with 30 mg of oral morphine or placebo in a randomized, double-blinded, cross-over study design. Pain was evoked by skin stimulation applied to the right upper leg using a contact heat-evoked potential stimulator. Results: Data from 12 subjects were valid for analysis. Painful stimulation induced an increase in N-acetylaspartate/creatine compared with rest (F=5.5, P=0.04). During treatment with morphine, painful stimulation induced decreased glutamate/creatine (F=7.3, P=0.02), myo-inositol/creatine (F=8.38, P=0.02), and N-acetylaspartate/creatine (F=13.8, P=0.004) concentrations, whereas an increase in the pain-evoked N-acetylaspartate/creatine concentration (F=6.1, P=0.04) was seen during treatment with placebo. Conclusion: This explorative study indicates that neuronal metabolites in the anterior cingulate cortex, such as N-acetylaspartate, glutamate, and myo-inositol, could be related to the physiology of pain and treatment with morphine. This experimental method has the potential to enable the study of brain metabolites involved in pain and its treatment, and may in the future be used to provide further insight into these mechanisms.
World Journal of Gastrointestinal Pathophysiology, 2014
Intense abdominal pain is the most common symptom in chronic pancreatitis, but the underlying mec... more Intense abdominal pain is the most common symptom in chronic pancreatitis, but the underlying mechanisms are not completely understood and pain management remains a significant clinical challenge. The focus of pain origin in chronic pancreatitis traditionally has been on the pancreatic gland, assuming pain to originate in the pancreas or its surrounding organs. However, research in the last decade points to abnormal central nervous system pain processing. For this reason, electroencephalography has been receiving increasing attention. In contrast to imaging methods such as functional magnetic resonance imaging and positron emission tomography, electroencephalogram has excellent temporal resolution making it possible to investigate central processing of pain on a millisecond time scale. Moreover, continuously advancing methodology made it possible to explore brain sources responsible for generation of evoked potentials and hence to study brain reorganization due to pain in chronic pancreatitis. The aim of this review is to give an overview of the current methods and findings in electroencephalography as a tool to unravel the origin of pancreatic pain.
Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindivid... more Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.
British journal of clinical pharmacology, Jan 31, 2014
The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (... more The cortical response to nociceptive thermal stimuli recorded as contact heat evoked potentials (CHEPs) may be altered by morphine. However, previous studies have averaged CHEPs over multiple stimuli, which is confounded by jitter between sweeps. Thus, the aim was to assess single-sweep characteristics to identify alterations induced by morphine. In a cross-over study 15 single-sweep CHEPs were analysed from 62 electroencephalography electrodes in 26 healthy volunteers before and after administration of morphine or placebo. Each sweep was decomposed by a continuous wavelet transform to obtain normalised spectral indices in the delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-80 Hz) bands. The average distribution over all sweeps and channels was calculated for the four recordings for each volunteer, and the two recordings before treatments were assessed for reproducibility. Baseline corrected spectral indices after morphine and placebo treatments were...
Variability in patients' postoperative pain experience and response to treatment challenges e... more Variability in patients' postoperative pain experience and response to treatment challenges effective pain management. Variability in pain reflects individual differences in inhibitory pain modulation and psychological sensitivity, which in turn may be clinically relevant for the disposition to acquire pain. The aim of this study was to investigate the effects of conditioned pain modulation and situational pain catastrophizing on postoperative pain and pain persistency. Preoperatively, 42 healthy males undergoing funnel chest surgery completed the Spielberger's State-Trait Anxiety Inventory and Beck's Depression Inventory before undergoing a sequential conditioned pain modulation paradigm. Subsequently, the Pain Catastrophizing Scale was introduced and patients were instructed to reference the conditioning pain while answering. Ratings of movement-evoked pain and consumption of morphine equivalents were obtained during postoperative days 2-5. Pain was reevaluated at six ...
The current study aimed to refine the conventional distension model in the human rectum by measur... more The current study aimed to refine the conventional distension model in the human rectum by measuring the cross-sectional area with a ramp-controlled impedance planimetric system. After preconditioning, the rectum in seven volunteers was distended 56 times with infusion rates of 50, 100 and 200 ml/min and at 100 ml/min during relaxation of the smooth muscle with glucagon. The pump was reversed at maximal tolerated pain. The subjects tolerated a higher volume and pressure with a more reliable sensory rating after preconditioning of the tissue. The three distension rates resulted in different pressure and tension at the maximal pain intensity (P < 0.02 and P < 0.05) with a decrease after relaxation of the smooth muscle with glucagon (P < 0.05). On the other hand, the cross-sectional area and volume were robust, did not show strain-rate dependency, and were not affected by muscle relaxation. Since the cross-sectional area is directly related to the deformation of the gut wall a...
World journal of gastroenterology : WJG, Jan 28, 2005
Sensitization most likely plays an important role in chronic pain disorders, and such sensitizati... more Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization. Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine. The sensitization resul...
Introduction and aimPain sensitivity has been linked to the melanocortin-1 receptor (MC1R) gene. ... more Introduction and aimPain sensitivity has been linked to the melanocortin-1 receptor (MC1R) gene. A mutation in MC1R can result in pale skin and red hair in humans and may modulate pain responses in general. Human studies have shown that women with non-functional MC1R&amp;#x27;s were sensitive to experimental induced cold and heat pain. A study demonstrated that females with red hair
Background: Normal upper endoscopy may be a marker of ischemic heart disease in patients with une... more Background: Normal upper endoscopy may be a marker of ischemic heart disease in patients with unexplained chest/epigastric pain.
World journal of gastroenterology : WJG, Jan 7, 2015
Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., in... more Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including qu...
To explore changes in current source density locations after remifentanil infusion in healthy vol... more To explore changes in current source density locations after remifentanil infusion in healthy volunteers using source localization of the electroencephalography (EEG). EEG data was collected from 21 males using a 62-electrode system. Additionally, cognitive performance was evaluated by a continuous reaction time paradigm, and pain scores were obtained for experimental bone and heat stimuli. Data were recorded before and during treatment with remifentanil and placebo. Source localization was performed by sLORETA at delta (1-3.9Hz), theta (4-7.9Hz), alpha (8-12Hz), beta1 (12.1-18Hz), and beta2 (18.1-30Hz) frequency bands. Pre-treatment recordings demonstrated reproducible source characteristics. The alterations (i.e., pre- versus post-treatment) due to remifentanil were significantly and robustly different from placebo infusions. The results indicated that neurons in several brain areas including inferior frontal gyrus and insula at frontal lobe oscillated more strongly after remifentanil infusion compared to placebo. Furthermore, the source activity at delta band was correlated with continuous reaction time index. These results indicate that alterations in brain oscillations during remifentanil are mostly localized to frontal, fronto-temporal and fronto-central lobes and related to cognitive function. The approach offers the potential to be used for understanding the underlying mechanism of action of remifentanil on brain activity.
Introduction: Opioid analgesia can be explored with quantitative sensory testing, but most invest... more Introduction: Opioid analgesia can be explored with quantitative sensory testing, but most investigations have used models of phasic pain, and such brief stimuli may be limited in the ability to faithfully simulate natural and clinical painful experiences. Therefore, identification of appropriate experimental pain models is critical for our understanding of opioid effects with the potential to improve treatment. Objectives: The aim was to explore and compare various pain models to morphine analgesia in healthy volunteers.
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Papers by Asbjørn Drewes