Colonic Motor Patterns in Healthy Volunteers
Condition: Opioid-Induced Constipation
MeSH terms: Constipation; Opioid-Induced Constipation
Study type: Interventional
Phase: Phase 4

Summary: 
      Characterization of motor patterns with opioid agonists (codeine) ingestion, and their
      reversal by a peripherally acting mu-opioid receptor antagonist (Naloxegol).
    

Detailed description: 
      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.
    

Intervention name(s): Naloxegol; codeine phosphate; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): Oral administration of Naloxegol after waking up from the Midazolam administration during the colonoscopy.; Oral administration of Codeine after waking up from the Midazolam administration during the colonoscopy.; Oral administration of siripus simplex syrup after waking up from the Midazolam administration during the colonoscopy.
Other intervention name(s): Movantik; Moventig; Bronchodine; Siripus simplex syrup
Intervention MeSH terms: Codeine; Naloxegol
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized double-blind cross-over design (three-way)
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Naloxegol; Codeine; Colonic manometry; HRM; Motility; Opioid induced constipation; OIC