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.

Aims & Methods

Our aim was to evaluate the effects of opioids and the reversal effects of a peripheral-acting mu-opioid receptor antagonist (PAMORA) on colonic motor patterns in healthy volunteers (HV), using colonic high-resolution colonic manometry.
We invited 15 healthy volunteers for our randomized, placebo-controlled, double-blind crossover study. The combination of naloxegol/placebo, placebo/codeine, or naloxegol/codeine was administered during three study visits, each separated by at least 1 week of wash-out. Participants underwent a colonoscopy after a half dose of standard PEG preparation for colonic manometry catheter (40-sensor high-resolution manometry catheter 2.5 cm spacing, Laborie, Mississauga, Canada with attached perfusion catheter) placement. Colonic pressure waves (PWs) were evaluated during sleep (1h), in the fasted state (1h), after a standardized bread meal (645 kcal) (2h), and after intraluminal administration of 10 mg bisacodyl (1h). We analyzed the number and direction of propagation of short PWs (over 3-4 sensors), long PWs (>4 sensors), and high-amplitude propagating contractions (HAPCs; long PWs with an amplitude of ≥100 mmHg for at least 1 sensor and 2 sensors of ≥90 mmHg). Upon awakening, participants received 25 mg of naloxegol or matching placebo. In addition, placebo or 60 mg codeine was administered orally, followed by another intake of half this dose one-hour post-prandial. Statistical analyses used a Friedman test and corrected for multiple testing.

Results

Fifteen HV (6 men/9 women, 31.9±3.6 years) finalized all three study visits; one participant was omitted from the analysis because of a missing trace. Both short and long synchronous PWs did not occur statistically significantly more or less in one of the 3 conditions, for all time periods. The same result was found for the antegrade PWs in all time periods. Postprandially, long retrograde PWs occurred statistically significantly less often with naloxegol/placebo compared to placebo/codeine (p=0.04). Additionally, short retrograde PWs occurred less often with naloxegol/placebo than with placebo/codeine (p=0.03). Post bisacodyl administration, both short and long retrograde PWs occurred more often with placebo/codeine, and HAPCs occurred less compared to both naloxegol conditions (Table).

Conclusion

Codeine administration enhances retrograde contractions and inhibits high-amplitude propagating contractions after intraluminal bisacodyl administration in healthy volunteers and these effects are reversed by the PAMORA naloxegol. These observations enhance our understanding of the mechanisms underlying OIC and its treatment with naloxegol.

Introduction

Although irritable bowel syndrome (IBS) is defined as a motility disorder, there is a lack of studies assessing colonic motility in these patients and linking it to symptoms. A recent FODMAP (Fermentable Oligo-, Di-, Monosaccharides, and Polyols) reintroduction study showed that fructans and mannitol triggered IBS symptoms in the majority of patients, while fructose did not, but the mechanism is unclear. Therefore, we set up a study investigating how these FODMAPs trigger colonic motor patterns in healthy volunteers (HV).

Aims & Methods

HV were included in a randomized, double-blind, 3-way crossover study where a 200 mL solution of either fructose, fructans, or mannitol was administered during three study visits, each separated by ≥ 2 weeks of wash-out. Participants followed a low-FODMAP and low-fiber diet for 3 days before each study visit. On the study day, they received a 250mL tap water enema for HRCM catheter placement (36-sensor solid-state) via colonoscopy. After recovery of 1h, colonic pressure waves (PWs) were measured in a fasted state (1h), after a 20-min FODMAP infusion (2h), and after a standardized meal (1h). The number and propagation direction of short PWs (3 sensors), long PWs (≥4 sensors), cyclic PWs, and high-amplitude propagating (retrograde) contractions (HA(R)PCs) were analyzed.

Results

A total of 15 study visits from five HV (40%men, 38±8 years, BMI 23.7±1.6 kg/m²) who finished the full protocol were analyzed. Although none of the motor patterns occurred more frequently with one of the FODMAPs in the fasted state, during FODMAP infusion, 1h post-infusion and postprandially, the short anterograde PWs occurred more frequently in the 2h post-infusion period with fructans compared to fructose and mannitol (p=0.03). Additionally, long synchronous PWs occurred more frequently 1h post-infusion with fructans compared to the fasted state (p=0.01) and there was a trend toward a higher occurrence of long synchronous PWs (p=0.054) and cyclic retrograde PWs (p=0.06) with mannitol

Conclusion

At the current number of healthy volunteers finalizing all 3 visits, fructans and to a lesser extent mannitol but not fructose intracolonic infusions are associated with increased occurrence of synchronous and anterograde colonic motor patterns. Triggering of colonic motor patterns may contribute to symptom triggering by these FODMAPs in IBS.

