Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial.

BACKGROUND: Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS). OBJECTIVE: To assess the efficacy of alvimopan to accelerate GI recovery after RC. DESIGN, SETTING, AND PARTICIPANTS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics. INTERVENTION: Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed. RESULTS AND LIMITATIONS: Patients were randomized to alvimopan (n=143) or placebo (n=137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p<0.0001), shorter mean LOS (7.4 vs 10.1 d; p=0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p<0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p=0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy. CONCLUSIONS: Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo. PATIENT SUMMARY: This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00708201.

Alvimopan, a peripherally acting µ-opioid receptor antagonist, is associated with reduced costs after radical cystectomy: economic analysis of a phase 4 randomized, controlled trial.

PURPOSE: We evaluated the effect of alvimopan treatment vs placebo on health care utilization and costs related to gastrointestinal recovery in patients treated with radical cystectomy in a randomized, phase 4 clinical trial. MATERIALS AND METHODS: Resource utilization data were prospectively collected and evaluated by cost consequence analysis. Hospital costs were estimated from 2012 Medicare reimbursement rates and medication wholesale acquisition costs. Differences in base case mean costs between the study cohorts for total postoperative ileus related costs (hospital days, study drug, nasogastric tubes, postoperative ileus related concomitant medication and postoperative ileus related readmissions) and total combined costs (postoperative ileus related, laboratory, electrocardiograms, nonpostoperative ileus related concomitant medication and nonpostoperative ileus related readmission) were evaluated by probabilistic sensitivity analysis using a bootstrap approach. RESULTS: Mean hospital stay was 2.63 days shorter for alvimopan than placebo (mean±SD 8.44±3.05 vs 11.07±8.23 days, p=0.005). Use of medications or interventions likely intended to diagnose or manage postoperative ileus was lower for alvimopan than for placebo, eg total parenteral nutrition 10% vs 25% (p=0.001). Postoperative ileus related health care costs were $2,340 lower for alvimopan and mean total combined costs were decreased by $2,640 per patient for alvimopan vs placebo. Analysis using a 10,000-iteration bootstrap approach showed that the mean difference in postoperative ileus related costs (p=0.04) but not total combined costs (p=0.068) was significantly lower for alvimopan than for placebo. CONCLUSIONS: In patients treated with radical cystectomy alvimopan decreased hospitalization cost by reducing the health care services associated with postoperative ileus and decreasing the hospital stay.

Alvimopan for acceleration of GI recovery after bowel resection.

Nurses play a critical role in the management of postoperative ileus during the perioperative phase of recovery. Alvimopan is an oral, peripherally acting, mu-opioid receptor antagonist that accelerates time to gastrointestinal recovery (resolution of postoperative ileus), representing a potential advance in management of these patients.

Evaluation of clinical outcomes with alvimopan in clinical practice: a national matched-cohort study in patients undergoing bowel resection.

OBJECTIVE: To evaluate in-hospital clinical outcomes after open and laparoscopic bowel resection (BR) with or without alvimopan treatment. BACKGROUND: Delayed return of gastrointestinal function after BR may be associated with greater postoperative morbidity and increased hospital length of stay (LOS). In clinical trials, alvimopan--a peripherally acting µ-opioid receptor antagonist--accelerated gastrointestinal recovery after open BR. METHODS: A retrospective matched-cohort study (NCT01150760) was conducted using a national inpatient database. Each alvimopan patient was exact matched (surgical procedure, surgeon specialty) and propensity score matched (baseline characteristics) to a nonalvimopan BR patient. Outcomes included gastrointestinal and other morbidity (cardiovascular, pulmonary, infection, cerebrovascular, thromboembolic); mortality; readmission rate; and intensive care unit (ICU) stay (intent-to-treat [ITT] population). Postoperative LOS and estimated cost were also compared (modified ITT population). RESULTS: Each cohort included 3525 ITT patients with similar baseline characteristics. Gastrointestinal (29.8% vs 35.7%) and other morbidity (cardiovascular [19.4% vs 24.0%], pulmonary [7.3% vs 10.5%], infectious [9.6% vs 11.8%], thromboembolic [1.2% vs 2.1%]), mortality (0.4% vs 1.0%), and mean ICU stay (0.3 vs 0.6 days) were lower in the alvimopan group (P ≤ 0.003 for each). Postoperative LOS and estimated direct cost were lower for all alvimopan patients and after laparoscopic and open BR (LOS: -1.1, -0.8, and -1.8 days respectively; cost: -$2345, -$1382, and -$3218, respectively; P ≤ 0.0008 for each). CONCLUSIONS: On average, alvimopan-treated patients had a lower incidence of mortality and most incidents of morbidities. Length of stay, ICU use, and estimated cost were also lower with comparable readmissions. These results in patients outside the clinical trial setting include laparoscopic colectomy and demonstrate a potential association between acceleration of gastrointestinal recovery and improved early postoperative outcomes.

