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

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.

Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION).

INTRODUCTION: Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility. METHODS: This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects. ETHICS AND DISSEMINATION: The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. TRIAL REGISTRATION NUMBER: 2014-004687-37; Pre-results.

Poor analgesic efficacy of epidural analgesia in critical care patients after pancreaticoduodenectomy.

OBJECTIVES: The objective of this study was to investigate the analgesic efficacy of functional and prematurely aborted epidurals after pancreaticoduodenectomy in critical care, as this is unknown. METHODS: Data from elective pancreaticoduodenectomy recipients admitted to the critical care unit over 44 months were prospectively collected. Epidural (0.1% bupivacaine and 2 µg/mL fentanyl) analgesic efficacy was assessed with a ranked categorical verbal pain score (primary end point). If no epidural was placed, intravenous (IV) fentanyl patient-controlled analgesia (PCA) was used. RESULTS: Eighty-six pancreaticoduodenectomy patients had a mean age of 66.5 years; 61.6% were men; and 73 received an epidural, whereas 13 received an IV PCA. Epidural abortion rate was 42.5%, associated with a higher 24-hour (P = 0.02) but not 48-hour pain score. Overall, fewer patients reported any pain (P = 0.010; number needed to harm, 3.2; 95% confidence interval, 1.7-3.2) or severe pain (P = 0.006; number needed to harm, 2.9; 95% confidence interval, 2.1-4.7) with functional epidurals. Pain (sensitivity, 93.8%) and severe pain (specificity, 87.8%) were predictive of epidural abortion. Most postepidural analgesia was IV PCA (P = 0.097) after both functional and aborted epidurals. CONCLUSIONS: Premature epidural abortion rate was high and associated with analgesic morbidity. Pain score was predictive of epidural abortion. Thus, preference toward epidural analgesia cannot be supported.

Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients.

Gastrointestinal dysmotility and constipation are common problems in critical care patients. The majority of critical care patients are treated with opioids, which inhibit gastrointestinal (GI) motility and lead to adverse outcomes. We reasoned that methylnaltrexone (MNTX), a peripheral opioid antagonist approved for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxative therapy has not been sufficient, could improve GI function in critically ill patients. The present study included all patients in our intensive care unit who required rescue medication for GI stasis during the 10-week period from September 1 to November 15, 2009. We compared conventional rescue therapy with subcutaneous MNTX. We performed a retrospective chart review of the 88 nonsurgical critical care patients receiving fentanyl infusions, 15 (17%) of whom met the criteria of absence of laxation within 72 hours of intensive care unit admission despite treatment with senna and sodium docusate. Eight of these 15 patients subsequently received conventional rescue therapy (combination of sodium picosulfate [5 mg] and 2 glycerin suppositories [4-g mold]), and 7 patients received MNTX (subcutaneous injection, 0.15 mg/kg). Laxation occurred within 24 hours in 6 of the 7 MNTX patients (86%) but in none of the 8 patients receiving conventional rescue therapy (P=.001). The median difference in time to laxation between the 2 groups was 3.5 days (P<.001). Although not statistically significant, all 7 patients treated with MNTX, but only 4 of 8 (50%) who received conventional rescue therapy, progressed to full target enteral feeding (P=.08). Intensive care unit mortality was 2 of 7 MNTX patients (29%) vs 4 of 8 (50%) in the standard therapy group (P=.61). We hypothesize that MNTX may play an important role in restoration of bowel function in critically ill patients.