Introduction

Besides analgesia, opioids affect gastrointestinal (GI) motility, including decreased bowel peristalsis and delayed gastric emptying. Peripherally acting mu-opioid receptor antagonists, like naloxegol, are approved for treating opioid-induced constipation.

Aims & Methods

We aimed to evaluate the effects of naloxegol on opioid-induced lower GI tract dysfunction using magnetic resonance imaging (MRI) to assess changes in colonic volumes in healthy volunteers (HV).
In this double-blind, randomised, three-way crossover study, 15 HV complete three study visits, separated by ≥1 week washout, with administration of 25 mg naloxegol + 60 mg codeine, 60 mg codeine + placebo, or double placebo. During each visit, five abdominal MRI scans (each 20 min.) are obtained at 30 min intervals, at baseline, after drug intake, after a standardized 44 g oatmeal and 100 mL Nutridrink (313 kCal) meal, after a second drug dose, and after a bisacodyl 10 mg suppository administration. Colonic segmental volumes were quantified from all MRI scans using Entrolytics (Motilent, London, UK) in the ascending, transverse, descending, and rectosigmoid colon. We recorded the passage of stool during the study visit. Results are presented as medians with min. and max. P-values <0.05 are considered statistically significant. Adjusted p-values are used in case of post-hoc analysis.

Results

Interim analysis on 8 HVs (mean age 36±5y, 75% females) revealed that two subjects made stool on 2 mornings before the study visit. Four subjects passed stool in the double placebo group (2 postprandial, 2 post-bisacodyl), and 2 of them passed stool in the other 2 groups as well, around the same time. A significant scan x group effect was found for the whole colon volumes (p<0.05). More specifically, there was a significant difference in median ascending colon volumes between the scans (p=0.03), and especially in the double placebo group (Table). Although there was no significant difference in the median transverse colon volumes, bisacodyl led to a significant decrease in descending colon volume (p<0.0001), more specifically in the naloxegol+codein group and the double placebo group (ps<0.05), but not in the codein+placebo group. No significant differences in volumes of the rectosigmoid were detected.

Conclusion

Interim MRI analysis of 8 HVs suggests different colonic motility responses across groups and timepoints. Toilet visits were suppressed in both codeine groups. Different responses to drug and food intake were found in the ascending and descending colon between the naloxegol+codein and double placebo group on one hand compared to the codein+placebo group. Expansion and analysis of the full number of subjects will further clarify insights into the acute colonic responses to opioids and potential reversal by naloxegol.

Introduction

Irritable bowel syndrome (IBS) pathophysiology is multifactorial, with fermentable, oligo, di- and mono-saccharides and polyols (FODMAP) playing a role in symptom induction, presumably through osmotic effects and rapid colonic fermentation. While dietary studies assessed effects on symptoms, few have investigated the direct impact on colonic motility.

Aims & Methods

Using high-resolution colonic manometry (HRCM), we examined the effects of intracolonic fructose, fructans (fructo-oligosaccharides), or mannitol infusion on colonic motility in healthy volunteers (HV).
A double-blind three-way crossover study was conducted in 15 HVs, with a ≥ 2-week wash-out period between visits. After three days of a low FODMAP and low fiber diet, subjects came fasted to the hospital's endoscopy unit. They received a 250 mL water enema before advancing a 36-sensor solid state HRCM catheter with perfusion lumen into the ascending colon via colonoscopy under conscious sedation. After a 1 h recovery period, colonic pressures were recorded 1 h in the fasted state, for 20 min during infusion of FODMAP in the ascending colon (200 mL 290 mOsm/kg fructose, fructans, or mannitol), 2 h post-infusion, and 1 h postprandially after a standardized low-calorie meal. Colonic motor patterns were manually identified and compared between the three FODMAPs, with long ones ≥12 cm and high amplitude ones with at least 3 sensors ≥100 mmHg. Gastrointestinal symptoms were recorded every 15 minutes during the 4.5 h measurement. Results are presented as median with minimum and maximum ranges.