Impact of alvimopan (entereg) on hospital costs after bowel resection: results from a large inpatient database.

PURPOSE: Delayed gastrointestinal (GI) recovery after bowel resection is associated with longer hospital stays and increased health care costs. Alvimopan (Entereg), a peripherally acting mu-opioid receptor antagonist, accelerates GI recovery after bowel-resection surgery. We undertook a study to evaluate the economic impact of alvimopan in clinical practice. METHODS: We conducted a retrospective matched cohort study using data from a large national hospital database and identified adults who had undergone small-bowel or large-bowel resection with primary anastomosis. The patients were discharged between January 1, 2009, and June 30, 2009. The surgery was performed at a hospital where alvimopan was used at least once during the study period. We matched each alvimopan patient ("user") with two controls ("non-users"). The primary outcome of total hospital costs (including the cost of alvimopan) and secondary outcomes of cost components and length of stay were compared between groups. RESULTS: The final study cohort included 480 alvimopan patients and 960 matched controls. The mean total hospital cost was $12,865 for alvimopan patients, compared with $13,905 for controls, for a difference of $1,040 (P = 0.033). There was a non-significant trend toward lower ileus-related costs between groups ($83 for alvimopan vs. $114 for controls, P = 0.086). Pharmacy and diagnostic radiology costs did not differ significantly. The mean length of stay was 5.6 days for alvimopan patients and 6.5 days for controls (P < 0.001). CONCLUSION: Patients receiving alvimopan capsules had significantly lower total hospital costs compared with controls. Along with other initiatives to improve quality and reduce costs of surgical care, alvimopan might be a good choice for use in the perioperative management of patients who undergo segmental bowel resection with primary anastomosis.

Alvimopan for the management of postoperative ileus after bowel resection: characterization of clinical benefit by pooled responder analysis.

BACKGROUND: A pooled post hoc responder analysis was performed to assess the clinical benefit of alvimopan, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, for the management of postoperative ileus after bowel resection. METHODS: Adult patients who underwent laparotomy for bowel resection scheduled for opioid-based intravenous patient-controlled analgesia received oral alvimopan or placebo preoperatively and twice daily postoperatively until hospital discharge or for 7 postoperative days. The proportion of responders and numbers needed to treat (NNT) were examined on postoperative days (POD) 3-8 for GI-2 recovery (first bowel movement, toleration of solid food) and hospital discharge order (DCO) written. RESULTS: Alvimopan significantly increased the proportion of patients with GI-2 recovery and DCO written by each POD (P < 0.001 for all). More patients who received alvimopan achieved GI-2 recovery on or before POD 5 (alvimopan, 80%; placebo, 66%) and DCO written before POD 7 (alvimopan, 87%; placebo, 72%), with corresponding NNTs equal to 7. CONCLUSIONS: On each POD analyzed, alvimopan significantly increased the proportion of patients who achieved GI-2 recovery and DCO written versus placebo and was associated with relatively low NNTs. The results of these analyses provide additional characterization and support for the overall clinical benefit of alvimopan in patients undergoing bowel resection.

Gastrointestinal recovery after laparoscopic colectomy: results of a prospective, observational, multicenter study.

