Opioid induced constipation (OIC) is a highly prevalent condition amongst patients treated with opioids, usually for the treatment of chronic pain, both for malignant and non-malignant causes. The prevalence of constipation and other gastrointestinal side effects among chronic opioid users is 40-90%, depending on the underlying pathology, resulting in non-compliance with pain medication or a reduction in quality of life.~Opioid receptors in the brain are the target for opioids to induce analgesia. Peripheral opioid receptors, mostly μ receptors, are prevalent in the enteric nervous system, and their activation underlies the occurrence of gastrointestinal side effects of opioids. Opioid-agonist binding to enteric μ receptors results in inhibition of gastric emptying, pyloric muscle tone increase, disturbance of the migrating motor complex, delayed bowel transit, decreased intestinal secretions and an elevation of anal sphincter resting pressure.~Peripherally acting μ-opioid receptor antagonists are the treatment of preference for opioid-induced constipation, because they do not cross the blood-brain barrier (BBB) and so do not interfere with central analgesic effects. This peripheral mechanism is the core mechanism of Naloxegol, the most well-known agent for treating opioid overdosing. Through PEGylating, Naloxegol is a P-glycoprotein substrate with very low ability to cross the blood brain barrier (BBB). Studies have shown the ability of Naloxegol improve opioid-induced constipation in patients chronically treated with opioids, not responding to laxatives, significantly. However, the effects of opioids on colonic motor function and their reversal by opioid antagonists are poorly studied.~High-resolution manometry (HRM) of the colon is a sophisticated system for studying colonic motility. Over the last few years, using this approach, it has been possible to differentiate multiple motor patterns. Research is ongoing in different functional bowel disorders (FBDs) to establish the contribution of changes in colonic motor patterns to the disease mechanism and/or symptom generation.~By measuring pressures with HRM during drug administration, we want to gain insight in bowel function and motor pattern changes during treatment. HRM motor pattern analysis will help to substantiate previous findings in bowel function and OIC symptom improvements in OIC patients treated with Naloxegol.(5) We will study colonic motor patterns in healthy volunteers (HV) in a randomized, double-blind, cross-over designed trial with codeine and Naloxegol, using previously established HRM protocols and drug doses.
Characterization of motor patterns with opioid agonists (codeine) ingestion, and their reversal by a peripherally acting mu-opioid receptor antagonist (Naloxegol).