Offset Analgesia and The Impact of Treatment with Oxycodone and Venlafaxine: A Placebo-Controlled, Randomized Trial in Healthy Volunteers.

Offset analgesia (OA) is a pain-modulating mechanism described as a disproportionately large decrease in pain intensity evoked by a discrete decrease in stimulus temperature. The role of the opioidergic, serotonergic and noradrenergic systems on OA remains unclear. The aim of this study was to evaluate whether OA is modulated by an opioid (oxycodone) and a serotonin and noradrenaline reuptake inhibitor (venlafaxine) in terms of psychophysical assessments. In this randomized, double-blinded, placebo-controlled cross-over study, 20 healthy male participants (mean age: 24.6 ± 2.5 years) received 10 mg oxycodone, 37.5 mg venlafaxine or placebo twice daily for 5 days in three periods. OA was induced by noxious thermal stimulation on the forearm at baseline and last day of treatment. A control session of constant stimulus intensity was included for comparison. OA magnitude was unaffected by oxycodone and venlafaxine (p = 0.20 and p = 0.90, respectively). Oxycodone affected the control paradigm where a decreased rating of pain intensity was observed compared to placebo (p = 0.001). OA could not be modulated by oxycodone or venlafaxine and may be a robust phenomenon in healthy volunteers and not suitable for exploring pharmacological mechanisms of analgesia in human beings.

The Impact of Opioid Treatment on Regional Gastrointestinal Transit.

BACKGROUND/AIMS: To employ an experimental model of opioid-induced bowel dysfunction in healthy human volunteers, and evaluate the impact ofopioid treatment compared to placebo on gastrointestinal (GI) symptoms and motility assessed by questionnaires and regional GItransit times using the 3-dimensional (3D)-Transit system. METHODS: Twenty-five healthy males were randomly assigned to oxycodone or placebo for 5 days in a double blind, crossover design. AdverseGI effects were measured with the bowel function index, gastrointestinal symptom rating scale, patient assessment of constipationsymptom questionnaire, and Bristol stool form scale. Regional GI transit times were determined using the 3D-Transit system, and segmental transit times in the colon were determined using a custom Matlab(®) graphical user interface. RESULTS: GI symptom scores increased significantly across all applied GI questionnaires during opioid treatment. Oxycodone increased median total GI transit time from 22.2 to 43.9 hours (P < 0.001), segmental transit times in the cecum and ascending colon from 5.7 to 9.9 hours (P = 0.012), rectosigmoid colon transit from 2.7 to 9.0 hours (P = 0.044), and colorectal transit time from 18.6 to 38.6 hours (P= 0.001). No associations between questionnaire scores and segmental transit times were detected. CONCLUSIONS: Self-assessed GI adverse effects and increased GI transit times in different segments were induced during oxycodone treatment. This detailed information about segmental changes in motility has great potential for future interventional head-to-head trials of different laxative regimes for prevention and treatment of constipation.

Opioid-induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI.

OBJECTIVE: Opioid treatment is associated with numerous gastrointestinal adverse effects collectively known as opioid-induced bowel dysfunction (OIBD). Most current knowledge of the pathophysiology derives from animal studies limited by species differences and clinical studies, which have substantial confounders that make evaluation difficult. An experimental model of OIBD in healthy volunteers in a controlled setting is therefore highly warranted. The aim of this study was to assess bowel function in healthy volunteers during opioid treatment using subjective and objective methods. METHODS: Twenty-five healthy men were assigned randomly to oxycodone or placebo for 5 days in a cross-over design. The analgesic effect was assessed with muscle pressure algometry and adverse effects were measured using questionnaires including the bowel function index, gastrointestinal symptom rating scale, patient assessment of constipation symptoms and the Bristol stool form scale. Colorectal volumes were determined using a newly developed MRI method. RESULTS: Compared with baseline, oxycodone increased pain detection thresholds by 8% (P=0.02). Subjective OIBD was observed as increased bowel function index (464% increase; P<0.001), gastrointestinal symptom rating scale (37% increase; P<0.001) and patient assessment of constipation symptoms (198% increase; P<0.001). Objectively, stools were harder and drier during oxycodone treatment (P<0.001) and segmental colorectal volumes increased in the caecum/ascending colon by 41% (P=0.005) and in the transverse colon by 20% (P=0.005). No associations were detected between questionnaire scores and colorectal volumes. CONCLUSION: Experimental OIBD in healthy volunteers was induced during oxycodone treatment. This model has potential for future interventional studies to discriminate the efficacies of different laxatives, peripheral morphine antagonists and opioid treatments.

