Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial
Authors: Anthony C Gordon
Parind B Patel
Stephen J Brett
Mary Cross
David O&#x27;Callaghan
Jane Warwick
Aisha Anjum
Journal: Intensive care medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: Constipation; Critical care; Laxatives; Methylnaltrexone.
Affiliations: Centre for Perioperative Medicine and Critical Care Research, Imperial College Healthcare NHS Trust, London, UK. ., Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK. ., Centre for Perioperative Medicine and Critical Care Research, Imperial College Healthcare NHS Trust, London, UK., Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, London, UK., Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, UK., Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Abstract:  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. 

Retracted: No

PubPeer comments:
 In this commentary, Mario Nuvolone and Adriano Aguzzi fails to properly criticize the work by Beckman et al., 2015. Find below the reply by the authors: https: www.ncbi.nlm.nih.gov pmc articles PMC4646283 This is a response to a letter by Nuvolone and Aguzzi (1). Nuvolone and Aguzzi (1) ascribed to the effect of a 129-Sirpa polymorphism, a macrophage phenotype we had previously attributed to PrPC, and we acknowledge that comparisons of wild-type and Prnp-null mice are subject to the flanking gene problem, as are many other studies of genetically modified mice. However, our current suggestion of a PrPC-monoaminergic link, consistent with the scaffold hypothesis, additionally relies on the binding of PrPC to monoaminergic markers. Indeed, inference that Beckman s data result from Sirpa polymorphisms is unlikely. Our Prnp-null mice differed from wild-type in forced swim (FST), tail suspension (TST), and novelty suppressed feeding tests, whereas a truncated SIRPu03b1 modulated FST, but not TST, probably due to FST properties not shared with TST and, also differing from our results (2), produced no change in dopamine levels (3). Moreover, the inconsistent relative performances of B6 and 129 mice in depression-related tests reviewed by Jacobson and Cryan (4) do not corroborate the attribution of results in B10.129 Ola Prnp-null mice to the 129-Sirpa polymorphism. Notably, ischemic damage is affected in opposite ways by either truncated SIRPu03b1 or B6.129Sv Prnp-KO (5, 6). As for immune responses known to depend on SIRPu03b1, neither the sensitivity of neutrophils to spontaneous or peroxide-induced killing, their recruitment in vivo, nor phagocytosis by primary microglia differed between wild-type and Prnp-null mice of our B10.129 Ola colony (7, 8), which encompasses 10 years of inbreeding and 24 generations. Further investigation is therefore required to explain this apparent lack of differential effects of 129 Ola Sirpa polymorphism, as well as possible consequences of other Prnp-flanking genes. ,