NALOXEGOL RESTORES CODEINE-INDUCED INHIBITION OF HIGH-AMPLITUDE PROPAGATING CONTRACTIONS AND INCREASE OF RETROGRADE CONTRACTIONS IN A RANDOMIZED, THREE-WAY CROSSOVER COLONIC HIGH-RESOLUTION MANOMETRY STUDY IN HEALTHY VOLUNTEERS

Introduction
Opioid-induced constipation (OIC) is a highly prevalent condition among patients treated with opioids for chronic pain. Although constipation and other gastrointestinal side effects can present in 40-90% of opioid users, their effects on colonic motor function and their reversal by opioid antagonists are poorly understood.
Our aim was to evaluate the effects of codeine and the reversal effects of naloxegol on colonic motor patterns in healthy volunteers (HV), using high-resolution colonic manometry.
Methods
We invited 15 HVs for our randomized, placebo-controlled, double-blind 3-way crossover study. The combination of naloxegol+placebo, placebo+codeine, or naloxegol+codeine was administered during three study visits, each separated by ≥1 week of wash-out. Participants underwent a colonoscopy after a half-dose of standard polyethylene glycol (PEG) preparation for high-resolution colonic manometry catheter (40-sensors 2.5 cm spacing) placement. Colonic pressure waves (PWs) were evaluated during sleep, in the fasted state, after a standardized meal, and after intraluminal bisacodyl (10 mg) administration. We analyzed the number and propagation direction of short PWs (3-4 sensors), long PWs (>4 sensors), cyclic PWs, and high-amplitude propagating contractions, both anterograde (HAPCs) and retrograde (HARPCs).
Results
A completed analysis of 11 participants is presented in the table. Postprandially, long retrograde PWs occurred more frequently in the codeine+placebo arm compared to the naloxegol+placebo arm. This was also the case for the cyclic retrograde PWs, but not for the short retrograde motor patterns. Post-intraluminal bisacodyl administration, HARPCs occurred more often in the codeine+placebo group compared to the naloxegol groups, while the opposite is true for the HAPCs.
Abbreviations; PW, pressure wave. The number of pressure waves is presented as median (25-75% interquartile range) (n=11).
Conclusion
Codeine administration enhances retrograde contractions including HARPCs and inhibits antegrade HAPCs after intraluminal bisacodyl administration in healthy volunteers and these effects are reversed by naloxegol. These observations enhance our understanding of the mechanisms underlying OIC and its treatment with naloxegol.