Short-term oxycodone treatment does not affect electrogenic ion transport in isolated mucosa from the human rectosigmoid colon.

OBJECTIVE: Opioid therapy is associated with altered secretion and motility of the gut. The relative contribution of decreased secretion to the development of opioid-induced constipation remains unknown. MATERIALS AND METHODS: Twenty-five healthy males were treated with oxycodone for 5 d in a placebo-controlled, randomised cross-over design. Gastrointestinal adverse effects were assessed with validated questionnaires (bowel function index and gastrointestinal symptom rating scale). Rectosigmoid mucosal biopsies were taken at baseline and on day 5 during both treatments and mounted in Ussing chambers. Electrogenic ion transport parameters (short circuit current (SCC) and slope conductance) were measured after addition of secretagogues (prostaglandin E2 (PGE2) (6 µm), theophylline (400 µm)), and an inhibitor (ouabain (200 µm)). Additionally, morphine (50 µm) was added to investigate the direct opioid effect on colonic mucosa. RESULTS: Questionnaires showed pronounced bowel symptoms, including constipation during oxycodone treatment (eight-fold increase in bowel function index score from day 1 to day 5 (p < 0.001) while no significant change occurred during placebo treatment (p = 0.47). Basal SCC and slope conductance did not differ between treatments (all p > 0.05) and application with PGE2, theophylline, and ouabain yielded comparable results on all examinations (all p > 0.05). Morphine application consistently did not evoke a change in ion transport. CONCLUSION: Compared to placebo, epithelial electrogenic ion transport is not altered in mucosal biopsies from the rectosigmoid colon following 5-d oxycodone treatment. The secretory mechanisms in isolated mucosa appear to play a negligible role in the development of opioid-induced constipation.

Intradermal Injection with Nerve Growth Factor: A Reproducible Model to Induce Experimental Allodynia and Hyperalgesia.

BACKGROUND: Nerve growth factor (NGF) plays a pivotal role in survival, growth, and differentiation of the nervous system. Increased levels of NGF have been reported in human pain disorders. Experimental injection of NGF in humans is known to evoke long-lasting mechanical sensitization and subsequent allodynia and hyperalgesia. METHODS: Reproducibility of intradermal injection of NGF was investigated. Twenty healthy male volunteers were included (mean age 24 years, range 19 to 31). The experiment consisted of 3 identical treatment periods with period 1 stimulating the right arm, period 2 the left arm, and period 3 stimulating the right arm again (period one and three were separated by at least 21 days). Pain intensity was assessed in response to several phasic stimuli in 3 adjacent sites of the volar forearm: pressure; pinprick; brush; and heat before and after NGF injection. Additionally, areas of allodynia and secondary hyperalgesia were assessed. Rekindling with pressure was performed 1 hour and 24 hours after injection. Reproducibility was assessed with intraclass correlation coefficient (ICC 3,1). RESULTS: ICC values > 0.6 for all phasic stimuli and for the area of hyperalgesia. After NGF injection, pressure pain (P < 0.001) and heat pain (P < 0.01) sensitivity increased significantly. After rekindling, the area of hyperalgesia (von Frey 26 g) was significantly increased (P = 0.03) and sensitivity to pinprick was increased (P < 0.02). CONCLUSION: Intradermal NGF injection is capable of inducing reproducible allodynia and hyperalgesia, and the model is recommended for future experimental and pharmacological pain studies.

Evolving paradigms in the treatment of opioid-induced bowel dysfunction.

In recent years prescription of opioids has increased significantly. Although effective in pain management, bothersome gastrointestinal adverse effects are experienced by a substantial proportion of opioid-treated patients. This can lead to difficulties with therapy and subsequently inadequate pain relief. Collectively referred to as opioid-induced bowel dysfunction, these adverse effects are the result of binding of exogenous opioids to opioid receptors in the gastrointestinal tract. This leads to disturbance of three important gastrointestinal functions: motility, coordination of sphincter function and secretion. In the clinic this manifests in a wide range of symptoms such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation, although the most known adverse effect is opioid-induced constipation. Traditional treatment with laxatives is often insufficient, but in recent years a number of novel pharmacological approaches have been introduced. In this review the pathophysiology, symptomatology and prevalence of opioid-induced bowel dysfunction is presented along with the benefits and caveats of a suggested consensus definition for opioid-induced constipation. Finally, traditional treatment is appraised and compared with the latest pharmacological developments. In conclusion, opioid antagonists restricted to the periphery show promising results, but use of different definitions and outcome measures complicate comparison. However, an international working group has recently suggested a consensus definition for opioid-induced constipation and relevant outcome measures have also been proposed. If investigators within this field adapt the suggested consensus and include symptoms related to dysfunction of the upper gut, it will ease comparison and be a step forward in future research.

