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.
| Naloxegol+codein
| Codein+placebo
| Double placebo
| Naloxegol+codein
| Codein+placebo
| Double placebo
|
|---|
Scan1 (fasted, T0)
| 159 (118-202)
| 137 (92-247)
| 148 (122-226)
| 73 (63-92)
| 64 (48-105)
| 75 (53-98)
|
Scan2 (first drug combination, T50)
| 154 (119-238)
| 128 (92-252)
| 191 (122-239)
| 95 (71-110)
| 66 (48-91)
| 63 (51-101)
|
Scan3 (postprandial, T100)
| 172 (122-230)
| 160 (113-275)
| 151 (97-238)
| 74 (61-86)
| 59 (48-81)
| 74 (55-85)
|
Scan4 (Second drug dose, T150)
| 157 (103-242)
| 150 (77-254)
| 144 (94-207)
| 72 (53-92)
| 68 (56-80)
| 63 (41-85)
|
Scan5 (post bisacodyl, T185)
| 156 (63-213)
| 159 (103-233)
| 156 (106-204)
| 43 (26-62)
| 64 (37-86)
| 40 (27-53)
|
Adjusted p-value
|
|
| 0.025
| 0.049
|
| 0.04
|
Table 1. Results of ascending and descending colonic volumes (median with min and max, mL). Bold numbers represent significant differences within groups, between scans. Adjusted p-values are for differences within groups, between scans.
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.