BACKGROUND: Although evidence suggests that laparoscopic colectomy (LC) results in faster gastrointestinal (GI) recovery than open bowel resection, previous studies were performed at single institutions or generally not controlled for diet introduction or perioperative care, making the results difficult to interpret. A prospective, observational, multicenter study was planned to investigate GI recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity after LC. METHODS: Patients scheduled to undergo LC or hand-assisted laparoscopic (HAL) bowel resection and to receive opioid-based postoperative intravenous patient-controlled analgesia were enrolled in 16 U.S. centers. The study design was similar to that for trials of alvimopan phase 3 open laparotomy bowel resection using a standardized accelerated postoperative care pathway. The primary end points were time to upper and lower GI recovery (GI-2: toleration of solid food and bowel movement) and postoperative LOS. The secondary end points included POI-related morbidity (postoperative nasogastric tube insertion or investigator-assessed POI resulting in prolonged hospital stay or readmission), conversion rate, and protocol-defined prolonged POI (GI-2 > 5 postoperative days). RESULTS: In this study, 148 patients received hemicolectomy by the LC (42 left and 67 right) or HAL (39 left) approach. The conversion rate was 18.8% (25.4% LC left, 17.3% HAL left, 15% LC right). The mean time to GI-2 recovery was 4.4 days, and the mean postoperative LOS was 4.9 days, neither of which varied substantially by surgical approach. Prolonged POI occurred for 15 patients (10.1%), and POI-related morbidity occurred for 17 patients (11.5%). No patients were readmitted because of POI, whereas 3 patients (2%) were readmitted for all other causes. CONCLUSIONS: Mean GI recovery and LOS after LC were accelerated compared with those for patients in open laparotomy bowel resection clinical trials or those reported in large hospital databases (0.7 and 1.7-2.2 days, respectively). Overall POI-related morbidity was similar between the open bowel resection and LC populations, demonstrating that POI continues to present with important morbidity regardless of the surgical approach.

Economic analysis of alvimopan in North American Phase III efficacy trials.

PURPOSE: The economic effect of the use of alvimopan in four randomized, double-blind, placebo-controlled, Phase III, North American efficacy trials was analyzed. METHODS: Patients were eligible for the study if they were 18 years or older, were undergoing laparotomy for partial small or large bowel resection with primary anastomosis, and were scheduled for postoperative pain management with opioid-based i.v. patient-controlled analgesia. Patients analyzed in the North American Phase III trials received placebo or alvimopan 12 mg orally before surgery. Doses were administered twice daily beginning the day after surgery until hospital discharge or for a maximum of 15 doses. RESULTS: Compared with placebo, alvimopan was associated with a significantly shorter mean time to gastrointestinal (GI) recovery and a significantly shorter mean time to a written discharge order. Alvimopan was also associated with a mean hospital length of stay (LOS) of one full day less than placebo. The mean cost of alvimopan based on a mean of 8.9 12-mg doses was $558.00; the alvimopan cost at the upper limit of allowed dosing was $937.50. Combining the alvimopan and hospital costs for each patient, total costs for the alvimopan group were estimated to be lower than for the placebo group. CONCLUSION: In a post hoc analysis, alvimopan was associated with significantly faster upper and lower GI recovery after bowel resection and a mean LOS reduction of one day compared with placebo. The mean estimated hospital cost was $879-$977 less for patients who received alvimopan compared with placebo. The base-case and sensitivity analyses suggest that, on average, the use of alvimopan compared with placebo may have a cost-saving effect in the hospital setting.

Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway.

OBJECTIVE: To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection. DESIGN, SETTING, AND PATIENTS: This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients. MAIN OUTCOME MEASURES: The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded. RESULTS: Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo. CONCLUSIONS: Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.

The involvement of the mu-opioid receptor in gastrointestinal pathophysiology: therapeutic opportunities for antagonism at this receptor.

The localization of opioid receptors and their endogenous peptide ligands within the gastrointestinal (GI) tract and their role in the coordination of propulsion and secretion underscores the importance of opioid receptors in the maintenance of GI homeostasis. The peripherally acting micro-opioid receptor antagonists alvimopan and methylnaltrexone (MNTX) are currently under investigation as therapeutic agents to treat the deleterious GI side effects associated with opioid administration. These compounds have demonstrated efficacy in numerous animal models of GI function, and clinical studies have revealed their efficacy in the treatment of postoperative ileus (POI) and opioid-induced bowel dysfunction. Preservation of opioid-mediated analgesia has been demonstrated for these compounds in both the preclinical and clinical settings. Future studies exploring the benefits of selective antagonism of the peripheral mu-opioid receptor in the treatment of other GI conditions may open new therapeutic opportunities for alvimopan and MNTX.

Alvimopan accelerates gastrointestinal recovery after bowel resection regardless of age, gender, race, or concomitant medication use.

