Taguchi, A., Sharma, N., Saleem, R.M., Sessler, D.I., Carpenter, R.L., Seyedsadr, M., & Kurz, A. (2001). Selective postoperative inhibition of gastrointestinal opioid receptors. New England Journal of Medicine, 345, 935–940.

To evaluate the effects of alvimopan on postoperative gastrointestinal (GI) function and length of hospitalization.

Alvimopan is an investigational opioid antagonist with limited oral absorption that does not readily cross the blood-brain barrier and, therefore, acts on the peripheral opioid receptors in the GI tract without affecting analgesia in patients taking opioids. Doses used in the study were 1 mg and 6 mg by mouth. On the day of surgery, patients were randomly assigned in equal proportions to one of three arms using computer-generated randomization stratified according to type of surgery. The three arms were 1 mg of alvimopan, 6 mg of alvimopan, or an identical appearing placebo. Patients took the drug or placebo two hours before surgery and then twice daily postoperatively until the first bowel movement, until discharge from the hospital, or for a maximum of seven days. Patients were seen twice daily by the research team, from 6 am to 8 am and then from 4 pm to 6 pm.  At each visit, patients were asked about time of first passage of flatus and first bowel movement. Oral intake was measured until patients could tolerate regular meals. Subjects were considered ready for discharge if they had adequate oral intake to discontinue IV fluids, GI function had returned (defined as passage of flatus), they were afebrile, and they were free of major complications.

• The study reported on a sample of 78 patients who were generally healthy or had well-controlled systemic disease.
• Patient age ranged from 18 to 78 years.
• Patients were undergoing abdominal surgery (partial colectomy: n = 15; total abdominal hysterectomy: n = 63) with general anesthesia.
• Patients were included in the study if they were receiving opioids postoperatively for pain.
• Patients were excluded if they had received epidural administration of analgesia, had used corticosteroids or immunosuppressive drugs concomitantly within two weeks or opioid analgesics within four weeks before surgery, were likely to receive nonsteroidal anti-inflammatory drugs (NSAIDs) after surgery, had Crohn disease, or had a history of abdominal radiation therapy or treatment with vinca alkaloids. 

• Washington University in St. Louis, MO
• January 4 to July 22, 2000

This was a randomized, placebo-controlled study.

• Enrollment of 26 patients per group provided 95% power to identify a significant difference of one day in time to fitness for discharge between the 6-mg dose group and the placebo group at an alpha level of 0.05 with a two-tailed logrank test.
• Time to events (time in hours since end of surgery) was compared among groups using the logrank test. Other statistical analyses were described in detail.
• For patients who withdrew, administration of the drug or placebo was stopped; however, evaluation of the patients continued and all available data were entered into the analysis.
• Demographic data and type and duration of surgery were recorded.
• Primary efficacy outcomes were time to first passage of flatus, time to first bowel movement, and time until patient was ready for discharge.
• Secondary outcomes were time to first ingestion of solids, time until actual discharge, and visual analog scores (VAS) for nausea, abdominal cramping, itching, and pain.
• Severity of nausea, abdominal cramping, pain, and itching were also recorded using 100 mm VAS.
• Total daily use of opioids was also recorded.

• Twelve patients withdrew from the study (four in the placebo group and eight in the 1-mg dose group); however, none were from the 6-mg arm of the study.
• Time to recovery of GI function was significantly shorter in the 6-mg dose group than the placebo group.
• Median time to first passage of flatus decreased from 70 to 49 hours (p = 0.03), time to first bowel movement decreased from 111 to 70 hours (p = 0.01), and the time until patients were ready for discharge decreased from 91 to 68 hours (p = 0.03).
• Oral consumption and actual discharge occurred significantly earlier for the 6-mg dose group.
• VAS scores for pain, itching, and abdominal cramping were similar in the three groups. In contrast, nausea scores were significantly reduced in the 6-mg dose group compared with the 1-mg dose and placebo groups (p = 0.003).
• No vomiting occurred in the 6-mg dose group compared with 23% and 26% in the placebo and 1-mg dose groups, respectively (p = 0.03).

The 6-mg dose of alvimopan improved all major outcomes, with or without correction for the type of surgery. Analgesic efficacy of opioids was not affected by the study drug, and no adverse events occurred.

• The study was funded by the pharmaceutical company Adolor Corporation, a grant from the National Institutes of Health (NIH), and two other local funds.
• Two authors were employees of Adolor Corporation and contributed to the study design and statistical analysis.