Authors
A. GEERAERTS (1), H. GEYSEN (1), L. BALLET (1), C. HOFMANS (1), T. OMARI (2), A. MANOLAKIS (1), N. ROMMEL (3), T. VANUYTSEL (1), J. TACK (1), A. PAUWELS (1) / [1] KU Leuven, , Belgium, TARGID, [2] Flinders University, , Australia, Department of Human Physiology, [3] KU Leuven, , Belgium, ExpORL Department of Neuroscience, Deglutology
Introduction
The adverse effects of short- and long-term opioid use, such as codeine and morphine, on the gastrointestinal tract are well known. More recently, studies showed that chronic use of opioids may induce oesophageal dysfunction with symptoms similar to achalasia (dysphagia) and a manometric pattern of functional oesophagogastric junction outflow obstruction (OGJ-OO). However, little is known whether this is generalised or occurs only in susceptible subjects, and whether acute opioid administration has similar effects.
Aim
We aimed to investigate the effect of acute codeine intake on oesophageal motility in healthy volunteers (HV) in a randomised, double-blind, placebo-controlled, crossover trial.
Methods
Participants were tested during two visits, at least one week apart: one placebo (30mL glucose syrup) and one codeine (30mL of codeine phosphate 10mg/5mL) visit. During both visits, a High-Resolution impedance Manometry (HRiM, Unisensor, Attikon, Switzerland) catheter was placed transnasally. Thereafter, a feeding tube was placed transnasally to infuse codeine or placebo in the proximal stomach. Forty-five minutes post-infusion, the participants received different volumes (5mL and 20mL) of liquid and semi-solid boluses, classified as 0-4 according to the International Dysphagia Diet Standardisation Initiative (IDDSI) classification and bread boluses (2x2cm/4x4cm). HRiM analysis was performed adhering to the Chicago classification v3.0 using dedicated software (Solar GI, Laborie, Canada).
Results
Twenty-two HV (6 men, 36±3y) completed the study. Two participants were excluded from analysis: one due to colicky pain (rare side effect of codeine) and one because of the presence of an OGJ-OO during placebo. Median (IQR) values for the studied parameters are presented in Table 1. After codeine infusion, significantly higher values for integrated relaxation pressure 4 seconds (IRP4) were observed for all given boluses (liquid, semi-solid and bread). The distal contractile integral (DCI) was significantly increased after codeine intake only for the boluses of 5mL IDDSI0, 5mL IDDSI4 and for 20 mL IDDSI0. Furthermore, distal latency (DL) was significantly lower after administration of codeine in all conditions except for 20 mL IDDSI0 and 5 mL IDDSI3 (Table 1). Based on the Chicago Classification v3.0, acute administration of codeine induced a major oesophageal disorder in five HV (2 type III achalasia, 2 OGJ-OO, 1 distal oesophageal spasm) (p-value=0.047). Table 1: Median (interquartile range) values of IRP4, DCI and DL for codeine and placebo administration Placebo Codeine p-value 5mL IDDSI0 IRP4 8.3 (6.3 – 14.8) 15.5 (13.3 – 17.8) <.0001* 5mL IDDSI0 DCI 1236 (548 – 1826) 1266 (913 – 3782) 0.014* 5mL IDDSI0 DL 7 (6.6 – 7.9) 5.9 (5.3 – 6.3) 0.009* 20mL IDDSI0 IRP4 8 (4.4 – 12.8) 13 (9.3 – 16.8) 0.017* 20mL IDDSI0 DCI 811 (627 – 1442) 1386 (1051 – 2133) 0.018* 5mL IDDSI1 IRP4 10.5 (7 – 18.3) 18.5 (10.5 – 25.3) 0.009* 5mL IDDSI1 DL 7.1 (6.4 – 10.3) 6 (4.9 – 6.6) <0.0001* 5mL IDDSI2 IRP4 9 (7 – 13) 18 (10.4 – 21.8) 0.014* 5mL IDDSI2 DL 7.6 (6.7 – 8.3) 6.5 (5.6 – 7.1) 0.008* 5mL IDDSI3 IRP4 9 (7 – 14.5) 18.5 (12.5 – 25) 0.005* 5mL IDDSI4 IRP4 11.5 (7 – 15.4) 20 (11 – 25.8) 0.005* 5mL IDDSI4 DCI 1010 (532 – 1611) 1386 (689 – 2291) 0.005* 5mL IDDSI4 DL 7.9 (7.1 – 8.5) 6.6 (6.1 – 7.3) <0.0001* Bread2x2 IRP4 12 (10 – 16.5) 24 (14 – 29.5) <0.0001* Bread2x2 DL 7.9 (7.6 – 8.5) 6.1 (5.6 – 6.8) 0.003* Bread4x4 IRP4 13 (8.3 – 19) 18.5 (13.3 – 29) 0.0196* Bread4x4 DL 9.8 (7.7 – 10.5) 7.2 (6.6 – 8) 0.004* * survives stepdown Bonferroni correction IRP4=integrated relaxation pressure; DCI=distal contractile integral; DL=distal latency; IDDSI=international dysphagia diet standardisation initiative
Conclusions
This study shows that acute administration of codeine increases OGJ resistance in HV and is able to induce major motility disorders such as achalasia and outflow obstruction in a subset of subjects. Further analysis is needed to explain the mechanism underlying this phenomenon.
