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To examine the impact of alvimopan on outcomes and costs in a rigorous enhanced recovery colorectal surgery protocol.Postoperative ileus remains a major source of morbidity and costs in colorectal surgery. Alvimopan has been shown to reduce incidence of postoperative ileus in enhanced recovery colorectal surgery; however, data are equivocal regarding its benefit in reducing length of stay and costs.Patients undergoing major elective enhanced recovery colorectal surgery were identified from a prospectively-collected database (2010-2013). Multivariable analyses were employed to compare outcomes and hospital costs among patients who had alvimopan versus no alvimopan by adjusting for demographic, clinical, and treatment characteristics.A total of 660 patients were included; 197 patients received alvimopan and 463 patients had no alvimopan. In unadjusted analysis, the alvimopan group had a faster return of bowel function, shorter length of stay, and lower rates of ileus, Foley re-insertion, and urinary tract infection (all P 0.01). After adjustment, alvimopan was associated with a faster return of bowel function by 0.6 day (P = 0.0006), and lower incidence of postoperative ileus (odds ratio 0.23, P = 0.0002). With adjustment, alvimopan was associated with a shorter length of stay by 1.6 days (P = 0.002), and a hospital cost savings of $1492 per patient (P = 0.01).Alvimopan administration as an element of enhanced recovery colorectal surgery is associated with faster return of bowel function, lower incidence of postoperative ileus, shorter hospitalization, and a significant cost savings. These results suggest that alvimopan is cost-effective in the setting of enhanced recovery colorectal surgery protocols, and should therefore be considered in these programs.

In the United States, nearly 350,000 patients undergo colorectal or small bowel resection (BR) annually.1 These patients spend an average of 11 days in the hospital and account for >$15 billion in annual national healthcare costs.1 All of these patients experience postoperative ileus (POI), a temporary impairment of gastrointestinal (GI) function.2–4 Moreover, associated GI complications are common.5 For patients who undergo BR, length of hospital stay (LOS) is dictated mostly by timing of GI recovery. To facilitate GI recovery, some specialized centers have used accelerated care pathways, although readmission rates have been increased in some cases.6–10 Reducing surgical complications and further accelerating GI recovery after BR could increase patient comfort, decrease the average LOS, and reduce costs, readmission rates, and other demands on healthcare resources.11 The etiology of POI is complex, and major intrinsic contributing factors include surgical stress (ie, from physical manipulation of the bowel), secretion of inflammatory mediators and endogenous opioids in the GI tract, and changes in hormone levels and electrolyte and fluid balance.12–15 Opioids are the most widely prescribed analgesics used to treat postoperative pain.16 However, opioids bind to mu-opioid receptors within the gut, exacerbating POI.12,14 No specific treatment currently exists for the treatment or prevention of POI. Alvimopan is a novel, oral, peripherally acting, mu-opioid receptor (PAM-OR) antagonist that has been studied in patients undergoing abdominal and pelvic surgery.17–19 In 3 phase III multicenter trials, alvimopan accelerated GI recovery after BR or total abdominal hysterectomy (TAH).17–19 Although the results favored alvimopan across studies, statistical significance and magnitude of treatment effect were not consistent with regard to the primary endpoint, a composite assessment that included toleration of solid food and first passage of flatus or stool (GI-3). Further, the individual studies were not powered sufficiently to investigate infrequent but clinically important postoperative morbidities or investigate potential differences between the 6- and 12-mg doses. Hence, a pooled analysis was performed to examine the safety and efficacy of alvimopan within the subgroup of patients who underwent BR.