A novel semi-automatic segmentation method for volumetric assessment of the colon based on magnetic resonance imaging.

PURPOSE: To develop a novel semi-automatic segmentation method for quantification of the colon from magnetic resonance imaging (MRI). METHODS: Fourteen abdominal T2-weighted and dual-echo Dixon-type water-only MRI scans were obtained from four healthy subjects. Regions of interest containing the colon were outlined manually on the T2-weighted images. Segmentation of the colon and feces was obtained using k-means clustering and image registration. Regional colonic and fecal volumes were obtained. Inter-observer agreement between two observers was assessed using the Dice similarity coefficient as measure of overlap. RESULTS: Colonic segmentations showed wide variation in volume and morphology between subjects. Colon volumes of the four healthy subjects for both observers were (median [interquartile range]) ascending colon 200 mL [169.5-260], transverse 200.5 mL [113.5-242.5], descending 148 mL [121.5-178.5], sigmoid-rectum 277 mL [192-345], and total 819 mL [687-898.5]. Overlap agreement for the total colon segmentation between the two observers was high with a Dice similarity coefficient of 0.91 [0.84-0.94]. The colon volume to feces volume ratio was on average 0.7. CONCLUSION: Regional colon volumes were comparable to previous findings using fully manual segmentation. The method showed good agreement between observers and may be used in future studies of gastrointestinal disorders to assess colon and fecal volume and colon morphology. Novel insight into morphology and quantitative assessment of the colon using this method may provide new biomarkers for constipation and abdominal pain compared to radiography which suffers from poor reliability.

Preliminary report: modulation of parasympathetic nervous system tone influences oesophageal pain hypersensitivity.

OBJECTIVES: Autonomic nervous system dysfunction has been implicated in visceral hypersensitivity. However, the specific contribution of the parasympathetic nervous system (PNS) is unclear. We aimed to determine whether physiological and pharmacological manipulation of parasympathetic tone influences the development of hypersensitivity in a validated model of acid-induced oesophageal pain. DESIGN: Prior to, and following, a 30-min distal oesophageal infusion of 0.15 M hydrochloric acid, pain thresholds to electrical stimulation were determined in the proximal non-acid exposed oesophagus in healthy subjects. Validated sympathetic (skin conductance response) and parasympathetic (cardiac vagal tone) parameters were measured at baseline and continuously thereafter. In study 1, 55 subjects were randomised in a pragmatic blinded crossover design to receive deep breathing or un-paced breathing during acid infusion. In study 2, 32 subjects were randomised in a blinded, crossover design to receive intravenous atropine or placebo (saline) with deep breathing during acid infusion. RESULTS: Study 1: Deep breathing increased cardiac vagal tone (2.1±2.3 vs -0.3±2.3, p=0.0006) with concomitant withdrawal of skin conductance response (-0.6±4.9 vs 3±4.8, p=0.03) in comparison with un-paced breathing. Deep breathing prevented the development of acid-induced oesophageal hypersensitivity in comparison with sham breathing (p=0.0001). Study 2: Atropine, in comparison with placebo, blocked the attenuating effect of deep breathing on the development of acid-induced oesophageal hypersensitivity (p=0.046). CONCLUSIONS: The development of oesophageal hyperalgesia is prevented by physiologically increasing parasympathetic tone. This effect is pharmacologically blocked with atropine, providing evidence that the PNS influences the development of oesophageal pain hypersensitivity.

Clinical potential of naloxegol in the management of opioid-induced bowel dysfunction.

