Jakob Lykke Poulsen

Impaired Pancreatic Innervation after Pyloric Transsection in Dogs: Reduced Pancreatic Polypeptide Response to Insulin Hypoglycaemia

Pancreatic polypeptide (PP) is released by efferent vagal impulses and its secretion is impaired after truncal and selective gastric vagotomy while remaining unchanged after parietal cell vagotomy. In three dogs an innervated antral pouch with transsection of the pylorus was constructed. After this operation the PP response to insulin hypoglycaemia was significantly reduced as compared to the preoperative response. In another four dogs an innervated antral pouch was constructed without transsecting the pylorus. Postoperatively we found that the PP response to insulin hypoglycaemia was unchanged compared to preoperatively. These results seem to indicate that vagal fibres to the pancreas run in close anatomic relation to the pylorus, and their inevitable damage during pyloric transsection results in reduced endocrine pancreatic secretion to vagal stimuli.

Pain and chronic pancreatitis: A complex interplay of multiple mechanisms

Despite multiple theories on the pathogenesis of pain in chronic pancreatitis, no uniform and consistently successful treatment strategy exists and abdominal pain still remains the dominating symptom for most patients and a major challenge for clinicians. Traditional theories focussed on a mechanical cause of pain related to anatomical changes and evidence of increased ductal and interstitial pressures. These observations form the basis for surgical and endoscopic drainage procedures, but the outcome is variable and often unsatisfactory. This underscores the fact that other factors must contribute to pathogenesis of pain, and has shifted the focus towards a more complex neurobiological understanding of pain generation. Amongst other explanations for pain, experimental and human studies have provided evidence that pain perception at the peripheral level and central pain processing of the nociceptive information is altered in patients with chronic pancreatitis, and resembles that seen in neuropathic and chronic pain disorders. However, pain due to e.g., complications to the disease and adverse effects to treatment must not be overlooked as an additional source of pain. This review outlines the current theories on pain generation in chronic pancreatitis which is crucial in order to understand the complexity and limitations of current therapeutic approaches. Furthermore, it may also serve as an inspiration for further research and development of methods that can evaluate the relative contribution and interplay of different pain mechanisms in the individual patients, before they are subjected to more or less empirical treatment.

Impaired pancreatic innervation after selective gastric vagotomy. Reduction of the pancreatic polypeptide response to food and insulin hypoglycemia.

The secretion of pancreatic polypeptide (PP) was studied in 38 duodenal ulcer patients before, 4 months after, and, in 25 patients, again 18 months after either selective gastric vagotomy or parietal cell vagotomy. Selective gastric vagotomy on average reduced the PP response to food measured 4 months after operation to 20% of the preoperative value. The prolonged PP response (30-120 min) increased to 50% from the 4th to the 18th postoperative month (p less than 0.005). Parietal cell vagotomy did not significantly change the PP response to food, although in a few patients (3/15) the response was reduced to below one third of the preoperative value. The PP response to insulin hypoglycemia was measured after operation in 16 patients; those who had a reduced PP response to food demonstrated a response to hypoglycemia which was reduced to the same extent. It is concluded that PP secretion is generally unaffected by parietal cell vagotomy but is impaired after selective gastric vagotomy and that the prolonged PP response to food is partially regenerated after vagotomy. It is suggested that selective gastric vagotomy interferes with the vagal innervation of the PP-rich head of the pancreas.

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.

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.

Quantification and variability in colonic volume with a novel magnetic resonance imaging method.

Segmental distribution of colorectal volume is relevant in a number of diseases, but clinical and experimental use demands robust reliability and validity. Using a novel semi‐automatic magnetic resonance imaging‐based technique, the aims of this study were to describe: (i) inter‐individual and intra‐individual variability of segmental colorectal volumes between two observations in healthy subjects and (ii) the change in segmental colorectal volume distribution before and after defecation.

An endoscopic method for thermal and chemical stimulation of the human oesophagus

Abstract  Previous methods for visceral thermal stimulation have lacked control of the temperature rate and visual inspection of the organ. The aims of this study was to develop a method for linear control of heat stimulation in the human oesophagus combined with endoscopy, to assess the reproducibility of this method and to investigate sensitivity to thermal stimulation of the distal oesophagus before and after acid perfusion. A probe with a 2.8 mm endoscope inside was constructed permitting heat and chemical stimulation. Three different temperature ramps were applied in the distal oesophagus in 12 healthy subjects by recirculation of heated water in a bag. Endoscopy of the oesophageal mucosa was performed prior to experimental stimulation. The temperature, the time of stimulation and the area under the temperature curve (AUC) were measured at the pain detection threshold. Thermal stimulation was repeated after perfusion of the oesophagus with acid. The method was tested on two subsequent days to assess reproducibility. All subjects had a normal endoscopic examination. Day‐to‐day reproducibility was good for the three temperature ramps (intra‐class correlations >0.6). The subjects tolerated less heat stimulation, a decrease in AUC (P = 0.0003), a decrease in time to pain detection threshold (P = 0.005) and decreased temperature at pain detection threshold (P = 0.0001) after acid perfusion. The slow ramp was the most sensitive, showing a decrease in AUC of 29%. The present method was easily implemented and showed good reproducibility. It can potentially be used in basic experiments, drug and clinical studies as it provides a controllable thermal stimulus.

Established and emerging methods for assessment of small and large intestinal motility

Gastrointestinal symptoms are common in the general population and may originate from disturbances in gut motility. However, fundamental mechanistic understanding of motility remains inadequate, especially of the less accessible regions of the small bowel and colon. Hence, refinement and validation of objective methods to evaluate motility of the whole gut is important. Such techniques may be applied in clinical settings as diagnostic tools, in research to elucidate underlying mechanisms of diseases, and to evaluate how the gut responds to various drugs. A wide array of such methods exists; however, a limited number are used universally due to drawbacks like radiation exposure, lack of standardization, and difficulties interpreting data. In recent years, several new methods such as the 3D‐Transit system and magnetic resonance imaging assessments on small bowel and colonic motility have emerged, with the advantages that they are less invasive, use no radiation, and provide much more detailed information.

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.

Assessment of colorectal length using the electromagnetic capsule tracking system: a comparative validation study in healthy subjects

We aimed to determine colorectal length with the 3D‐Transit system by describing a ‘centreline’ of capsule movement and comparing it with known anatomy, as determined by magnetic resonance imaging (MRI). Further, we aimed to test the day‐to‐day variation of colorectal length assessed with the system.