Alvimopan was approved by the Food and Drug Administration in May 2008 and has been shown to accelerate gastrointestinal recovery after colectomy. Our independent study evaluated alvimopan as it is used in actual hospital practice in the state of Michigan. We hypothesized that alvimopan significantly decreases incidence of prolonged ileus and reduces length of stay (LOS) in patients who have undergone colectomy.We identified 4749 patients from the Michigan Surgical Quality Collaborative (N = 28 hospitals) database between August 2007 and December 2010 who underwent elective colectomy operations. A total of 528 patients received alvimopan both pre- and postoperatively. We first selected a control group of patients from hospitals that had never administered alvimopan (n = 1833) and used propensity matching to manage differences in patient demographics and clinical characteristics. To control for hospital and surgeon characteristics, we then performed a sensitivity analysis, using a separate group of historical control patients treated before May 2008 in hospitals that would later administer alvimopan (n = 270). The Fisher exact test was used to compare complication rates, and the Student t test was used to compare LOS.Patients who received alvimopan had significantly lower incidence of prolonged ileus (2.3% vs 7.9%; P0.001) and a significantly shorter LOS (4.84 ± 4.54 vs 6.40 ± 4.45 days; P0.001) than control patients in hospitals that had never administered alvimopan. No differences were noted in these outcomes using sensitivity analysis.This study suggests that the actual utilization of alvimopan leads to a reduction in prolonged ileus and LOS in patients who underwent colectomy. By accelerating postoperative recovery, alvimopan has the potential to benefit patients and health care systems by improving outcomes, ensuring patient comfort, and reducing cost.

Objective: To demonstrate that alvimopan (6 or 12 mg) accelerates recovery of gastrointestinal (GI) function in patients undergoing laparotomy for bowel resection or radical hysterectomy. Background Data: Postoperative ileus (POI) following laparotomy may increase morbidity and extend hospitalization. Opioids can contribute to the duration of POI. Alvimopan is a novel opioid receptor antagonist in development for the management of POI. Methods: A total of 510 patients scheduled for bowel resection or radical hysterectomy were randomized (1:1:1) to receive alvimopan 6 mg, alvimopan 12 mg, or placebo orally ≥2 hours before surgery, then twice a day (b.i.d.) until hospital discharge or for up to 7 days. The primary efficacy end point was a composite of time to recovery of upper and lower GI function. An associated secondary end point was time to hospital discharge order written. Results: The modified intent-to-treat population included 469 patients (451 bowel resection and 18 radical hysterectomy patients). Time to recovery of GI function was accelerated for the alvimopan 6 mg (hazard ratio [HR] = 1.28; P < 0.05) and 12 mg (HR = 1.54; P < 0.001) groups with a mean difference of 15 and 22 hours, respectively, compared with placebo. The time to hospital discharge order written was also accelerated in the alvimopan 12 mg group (HR = 1.42; P = 0.003) with a mean difference of 20 hours compared with placebo. The incidence of adverse events was similar among treatment groups. Conclusions: Alvimopan accelerated GI recovery and time to hospital discharge order written compared with placebo in patients undergoing laparotomy and was well tolerated.

Over the last decade, we have witnessed a steady improvement in the understanding of basic mechanisms surrounding the development of postoperative ileus (POI). With this in mind, it now appears that new therapeutic options may be on the horizon. For the most part, postsurgical management of POI has been largely supportive and includes a multimodality approach with limitation of narcotic use, wider utilization of thoracic epidurals when possible, clinical pathways emphasizing early feeding, and ambulation with selective use of nasogastric decompression.1 Currently, treatment options, including wider utilization of epidural opioid anesthesia for postoperative pain control or epidural local anesthetics that limit opioid use, have not been demonstrated to affect the duration of POI.1 The greatest advance in limiting POI to date has probably resulted from the expanded use of laparoscopic surgery and the advantage of limiting tissue trauma. Animal and clinical trials have demonstrated significant reductions in POI after laparoscopic colectomy compared with open techniques, which translate into decreased hospital length of stay. The technical advances from laparoscopic techniques in terms of limiting POI have not been matched by similar advances on the pharmacologic front. Such a therapeutic advance would most likely benefit open procedures that undoubtedly require more surgical bowel manipulation. There has been little if any proven success in pharmacologic limitation of POI until