Lecia Møller Nielsen

Differences between opioids

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 physicians 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.

Pathophysiology of chronic pancreatitis

Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by progressive fibrotic destruction of the pancreatic secretory parenchyma. Despite the heterogeneity in pathogenesis and involved risk factors, processes such as necrosis/apoptosis, inflammation or duct obstruction are involved. This fibrosing process ultimately leads to progressive loss of the lobular morphology and structure of the pancreas, deformation of the large ducts and severe changes in the arrangement and composition of the islets. These conditions lead to irreversible morphological and structural changes resulting in impairment of both exocrine and endocrine functions. The prevalence of the disease is largely dependent on culture and geography. The etiological risk-factors associated with CP are multiple and involve both genetic and environmental factors. Throughout this review the M-ANNHEIM classification system will be used, comprising a detailed description of risk factors such as: alcohol-consumption, nicotine-consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors and miscellaneous and rare metabolic factors. Increased knowledge of the different etiological factors may encourage the use of further advanced diagnostic tools, which potentially will help clinicians to diagnose CP at an earlier stage. However, in view of the multi factorial disease and the complex clinical picture, it is not surprising that treatment of patients with CP is challenging and often unsuccessful.

Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review

On an individual level, there is a difference in the analgesic response to a given opioid. Various factors such as gender, age, and genetic variation can affect the analgesic response. The genetic variation can influence pharmacokinetics (eg drug transporters and drug‐metabolizing enzymes) and/or pharmacodynamics (eg opioid receptor and catechol‐O‐methyltransferase enzymes). We present recent experimentally induced pain, postoperative pain, and cancer pain and chronic non‐malignant pain conditions studies in humans, focusing on the association between genetic variation and analgesic response assessed as opioid consumption or changes in pain scores. Studies have shown promising results regarding pharmacogenetics as a diagnostic tool for predicting the individual response to a given opioid in the experimental settings; however, in the clinic, it is a more complicated task to accomplish.

The genetic influences on oxycodone response characteristics in human experimental pain

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 < 0.0001) and rs563649 (P < 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.

Efficacy and Safety of PPC-5650 on Experimental Rectal Pain in Patients with Irritable Bowel Syndrome

PPC‐5650 is a new pharmacological agent that can modulate acid‐sensing ion channel activity, leading to a reduction in the pain signal under up‐regulated conditions. The non‐clinical programme for PPC‐5650 supported a role for this novel agent in the treatment of pain in patients with irritable bowel syndrome (IBS). In patients with IBS, the aims of the study were: (1) to assess the efficacy of a single bolus of PPC‐5650 locally applied in the rectum using multi‐modal stimulations of the recto sigmoid and (2) to assess the safety profile of PPC‐5650. The study was a randomized, double‐blind, placebo‐controlled, cross‐over trial in patients with IBS, excluding females of child‐bearing potential. The study consisted of a training visit, study visit 1 and 2 and a follow‐up visit. Rectosigmoid electrical, thermal and mechanical stimulations were performed, pain perception was rated on a pain intensity scale and referred pain areas were assessed. All adverse events were registered.

Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

Aim A high inter‐individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p‐glycoprotein (ABCB1), and the UDP‐glucuronosyltransferase‐2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and ‐dynamics in healthy volunteers. Methods Pharmacokinetic and pharmacodynamic data were collected from a double‐blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time‐concentration relationship of morphine, morphine‐3‐glucuronide, and morphine‐6‐glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration‐time curve (AUC0–150 min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation (“the cold pressor test” where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n = 22), ABCB1 (n = 37), and UGT2B (n = 22)) were examined. Results Neither AUC0–150 min, ktr, CL, nor VD were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P > 0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P > 0.05). Conclusions In this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.

Randomized clinical trial: efficacy and safety of PPC-5650 on experimental esophageal pain and hyperalgesia in healthy volunteers