BACKGROUND: Postoperative ileus is a transient cessation of bowel motility that occurs after bowel resection (BR). Alvimopan, a peripherally acting mu-opioid receptor antagonist accelerated gastrointestinal (GI) recovery in 5 randomized, double-blind, phase III postoperative ileus trials. METHODS: Individual covariates (age, gender, race) were assessed separately using Cox proportional hazards models that included the main effects of treatment and covariate factor. Time-to-GI recovery (GI-3 [first toleration of solid food and first bowel movement or flatus]; GI-2 [first toleration of solid food and first bowel movement]) for patients who underwent open laparotomy for BR in the absence of epidural anesthesia and received alvimopan (12 mg) or placebo was analyzed within subgroups (age, gender, race, concomitant medication use) using Cox proportional hazards models to generate hazard ratios (HRs). P values were calculated with the Wald chi2 test. RESULTS: Elderly (>or=65 years), male, and nonwhite patients achieved GI-3 recovery later than younger (<65 years), female, and white patients (HR > 1 and P < .05 for all). Overall, alvimopan (12 mg) accelerated GI-3 recovery by 12 hours and GI-2 recovery by 17 hours compared with placebo. Within subgroups, regardless of covariate effect, patients who received alvimopan (12 mg) achieved GI-2 and GI-3 recovery sooner than patients who received placebo (HR > 1 and P < .05 for all). CONCLUSIONS: These post hoc analyses support that alvimopan (12 mg) accelerates GI recovery across various patient populations.

Patterns of gastrointestinal recovery after bowel resection and total abdominal hysterectomy: pooled results from the placebo arms of alvimopan phase III North American clinical trials.

BACKGROUND: Postoperative ileus (POI), a transient cessation of coordinated bowel motility, occurs to some extent after all major abdominal operations. This analysis examines gastrointestinal (GI) recovery and hospital discharge history in patients undergoing partial bowel resection (BR) or total abdominal hysterectomy (TAH) by laparotomy in the placebo arms of recent phase III alvimopan trials. STUDY DESIGN: This was a pooled post hoc analysis of placebo groups from randomized, double-blind, parallel-group, multicenter trials. All patients were uniformly managed with a standardized accelerated postoperative care pathway to facilitate GI recovery. RESULTS: Of the 727 BR patients and 140 TAH patients included in this analysis, POI as an adverse event was reported in approximately 14.7% of BR patients and 2.9% of TAH patients, and postoperative nasogastric tube insertion was required in 11.5% of BR patients and 0.8% of TAH patients. Time to first toleration of solid food was almost 2 days longer for BR patients than for TAH patients (BR, 4.1 days; TAH, 2.5 days). Approximately 34.4% of BR patients and 4.2% of TAH patients had discharge orders written 7 days or more after operation. Nearly half (40%) of patients undergoing TAH were discharged from the hospital before GI recovery was complete. Mean postoperative lengths of hospital stay after BR and TAH were 6.6 days and 3.4 days, respectively. CONCLUSIONS: Despite the relatively fast recovery observed with standardized accelerated postoperative care pathway use, POI as an adverse event was still reported in approximately 15% of BR patients and 3% of TAH patients. This analysis provides important clinical insight into the differences in GI recovery patterns and the incidence and impact of POI after BR and TAH.

Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies.

OBJECTIVE: To obtain further analysis regarding specific outcomes and alvimopan doses in bowel resection (BR) patients. SUMMARY BACKGROUND DATA: Although postoperative ileus (POI) is common after BR, there is currently no recognized treatment or prevention available. Alvimopan, a novel, peripherally active mu-opioid receptor antagonist, accelerated GI recovery after BR or hysterectomy in 3 phase III trials. METHODS: A pooled retrospective subset analysis of BR patients in alvimopan phase III trials was performed. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) >or=2 hours before surgery and twice daily until hospital discharge for

Postoperative ileus-related morbidity profile in patients treated with alvimopan after bowel resection.

BACKGROUND: Postoperative ileus (POI), an interruption of coordinated bowel motility after operation, is exacerbated by opioids used to manage pain. Alvimopan, a peripherally acting mu-opioid receptor antagonist, accelerated gastrointestinal (GI) recovery after bowel resection in randomized, double-blind, placebo-controlled, multicenter phase III POI trials. The effect of alvimopan on POI-related morbidity for patients who underwent bowel resection was evaluated in a post-hoc analysis. STUDY DESIGN: Incidence of POI-related postoperative morbidity (postoperative nasogastric tube insertion or POI-related prolonged hospital stay or readmission) was analyzed in four North American trials for placebo or alvimopan 12 mg administered 30 minutes or more preoperatively and twice daily postoperatively until hospital discharge (7 or fewer postoperative days). GI-related adverse events and opioid consumption were summarized for each treatment. Estimations of odds ratios of alvimopan to placebo and number needed to treat (NNT) to prevent one patient from experiencing an event of POI-related morbidity were derived from the analysis. RESULTS: Patients receiving alvimopan 12 mg were less likely to experience POI-related morbidity than patients receiving placebo (odds ratio = 0.44, p < 0.001). Fewer patients receiving alvimopan (alvimopan, 7.6%; placebo, 15.8%; NNT = 12) experienced POI-related morbidity. There was a lower incidence of postoperative nasogastric tube insertion, and other GI-related adverse events on postoperative days 3 to 6 in the alvimopan group than the placebo group. Opioid consumption was comparable between groups. CONCLUSIONS: Alvimopan 12 mg was associated with reduced POI-related morbidity compared with placebo, without compromising opioid-based analgesia in patients undergoing bowel resection. Relatively low NNTs are clinically meaningful and reinforce the potential benefits of alvimopan for the patient and health care system.

