Alvimopan
Ileus — a temporary impairment of gastrointestinal function — is a complication that affects almost all patients that undergo major bowel surgery1, 2. It results in abdominal discomfort, nausea and vomiting, and is a major reason for prolonged hospitalization1, 2. For example, it has recently been noted that patients in the United States undergoing colorectal or small-bowel resection surgery spend an average of 11 days in hospital and account for more than US$15 billion in annual national health-care costs2. So, approaches to accelerate gastrointestinal recovery following bowel surgery could improve patient comfort as well as reducing the major health-care expenditure associated with extended hospitalization.
Basis of discovery
The pathophysiology of post-operative ileus (POI) is complex. An important contributory factor is the activation of 
-opioid receptors in the gastrointestinal tract by endogenous opioids that are released in response to the stress caused by surgery, as well as by opioid analgesics that are the most common treatment for pain in patients undergoing surgery1, 2. Activation of these peripheral -opioid receptors leads to an increase in colonic muscle tone and a reduction in propulsive activity in the gastrointestinal tract1, 3, 4, 5. Consequently, opioid treatment to provide pain relief following surgery is thought to prolong POI.
The adverse effects of opioids on the gastrointestinal tract can be reversed by -opioid-receptor antagonists such as naloxone and nalmefene, but these drugs are also active in the central nervous system, and so inhibit the analgesic effects of systemic opioids. To overcome this issue, efforts have been directed at identifying -opioid receptor antagonists with peripherally restricted activity1, 3, 4. One such research programme resulted in the discovery of alvimopan4, 5 (Fig. 1).
Figure 1 | Alvimopan.
Altering the size and the polarity of the N-substituent within a series of N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines with the aim of discovering a peripherally selective opioid antagonist led to the discovery of alvimopan (also known as LY246736 and ADL 8-2698)4. It is a potent
-opioid-receptor antagonist following oral administration and distributes selectively (>200-fold selectivity) to peripheral receptors4.
Drug properties
Alvimopan is a potent and selective antagonist of the human -opioid receptor4, 5, 6. It is orally available, but its activity is peripherally restricted because its moderately large, zwitterionic form and polarity limit gastrointestinal absorption and prevent passage through the blood–brain barrier4, 5, 6. Preclinical and small-scale clinical studies demonstrated that alvimopan administered orally can selectively antagonize the gastrointestinal effects of opioid agonists such as morphine without affecting analgesia4, 5, 6, 7, providing the basis for evaluation in large-scale clinical trials in POI.
Clinical data
The safety and efficacy of alvimopan in the management of POI were evaluated in five randomized, double-blind, placebo-controlled studies — four in the US and one outside the US6. The trials involved 1,877 adult patients undergoing partial large- or small-bowel resection surgery with primary anastomosis, who were randomly assigned to receive alvimopan (12 mg doses orally) or placebo6. The initial dose was administered at least 30 minutes and up to 5 hours before the scheduled start of surgery for most patients, and subsequent doses were administered twice daily beginning on the first post-operative day and continued until hospital discharge or a maximum of 7 days6.
A standardized accelerated post-operative care pathway was implemented in all studies6. In the US studies, patients were scheduled to receive intravenous patient-controlled opioid analgesia, and in the non-US study, patients were scheduled to receive opioids either by intravenous patient-controlled opioid analgesia or bolus parenteral administration6. In all studies, there was no restriction on the type of opioid used or the duration of intravenous patient-controlled opioid analgesia6. In the non-US study, average daily post-operative opioid consumption was 
50% lower and the use of non-opioid analgesics substantially higher, as compared with the US studies for both treatment groups6.
The primary end point for all studies was time to achieve resolution of POI6. This was assessed by a clinically defined composite measure of both upper and lower gastrointestinal recovery known as GI2, which assesses toleration of solid food and first bowel movement6. The time from the end of surgery to when the discharge order was written represented the length of hospital stay6.
In each of the five studies, alvimopan accelerated the time to recovery of gastrointestinal function, as measured by the composite endpoint GI2, and time to discharge order written compared with placebo6. The mean difference in GI2 recovery time between patients receiving alvimopan and patients receiving placebo in the five studies was 10.7 hours in the non-US study, and 19.8 hours, 26.1 hours, 14.0 hours and 13.2 hours in the four US studies6. Across the four US studies, patients receiving alvimopan had their discharge order written 13–21 hours sooner compared with patients receiving placebo6. Across all five studies, alvimopan did not reverse opioid analgesia as measured by visual analogue scale pain intensity scores and/or amount of post-operative opioids administered6.
Indications
Alvimopan is approved by the FDA to accelerate the time to upper and lower gastrointestinal recovery following partial large- or small-bowel resection surgery with primary anastomosis6.
Post-operative ileus
Analysing issues in the treatment of post-operative ileus is Conor P. