Opioid-induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI

Nilsson, Matias; Poulsen, Jakob Lykke; Brock, Christina; Sandberg, Thomas Holm; Gram, Mikkel; Frøkjær, Jens Brøndum; Krogh, Klaus; Drewes, Asbjørn Mohr

doi:10.1097/meg.0000000000000574

Cited by 33 publications

(60 citation statements)

References 42 publications

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“…This strengthens the speculation of water reabsorption counterbalancing a potential increase in stool volume, which may be why no increase in descending fecal volume could be found. Since opioid treatment has been shown to increase transit time in the rectosigmoid colon, and more firm stool assessed via the Bristol Stool Form Scale in the same study subjects, one might have expected an increase in stool dryness in the rectosigmoid colon. However, baseline‐corrected values from both the T 2 ‐weighted and LAVA‐Flex images indicated no change in stool dryness in the rectosigmoid colon.…”

Section: Discussionmentioning

confidence: 98%

“…All data analysis was performed using a semiautomatic volumetric segmentation platform (MatLab v. R2016a, MathWorks, Natick, MA) that has been used in several other studies . In short, the observer outlines a coarse region of interest encapsulating the colon on each of the 35–40 abdominal coronal images where the colon is shown.…”

Section: Methodsmentioning

confidence: 99%

“…This segmentation method has previously been shown to offer good agreement between observers, when additional double segmentations were deemed not to be needed. The segmentation masks applied in the T 2 ‐weighted images were reused from a previous study . The obtained LAVA‐Flex images allow for segmentation of feces alone, where gas and colon wall can be excluded from analysis, as illustrated in Fig.…”

Section: Methodsmentioning

confidence: 99%

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MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone‐induced constipation model

Mark

Bodker

Grønlund

et al. 2019

Magnetic Resonance Imaging

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Background Opioids are known to affect gastrointestinal motility, but their effect on fluid absorption and secretion is poorly understood in humans. Purpose To investigate the effect of oxycodone on colonic fecal volume and stool dryness by using a novel MRI‐based technique. Study Type Prospective, randomized, double‐blinded, crossover study. Subjects Twenty‐five healthy male volunteers (median age: 24 years [range: 21–56]; mean body mass index [BMI]: 23.9 kg/m2 [range: 22.9–25.0]) without known gastrointestinal disease. Field Strength/Sequence T2‐weighted and two‐point Dixon MRI scans of the abdomen at 1.5 T. Assessment Subjects were treated for 5 days with prolonged‐release oxycodone or a placebo. Imaging was performed on the first and last study day in each period. Images of the colon were analyzed with semiautomatic k‐means‐based segmentation software. Regional colonic fecal volumes were quantified excluding gas volume and colon wall. Two‐point Dixon and T2‐weighted MRI signal intensity were assessed as a proxy of colonic stool dryness. Data were obtained in a previously reported study. Statistical Tests Intraclass correlation coefficients were used to test the reliability of measurements between days, while repeated measures mixed models were applied to test treatment effects. Results After oxycodone treatment, total colonic fecal volume was significantly increased compared with placebo (mean change 100 mL vs. –13 mL; P = 0.001), with the largest increase (24%) observed in the ascending colon/cecum (P = 0.001). Dixon signal increased (less water in colon content) after oxycodone treatment compared with placebo (mean 0.09 vs. –0.02; P < 0.001). T2‐weighted signal decreased (less water in colon content) after oxycodone treatment compared with placebo (mean –0.03 vs. 0.03; P = 0.002). Data Conclusion The 5‐day oxycodone treatment increased colonic fecal volume and increased stool dryness compared with placebo. This imaging‐based method for noninvasive analysis of colon content has the potential to characterize gastrointestinal symptoms in general, such as in constipation. Level of Evidence: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:733–745.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone‐induced constipation model

Mark

Bodker

Grønlund

et al. 2019

Magnetic Resonance Imaging

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“…Even with short-term use, opioid analgesic therapy can result in symptoms of constipation. The use of opioids for 5 days produced nearly twofold patient-reported symptoms of constipation in opioid-treated patients vs placebo patients ( P <0.001) and an objectively measured 41% segmental colorectal volume increase in the cecum and/or ascending colon ( P =0.005 vs placebo) 2. After 5 days of oxycodone therapy, the median gastrointestinal (GI) transit time increased from 22.2 hours to 43.9 hours ( P <0.001) 3.…”

