Randomized placebo-controlled study of intravenous methylnaltrexone in postoperative ileus

Abstract

Objective:

This phase 2 study evaluated the safety and activity of intravenous methylnaltrexone on the duration of postoperative ileus in patients undergoing segmental colectomy.

Methods:

Adults (aged 18 years or older) with American Society of Anesthesiologists physical status of I, II, or III who underwent segmental colectomy, including partial colectomy, sigmoidectomy, cecectomy, or anterior proctosigmoidectomy, via laparotomy with general anesthesia, received intravenous methylnaltrexone 0.30 mg/kg or placebo every 6 h beginning within 90 min after end of surgery. Treatment continued until 24 h after the patient tolerated solid foods, was discharged, or for 7 d maximum. Efficacy endpoints included measures of gastrointestinal recovery and time to discharge eligibility.

Results:

A total of 65 patients (methylnaltrexone, n = 33; placebo, n = 32) were randomized. Mean time to first bowel movement was accelerated by 20 h (p = 0.038) and time to discharge eligibility was accelerated by 33 h (p = 0.049) with methylnaltrexone vs placebo. Opioid use was similar between groups until postoperative day 4, then fluctuated in the placebo group. Methylnaltrexone was generally well tolerated.

Conclusions:

In this study, intravenous methylnaltrexone significantly decreased time to postoperative bowel recovery and eligibility for hospital discharge by ∼1 d, with an adverse event profile similar to placebo. These were two of several exploratory endpoints; not all efficacy endpoints showed a significant difference between methylnaltrexone and placebo. The efficacy results in this trial were not seen in two subsequent large-scale studies.

Key words::

• Methylnaltrexone
• Postoperative ileus
• Opioids
• Mu-opioid receptor antagonist

Transparency

Declaration of funding

This study was sponsored by Progenics Pharmaceuticals Inc., which has a proprietary commercial interest in methylnaltrexone. Funding for this manuscript was provided by Wyeth Research, which was acquired by Pfizer Inc. in October 2009. No author received an honorarium or other form of financial support related to the development of this manuscript.

Declaration of financial/other relationships

EV is a consultant and advisor for Salix Pharmaceuticals, Inc. JR, SB, AF, and DP have nothing to disclose. RI is an employee of Progenics Pharmaceuticals, which has a financial interest in Relistor. FG is a consultant for Progenics Pharmaceuticals. TG has received grants/research funding from Cubist Pharmaceuticals Inc., Purdue Pharma, LP.

Acknowledgments

The authors thank Cheryl Jones of On Assignment Clinical Research, who was a paid consultant to Pfizer in connection with the development of this manuscript. Editorial support was provided by John Simmons, MD, of Peloton Advantage and was funded by Pfizer. Editorial support was also provided by Andrew Barrett, PhD, of Salix Pharmaceuticals. Presented in part at the 2007 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology, January 19–21, 2007, in Orlando, FL. ClinicalTrials.gov identifier number: NCT00387309