Opioid-induced bowel dysfunction (OIBD) is a burdensome condition which limits the therapeutic benefit of analgesia. It affects the entire gastrointestinal tract, predominantly by activating opioid receptors in the enteric nervous system, resulting in a wide range of symptoms, such as reflux, bloating, abdominal cramping, hard, dry stools, and incomplete evacuation. The majority of studies evaluating OIBD focus on constipation experienced in approximately 60% of patients. Nevertheless, other presentations of OIBD seem to be equally frequent. Furthermore, laxative treatment is often insufficient, which in many patients results in decreased quality of life and discontinuation of opioid treatment. Novel mechanism-based pharmacological approaches targeting the gastrointestinal opioid receptors have been marketed recently and even more are in the pipeline. One strategy is prolonged release formulation of the opioid antagonist naloxone (which has limited systemic absorption) and oxycodone in a combined tablet. Another approach is peripherally acting, µ-opioid receptor antagonists (PAMORAs) that selectively target µ-opioid receptors in the gastrointestinal tract. However, in Europe the only PAMORA approved for OIBD is the subcutaneously administered methylnaltrexone. Alvimopan is an oral PAMORA, but only approved in the US for postoperative ileus in hospitalized patients. Finally, naloxegol is a novel, oral PAMORA expected to be approved soon. In this review, the prevalence and pathophysiology of OIBD is presented. As PAMORAs seem to be a promising approach, their potential effect is reviewed with special focus on naloxegol's pharmacological properties, data on safety, efficacy, and patient-focused perspectives. In conclusion, as naloxegol is administered orally once daily, has proven efficacious compared to placebo, has an acceptable safety profile, and can be used as add-on to existing pain treatment, it is a welcoming addition to the targeted treatment possibilities for OIBD.

Intradermal glutamate and capsaicin injections: intra- and interindividual variability of provoked hyperalgesia and allodynia.

Intradermal injections of glutamate and capsaicin are attractive to use in human experimental pain models because hyperalgesia and allodynia mimic isolated aspects of clinical pain disorders. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of glutamate and capsaicin in the volar forearm. Magnitudes of secondary pinprick hyperalgesia and brush-evoked allodynia were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P < 0.001) after glutamate injection. For capsaicin, secondary pinprick hyperalgesia was detected with all von Frey gauges (P < 0.001). Glutamate evoked reproducible VAS response to all von Frey gauges (ICC > 0.60) and brush strokes (ICC > 0.83). Capsaicin injection was reproducible for secondary hyperalgesia (ICC > 0.70) and allodynia (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia. In conclusion, glutamate and capsaicin yield reproducible hyperalgesic and allodynic responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena.

Morphological and functional evaluation of chronic pancreatitis with magnetic resonance imaging.

Magnetic resonance imaging (MRI) techniques for assessment of morphology and function of the pancreas have been improved dramatically the recent years and MRI is very often used in diagnosing and follow-up of chronic pancreatitis (CP) patients. Standard MRI including fat-suppressed T1-weighted and T2-weighted imaging techniques reveal decreased signal and glandular atrophy of the pancreas in CP. In contrast-enhanced MRI of the pancreas in CP the pancreatic signal is usually reduced and delayed due to decreased perfusion as a result of chronic inflammation and fibrosis. Thus, morphological changes of the ductal system can be assessed by magnetic resonance cholangiopancreatography (MRCP). Furthermore, secretin-stimulated MRCP is a valuable technique to evaluate side branch pathology and the exocrine function of the pancreas and diffusion weighted imaging can be used to quantify both parenchymal fibrotic changes and the exocrine function of the pancreas. These standard and advanced MRI techniques are supplementary techniques to reveal morphological and functional changes of the pancreas in CP. Recently, spectroscopy has been used for assessment of metabolite concentrations in-vivo in different tissues and may have the potential to offer better tissue characterization of the pancreas. Hence, the purpose of the present review is to provide an update on standard and advanced MRI techniques of the pancreas in CP.

Unravelling the mystery of capsaicin: a tool to understand and treat pain.

A large number of pharmacological studies have used capsaicin as a tool to activate many physiological systems, with an emphasis on pain research but also including functions such as the cardiovascular system, the respiratory system, and the urinary tract. Understanding the actions of capsaicin led to the discovery its receptor, transient receptor potential (TRP) vanilloid subfamily member 1 (TRPV1), part of the superfamily of TRP receptors, sensing external events. This receptor is found on key fine sensory afferents, and so the use of capsaicin to selectively activate pain afferents has been exploited in animal studies, human psychophysics, and imaging studies. Its effects depend on the dose and route of administration and may include sensitization, desensitization, withdrawal of afferent nerve terminals, or even overt death of afferent fibers. The ability of capsaicin to generate central hypersensitivity has been valuable in understanding the consequences and mechanisms behind enhanced central processing of pain. In addition, capsaicin has been used as a therapeutic agent when applied topically, and antagonists of the TRPV1 receptor have been developed. Overall, the numerous uses for capsaicin are clear; hence, the rationale of this review is to bring together and discuss the different types of studies that exploit these actions to shed light upon capsaicin working both as a tool to understand pain but also as a treatment for chronic pain. This review will discuss the various actions of capsaicin and how it lends itself to these different purposes.