Section: Introductionmentioning

confidence: 98%

Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy

Pergolizzi

Raffa

Pappagallo

et al. 2017

PPA

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Opioid-induced constipation (OIC), a prevalent and distressing side effect of opioid therapy, does not reliably respond to treatment with conventional laxatives. OIC can be a treatment-limiting adverse event. Recent advances in medications with peripherally acting μ-opioid receptor antagonists, such as methylnaltrexone, naloxegol, and alvimopan, hold promise for treating OIC and thus extending the benefits of opioid analgesia to more chronic pain patients. Peripherally acting μ-opioid receptor antagonists have been clinically tested to improve bowel symptoms without compromise to pain relief, although there are associated side effects, including abdominal pain. Other treatment options include fixed-dose combination products of oxycodone analgesic together with naloxone.

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“…We have previously developed a model of OIC in healthy volunteers and shown that oxycodone causes symptoms of OIC, prolongs regional GI transit times, 11 and increases colorectal volumes. 12 The model for OIC in healthy volunteers allows for interventional studies of OIC not influenced by confounders such as comorbidity, activity level or concomitant drug that can all cause constipation and hence make studies in patients difficult to interpret. We hypothesized that combined prolonged-release (PR) oxycodone/naloxone tablets would be more effective than PR oxycodone plus conventional laxative treatment with macrogol 3350 in preventing oxycodone-induced OIC.…”

Section: Introductionmentioning

confidence: 99%

Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350

Poulsen

Mark

Brock

et al. 2018

J Neurogastroenterol Motil

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Background/AimsOpioid-induced constipation (OIC) is the most common gastrointestinal (GI) side effect to opioid treatment. Opioid receptor antagonists against OIC have been introduced, but their efficacy has not been directly compared to conventional laxatives. Our aim was to compare symptoms and objective parameters of gut function in an experimental model of OIC during treatment with the opioid antagonist naloxone and oxycodone in prolonged-release (PR) formulation versus oxycodone plus macrogol 3350. MethodsIn this randomized, double-blind, crossover trial 20 healthy men received a 5-day treatment of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Regional GI transit times and segmental colorectal transit were assessed with the Motilis 3D-Transit electromagnetic capsule system. Colorectal volumes were determined by MRI. OIC symptoms were assessed with validated questionnaires, along with stool frequency and consistency. ResultsTotal colorectal volume did not change after 5 days' treatment with PR oxycodone/naloxone (941 vs 1036 mL; P = 0.091), but increased significantly after PR oxycodone plus macrogol treatment (912 vs 1123 mL; P < 0.001). Neither regional GI transit times nor segmental colorectal transit differed between the treatments (all P > 0.05). The Patient Assessment of Constipation Symptom Questionnaire abdominal symptoms score was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (0.2 vs 3.2; P = 0.002). Stool frequency was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (4.2 vs 5.4; P = 0.035). ConclusionsPR oxycodone plus macrogol increases colorectal volume, but does not improve GI transit compared to PR oxycodone/naloxone. However, PR oxycodone/naloxone results in a lower abdominal symptom burden, despite higher stool frequency during macrogol treatment.

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Opioid-induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI

Abstract: Experimental OIBD in healthy volunteers was induced during oxycodone treatment. This model has potential for future interventional studies to discriminate the efficacies of different laxatives, peripheral morphine antagonists and opioid treatments.

Cited by 33 publications

References 42 publications

MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone‐induced constipation model

MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone‐induced constipation model

Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy

Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350

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Opioid-induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI

Abstract: Experimental OIBD in healthy volunteers was induced during oxycodone treatment. This model has potential for future interventional studies to discriminate the efficacies of different laxatives, peripheral morphine antagonists and opioid treatments.

Cited by 33 publications

References 42 publications

MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone‐induced constipation model

MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone‐induced constipation model

Peripherally acting &mu;-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy

Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350

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Peripherally acting μ-opioid receptor antagonists as treatment options for constipation in noncancer pain patients on chronic opioid therapy