Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial

Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial

by Parind B. Patel,  Stephen J. Brett,  David O’Callaghan,  Aisha Anjum,  Mary Cross, Jane Warwick & 

Anthony C. Gordon 

Intensive Care Medicine (2020)

Purpose

Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation.

Methods

The MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality.

Results

A total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82–2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1–3. However, during days 4–28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4–28 (p = 0.007).

Conclusion

We found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded.

The Use of Bowel Protocols in Critically Ill Adult Patients: A Systematic Review and Meta-Analysis

The Use of Bowel Protocols in Critically Ill Adult Patients: A Systematic Review and Meta-Analysis

Oczkowski, Simon J. W. et al
Critical Care Medicine: July 2017 - Volume 45 - Issue 7 - p e718–e726

Objective: Constipation is common among critically ill patients and has been associated with adverse patient outcomes. Many ICUs have developed bowel protocols to treat constipation; however, their effect on clinical outcomes remains uncertain. We conducted a systematic review to determine the impact of bowel protocols in critically ill adults. 
Data Sources: We searched MEDLINE, Embase, CINAHL, CENTRAL, ISRCTN, ClinicalTrials.gov, and conference abstracts until January 2016. Study Selection: Two authors independently screened titles and abstracts for randomized controlled trials comparing bowel protocols to control (placebo, no protocol, or usual care) in critically ill adults. Data Extraction: Two authors independently, and in duplicate, extracted study characteristics, outcomes, assessed risk of bias, and appraised the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. 
Data Synthesis: We retrieved 4,520 individual articles, and excluded 4,332 articles during title and abstract screening and 181 articles during full-text screening. Four trials, including 534 patients, were eligible for analysis. The use of a bowel protocol was associated with a trend toward a reduction in constipation (risk ratio, 0.50 [95% CI, 0.25–1.01]; p = 0.05; low-quality evidence); no reduction in tolerance of enteral feeds (risk ratio, 0.94 [95% CI, 0.62–1.42]; p = 0.77; low-quality evidence), and no change in the duration of mechanical ventilation (mean difference, 0.01 d [95% CI, –2.67 to 2.69 d]; low-quality evidence). Conclusions: Large, rigorous, randomized control trials are needed to determine whether bowel protocols impact patient-important outcomes in critically ill adults.