Abstract: 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. Keywords: opioids, gut, dysfunction, constipation, naloxegol, opioid antagonists
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.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).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).Intradermal NGF injection is capable of inducing reproducible allodynia and hyperalgesia, and the model is recommended for future experimental and pharmacological pain studies.
Abstract Background and aims/objectives Offset analgesia (OA) is a newly discovered pain-inhibiting mechanism, defined as a disproportionately large decrease in pain perception in response to a decrease in noxious stimulus intensity. Offset analgesia is usually evoked using heat as noxious stimulus (44–47 °C) and a slight decrease (1 °C) in stimulus intensity causes the volunteers to be pain-free for 5–10 s, despite the presence of a constant noxious stimulus. The aim of the present study was to evaluate whether the OA phenomenon is reproducible within the same day and between different days in order to evaluate whether the phenomenon can be used as a prognostic/diagnostic tool or as a potential therapeutic target in pain treatment. Methods Eighteen healthy volunteers were presented to painful thermal stimuli on the volar forearm, in three contiguous phases (first phase: 46 °C applied for 5 s; second phase: 47 °C applied for 5 s; third phase: 46 °C applied for 20 s). Continuous sensory ratings obtained with a handheld sliding VAS-scale and continuous 64-channel electroencephalographic (EEG) recordings were obtained throughout the three phases. Volunteers participated on two different days separated by a minimum of 7 days. Results Reproducibility was examined for numerous parameters (e.g. peak pain intensity, magnitude of pain-relief, AUC) related to the continuous pain ratings. Two-way ANOVA, ICC, and CV displayed a high degree of reproducibility both within the same day as well as between different days ( P -values >0.05 and ICC values >0.6). EEG recordings were decomposed by spectral analysis, to obtain the normalized power in the delta, theta, alpha, beta and gamma frequency bands. Conclusion The present model displayed high reproducibility, making it suitable for further studies using OA. This may provide a unique approach to study basic pain and pharmacological intervention in healthy volunteers as well as in patients with dysfunctional pain inhibition. Continuous EEG recordings enable objective evaluation of dynamic changes in brainwave activity during OA, and can possibly be used as an objective biomarker to assess the underlying mechanisms of OA.
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.
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.
The purpose of this study was to investigate breathing-motion induced interplay effects for stereotactic body radiotherapy (SBRT) of liver tumours treated with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT). Ten patients previously treated with liver SBRT were included in this study. All patients had four-dimensional computed tomography (4DCT) scans acquired prior to treatment. The 4DCT was sorted into 8-10 phases covering an equal time interval. A FFF VMAT plan was created for one fraction in the mid-ventilation phase for each patient. To generate dose distributions including both interplay effects and dose blurring, a sub-plan was calculated for each phase. The total dose distributions were accumulated to the mid-ventilation phase using the deformed vector fields (DVF) from deformable image registration between the corresponding CT and the mid-ventilation phase CT. A blurred dose distribution, not including interplay effects, was also obtained by distributing the delivery of the whole plan uniformly on all phases, and was similarly accumulated to the mid-ventilation phase. To isolate interplay effects, this blurred dose distribution was subtracted from the total dose distribution with interplay effects. The near minimum dose (D 98%), mean dose (D mean), heterogeneity index (HI), and the near minimum dose difference (ΔD 98%) between the accumulated dose distributions with and without interplay effects were calculated within the gross tumour volume (GTV) for each patient. Comparing the accumulated dose distributions with and without interplay effects, the D 98% decreased for nine of the ten patients and the HI increased for all patients. The median and minimum differences in D 98% were -2.1% and -5.0% (p = 0.006), respectively, and the median HI significantly increased from 6.2% to 12.2% (p = 0.002). The median ΔD 98% was -4.0% (range -7% to -1.5%). In conclusion, statistically significant breathing-induced interplay effects were observed for a single fraction of FFF VMAT liver SBRT, resulting in heterogeneous dose distributions within the GTV.
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