A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy.

OBJECTIVE: The purpose of this study was to investigate the safety and efficacy of alvimopan, a novel peripherally acting mu-opioid receptor antagonist, in patients who undergo simple total abdominal hysterectomy. STUDY DESIGN: Women (n = 519) were randomized (4:1) to receive alvimopan 12 mg (n = 413) or placebo (n = 106) > or = 2 hours before the operation then twice daily for 7 days (hospital and home). Adverse events were monitored up to 30 days after the last dose of study drug was administered. Efficacy was assessed for 7 postoperative days. RESULTS: Overall, the most common adverse events were nausea, vomiting, and constipation; < 5% of patients discontinued use because of adverse events. Alvimopan significantly accelerated the time to first bowel movement (hazard ratio, 2.33; P <.001). Average time to first bowel movement was reduced by 22 hours, with more frequent bowel movement and better bowel movement quality found in the treatment cohort. CONCLUSION: Alvimopan has a safety profile that is similar to that of placebo and provides significantly improved lower gastrointestinal recovery in women who undergo simple total abdominal hysterectomy.

Postoperative upper and lower gastrointestinal recovery and gastrointestinal morbidity in patients undergoing bowel resection: pooled analysis of placebo data from 3 randomized controlled trials.

BACKGROUND: This analysis examines gastrointestinal recovery in patients who underwent bowel resection (BR) in 3 recent trials. METHODS: Patients who underwent BR in the placebo groups of 3 randomized, double-blind, phase III, parallel-group, multicenter alvimopan efficacy trials were analyzed. RESULTS: Most patients tolerated solid food and had a bowel movement by postoperative day 4. The majority of patients were discharged from the hospital by day 6, but 24.4% required a prolonged hospital stay or readmission. The incidence of nausea was highest on the day of surgery and decreased thereafter, whereas vomiting was uncommon on the day of surgery but increased slightly on postoperative days 1 to 6. The incidence of postoperative nasogastric tube insertion was highest (12%) on day 2. CONCLUSIONS: This analysis provides valuable clinical insight into gastrointestinal recovery after BR in a large homogenous patient population receiving multimodal care.

Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery.

PURPOSE: Postoperative ileus presents significant clinical challenges that potentially prolong hospital stay, contribute to readmission, and increase morbidity. There is no approved treatment for postoperative ileus. Alvimopan is a novel, peripherally acting, mu opioid receptor antagonist currently in development for the management of postoperative ileus. METHODS: Patients undergoing partial colectomy or simple or radical hysterectomy were randomized to receive alvimopan 6 mg (n = 152), alvimopan 12 mg (n = 146), or placebo (n = 153) orally 2 hours before surgery and twice daily thereafter until discharge or for up to seven days. The primary efficacy end point, time to return of gastrointestinal function, was a composite measure of passage of flatus or stool and tolerating solid food. Secondary end points included time to the hospital discharge order written. Adverse events were monitored throughout the study. RESULTS: Mean time to gastrointestinal recovery was significantly reduced in patients treated with alvimopan 6 mg vs. placebo (hazard ratio = 1.45; P = 0.003), with a smaller reduction seen with alvimopan 12 mg (hazard ratio = 1.28; P = 0.059). Mean time to the hospital discharge order written was significantly accelerated in patients treated with alvimopan 6 mg (hazard ratio = 1.50; P < 0.001). The most common treatment-emergent adverse events across all treatment groups were nausea, vomiting, and hypotension; the incidence of nausea and vomiting was reduced by 53 percent in the alvimopan 12-mg group. CONCLUSIONS: In patients undergoing major abdominal surgery, alvimopan accelerated gastrointestinal recovery and time to the hospital discharge order written compared with placebo and was well tolerated.