Abstract Objective. Gastroesophageal reflux disease (GERD) is a common condition associated with symptoms as heart burn, regurgitation, chest pain, and gastrointestinal discomfort. PPC-5650 is a new pharmacological agent that can modulate acid-sensing ion channel activity, potentially leading to reduction in the pain signal. In healthy volunteers the esophagus was sensitized with acid to mimic GERD with the aims: 1) to assess the efficacy of a single bolus of PPC-5650 locally applied to the esophagus using multimodal pain stimulations, and 2) to assess the safety profile of PPC-5650. Materials and methods. The study was a randomized, double-blinded, placebo-controlled, crossover trial in healthy males. Esophageal electrical, thermal, mechanical, and chemical stimulations were performed, pain perception was rated, and referred pain areas were drawn. Sensitization was induced by intraluminal esophageal acid perfusions. Adverse events were registered. Results. Twenty-five healthy males completed the study (mean age 23.4 ± 2.0 years). About 90 min after drug administration, PPC-5650 increased the volume tolerated at moderate pain during mechanical stimulation compared to placebo (difference 13.5, 95% CI: 0.58–26.47, p = 0.04), but there was no effects on thermal-, electrical-, and chemical-induced pain (all p > 0.05). PPC-5650 did not affect referred pain areas to any stimulation (all p > 0.05). Ten participants reported adverse events during the placebo treatment period, and nine participants reported adverse events during the PPC-5650 treatment period (p = 0.8). Conclusion. Sensitization to mechanical stimulation of the esophagus was reduced by PPC-5650 compared to placebo. The overall safety and tolerability of PPC-5650 was acceptable. Thus, PPC-5650 may play a role in the future treatment of patients with GERD.

Association between Gene Polymorphisms and Pain Sensitivity Assessed in a Multi-Modal Multi-Tissue Human Experimental Model - An Explorative Study

The genetic influence on sensitivity to noxious stimuli (pain sensitivity) remains controversial and needs further investigation. In the present study, the possible influence of polymorphisms in three opioid receptor (OPRM, OPRD and OPRK) genes and the catechol‐O‐methyltransferase (COMT) gene on pain sensitivity in healthy participants was investigated. Catechol‐O‐methyltransferase has an indirect effect on the mu opioid receptor by changing its activity through an altered endogenous ligand effect. Blood samples for genetic analysis were withdrawn in a multi‐modal and multi‐tissue experimental pain model in 40 healthy participants aged 20–65. Seventeen different single nucleotide polymorphisms in different genes (OPRM, OPRK, OPRD and COMT) were included in the analysis. Experimental pain tests included thermal skin stimulation, mechanical muscle and bone stimulation and mechanical, electrical and thermal visceral stimulations. A cold pressor test was also conducted. DNA was available from 38 of 40 participants. Compared to non‐carriers of the COMT rs4680A allele, carriers reported higher bone pressure pain tolerance threshold (i.e. less pain) by up to 23.8% (p < 0.015). Additionally, carriers of the C allele (CC/CT) of OPRK rs6473799 reported a 30.4% higher mechanical visceral pain tolerance threshold than non‐carriers (TT; p < 0.019). For the other polymorphisms and stimulations, no associations were found (all p > 0.05). In conclusion, COMT rs4680 and OPRK rs6473799 polymorphisms seem to be associated with pain sensitivity. Thus, the findings support a possible genetic influence on pain sensitivity.

Genetic Influences of OPRM1, OPRD1 and COMT on Morphine Analgesia in a Multi-Modal, Multi-Tissue Human Experimental Pain Model

Human studies on experimentally induced pain are of value to elucidate the genetic influence on morphine analgesia under controlled conditions. The aim of this study was to investigate whether genetic variants of mu‐, kappa‐ and delta‐opioid receptor genes (OPRM1, OPRK1 and OPRD1) and catechol‐O‐methyltransferase gene (COMT) are associated with the morphine analgesia. The study was a randomized, double‐blind, two‐way, crossover, single‐dose study conducted in 40 healthy participants, where morphine was compared with placebo. Pain was induced by contact heat, muscle pressure, bone pressure, rectal stimulations (mechanical, electrical and thermal) and cold pressor test (immersion of the hand into ice water). Sixteen genetic polymorphisms of four candidate genes were explored. Variability in morphine analgesia to contact heat stimulation was associated with COMT rs4680 (p = 0.04), and rectal thermal stimulation was associated with OPRM1 rs9479757 (p = 0.03). Moreover, in males, variability in morphine analgesia to rectal thermal stimulation was associated with OPRD1 polymorphisms: rs2234918 (p = 0.01) and rs533123 (p = 0.046). The study was explorative and hypothesis‐generating due to the relatively small study size. However, results suggest that genetic variants in the COMT and OPRM1 irrespective of gender, and OPRD1 in males may contribute to the variability in morphine analgesia in experimental pain models.

Does catastrophic thinking enhance oesophageal pain sensitivity?: An experimental investigation

Gastro‐oesophageal reflux disease (GORD) is a major health problem that is frequently accompanied by debilitating oesophageal pain symptoms.