the relatively recent reports investigating selective antagonism of opioid receptors.2 We now know that surgical manipulation sets into play a complex series of pathways for POI development that includes neurogenic, inflammatory, and pharmacologic mechanisms.2 Activation of opioid receptors, which occurs following major abdominal surgery, inhibits acetylcholine release, reduces gastrointestinal motility, and has been demonstrated to play a key role in POI regulatory pathways. Of the identified receptors, mu-opioid receptors have been the subject of investigative targets to block and thereby add a pharmacologic adjunct that has previously been lacking.3 Although the discovery of a selective opioid antagonist to the mu-receptor was discovered over a decade ago, we are now examining the potential of this novel approach to impact the management of POI.4,5 The report by Delaney et al6 presents the results of a more expanded analysis of alvimopan phase III trials for the management of POI. Alvimopan is an intriguing mu-opioid receptor antagonist and the only selective opioid receptor antagonist to be examined in phase III trials for the postoperative management of ileus. This report pools data from 3 randomized, double-blind, placebo-controlled, multicenter trials and analyzes for safety and efficacy of 2 different dosage regimens (6 and 12 mg) versus placebo controls. This pooled analysis appears to be valid since inclusion and exclusion criteria were the same across the 3 prospective randomized trials. This includes the appropriate exclusion of patients receiving epidural opioids as well as confirmation of matched groups for postoperative pain control opioid administration, both of which could impact interpretation of efficacy on limiting POI. This study basically confirms what previous trials of alvimopan have demonstrated with additional insight into impact on readmission rates when compared with placebo. The incidence of POI (6.7% placebo vs. l.8% for both 6 and 12 mg groups) favored alvimopan's positive effect as did the reduction in nasogastric tube reinsertion (12.2% placebo vs. 6.8% for both 6 and 12 mg alvimopan). Another important aspect of this pooled analysis is the demonstration that alvimopan significantly decreased hospital readmission (11.7% for placebo vs. 7.3% for 6 mg alvimopan). Furthermore, fewer patients were readmitted with a diagnosis of POI. These findings would be logical conclusions based upon previous phase III trials and clinical extensions of prior reports on the mechanistic role of mu-opioid receptor antagonism. Finally, the use of alvimopan appears to provide reduction in POI beyond what can be expected solely with the implementation of fast-track postoperative care pathways (as used in this study protocol). Will alvimopan be the first in a line of pharmacologic therapeutic modalities that may ultimately advance postoperative surgical management beyond the standard supportive measures to limit POI? As there are few toxicity or tolerance issues with alvimopan administration to limit POI, it would appear that the strategy of selective opioid receptor antagonism as an adjunct to postsurgical management strategies is on the right track. The present study analysis adds additional data to support this conclusion. Additionally, this work adds confirmatory evidence to bring this product forward in larger clinical trials or expanded use. Whether the additional cost of wider utilization of this or future similar pharmacologic products can positively affect the economic picture of POI remains to be seen. Equally as important to cost issues will be the potential enhanced benefits of decreased patient discomfort and improved quality of life secondary to limiting immediate and delayed POI and decreasing readmission rates. There will inevitably be questions raised about optimal patient selection. The present pooled analysis excludes laparoscopic bowel resections and patients with postoperative epidural pain control as did the initial phase III trials. Both of these are common management options that have already shown benefit in decreasing hospital length of stay. Can additional benefit be added by utilizing alvimopan in these subgroups of patients? In any event, for the first time, it would appear that we are examining alternatives for treatment of POI that challenge traditional treatment options. In conclusion, the present report is a pooled analysis of the three phase III trials examining the effects of the selective mu-opioid receptor antagonist (alvimopan) on the potential to limit POI. The mechanistic approach to this concept is sound from a scientific standpoint, and we are witnessing the first steps to translate this approach to alter current surgical guidelines to minimize POI. The lack of any major adverse effects secondary to alvimopan as reported in this pooled analysis, along with additional positive effects in limiting POI and decreasing readmission rates, should be enough to advance this treatment approach to more widespread clinical use.