Results

Fifteen HV, 40% male (mean age 32 years (range 19-64 y), mean BMI 22.6 kg/m² (range 19.6-33.1)), completed the three study visits. Post FODMAP infusion, a significant difference in long anterograde patterns (p=0.04) was detected (Table). Postprandially, long synchronous (p=0.001) and long anterograde (LA) (p=0.0008) were more frequently observed with fructans, while mannitol tended to induce long retrograde patterns (p=0.07). Many of the long anterograde patterns were pan-colonic interrupted pressurizations (IP; previously described as related to gas transit; Leibbrandt J Clin Med 2023), and these were significantly more frequent after fructans infusion (p=0.004). High-amplitude retrograde-propagating contractions occurred 36 times in five HV: 50% after mannitol, 25% after fructans, and 25% after fructose infusion. There was no significant difference in gastrointestinal symptoms between the three FODMAPs, although flatulence and abdominal cramps were slightly increased after infusion of fructans.

Conclusion

Fructans and mannitol alter colonic motility patterns in distinct ways. Upon fructan infusion, there is a higher frequency of anterograde and synchronous activity, including interrupted pressurizations, which are suggested to be linked to gas transit. However, the frequency of these motor patterns was not altered by mannitol. These responses to different FODMAPs may contribute to symptom generation in IBS.

References

Van den Houte et al. Gastroenterology 2024
Leibbrandt J et al. Clin Med 2023

Introduction

In patients with refractory constipation, subtotal colectomy with ileorectal anastomosis (SC-IRA) is considered when normal defecatory function and colonic inertia are confirmed, but the outcome is variable.

Aims & Methods

To compare the outcome of quality of life, symptoms, and colorectal physiology measures in medically refractory constipation patients, who were treated conservatively or by SC-IRA.
We contacted 126 refractory constipation patients, who underwent a colonic transit time test, an anorectal manometry (ARM) with balloon expulsion test (BET), and high-resolution colonic manometry (HRCM), for an extensive follow-up survey. This survey includes the Patient Assessment of Constipation quality of life (PACqol) (primary endpoint), and symptoms (PACsym) (secondary endpoint), depression (PHQ9), general anxiety (GAD7) and gastrointestinal specific anxiety (VSI). Colonic inertia was defined as reduced or absent contractions on HRCM after a meal or intracolonic bisacodyl administration. Co-variables were colonic transit time, and ARM with BET baseline results. Results are presented as mean ± standard error of the mean.

Results

We divided 71 respondents into 3 groups based on treatment after HRCM: conservative (n=36), SC-IRA with (n=9), and without (n=26) colonic inertia. The average transit time of the participants (3% men, 45±1.7 years) was 113±3.7 h and was higher in the inertia group compared to the 2 other groups (p=0.001). The 3 treatment groups did not differ in terms of balloon expulsion ability (p=0.80) and rectal sensitivity based on ARM (p=0.62). Follow-up data (n=66) were retrieved on average 4 years (range 1-7) after HRCM and 3 years (range 0-6) after SC-IRA (Table). Both surgical groups had a better (i.e. lower) PACqol satisfaction score than the conservative (both p<0.001). The surgical group without inertia had better outcomes compared to the conservative for general quality of life (p=0.002) and specifically physical discomfort (p=0.02) and worries/concerns (p=0.002). Psychosocial discomfort was lower in the surgical group without colonic inertia compared to those with colonic inertia (p=0.04). No differences were found between the treatment groups for PACsym average (p=0.25) and its subscales of abdominal (p=0.4), rectal (p=0.6), and stool scores (p=0.06), as well as for depression scores (p=0.30). In the surgical group without inertia, the GAD7 score was lower compared to the conservative (p=0.025), while VSI score was lower compared to the inertia group (p=0.046). Overall, depression, GAD, and VSI were correlated with PACqol satisfaction outcomes (r=0.35/p=0.005, r=0.33/p=0.008, and r=0.29/p=0.02 respectively).

Conclusion

On average 4 years after detailed investigation for severe refractory constipation, PACqol satisfaction with stool pattern was higher in those referred for subtotal colectomy, regardless of colonic inertia status, compared to those treated conservatively.

References

Sperber A.D et al. Gastroenterology 2021.
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Corsetti M et al. Gut 2016.
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Labus J.S et al.- Aliment Pharmacol Ther 2004