Use of Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Critical Care Patients

Abstract

IntroductionWe previously showed that erythropoietin (EPO) attenuates the morphological signs of spinal cord ischemia/reperfusion (I/R) injury in swine [1] without, however, improving neurological function. The clinical use of EPO has been cautioned most recently due to serious safety concerns arising from an increased mortality in acute stroke patients treated with EPO and simultaneously receiving systemic thrombolysis [2]. Carbamylated EPO (cEPO) is an EPO derivative without erythropoietic activity and devoid of the EPO side eff ects, but with apparently well maintained cytoprotective qualities [3]. We therefore tested the hypothesis whether cEPO may be equally effi cient as EPO in reducing morphological as well as functional aortic occlusion-induced spinal cord I/R injury. Methods In a randomized and blinded trial pigs received either vehicle (control, n = 9), EPO or cEPO, respectively (n = 9 each; 5,000 IU/kg over 30 minutes before and during the fi rst 4 hours of reperfusion). Animals underwent 30 minutes of thoracic aortic balloon occlusion with catheters placed immediately downstream of the A. subclavia and upstream of the aortic trifurcation. Spinal cord function was assessed by motor evoked potentials (MEP as percentage of the amplitude before aortic occlusion) and lower limb refl exes (assessed as the subjective strength of response) for a period of 10 hours after reperfusion. Tissue damage was evaluated using Nissl staining. Results Both EPO-treated and cEPO-treated animals presented with attenuated spinal cord injury in the Nissl staining (median (quartile) percentage of damaged neurons in the thoracic segments: control 27 (25,44), cEPO 8 (4,10), and EPO 5 (5,7), P <0.001 vs control group; in the lumbar segments: control 26 (19,32), cEPO 7 (5,13), EPO 8 (5,10), P <0.001 vs control group). However, while only cEPO treatment was associated with recovery of the MEP amplitude to pre-occlusion values when compared with the control group (P <0.05), lower limb refl ex response was comparably restored stronger in both treatment groups (P <0.05 vs control). Conclusions In a clinically relevant porcine model mimicking aortic crossclamping during vascular surgery repair of thoracic aortic aneurysm, cEPO protected spinal cord function and integrity as eff ective as EPO when applied at equipotent doses. Acknowledgements Supported by the Deutsche Forschungs gemeinschaft (SCHE 899/2-2). References Introduction Unfolded protein response (UPR)-mediated apoptosis plays a pivotal role in ischemia-reperfusion injury. Sodium 4-phenylbutyrate (PBA) has been reported to act as a chemical chaperone inhibiting UPR-mediated apoptosis triggered by ischemia in various organs other than the heart. Therefore we investigated whether PBA reduces UPR-mediated apoptosis and protects against myocardial ischemia-reperfusion injury in mice. Methods C57BL/6 mice were subjected to 30 minutes LAD ischemia followed by reperfusion. PBA (100 mg/kg) or PBS (control) was administrated intraperitoneally just before ischemia. Apoptosis, infarct ...

Sirolimus in Severe Hyperinsulinemic Hypoglycemia

“…However, we and others have used it in critically ill patients in the burn unit, the cardiovascular unit, and the medical ICU to facilitate upper and lower gastrointestinal motility. 4,5 In our own retrospective study, 4 six of seven patients without bowel motility for 3 to 5 days had almost instant restoration of bowel function after the subcutaneous administration of methylnaltrexone -3.5 days before eight patients who received conventional therapy. There was also a clinically significant effect on gastric residuals.…”

Off-label uses of alvimopan and methylnaltrexone

“…17,18,[21][22][23][24] Among these, most research has been for the treatment of OIC due to noncancer-related pain. Michna et al 17 conducted a randomized controlled trial of 460 patients with this condition to evaluate subcutaneous methylnaltrexone bromide 12 mg daily or every other day.…”

“…[22][23][24] Benefit was observed in one study of patients in an intensive care unit with OIC due to opioid sedation. 22 Bowel movements occurred within 24 hours in 6 of 7 patients treated with as-needed rescue therapy with subcutaneous methylnaltrexone bromide 0.15 mg/kg versus 0 of 8 treated with as-needed sodium picosulfate and glycerin suppositories (p = 0.001). However, the sample size was small, and data collection was retrospective.…”

A critical appraisal of lubiprostone in the treatment of chronic constipation in the elderly

“…Alvimopan has been approved by the FDA as a short-term treatment to accelerate the time of upper and lower gastrointestinal recovery after bowel resection 63. Methylnaltrexone has been approved to treat OIC in patients with advanced illness receiving palliative care, when the response to laxatives has been insufficient 64. Additional pharmacodynamic and clinical data suggest methylnaltrexone has potential effects on gastric emptying, on relief of nausea and vomiting, and on reduction of episodes of airway aspiration 65…”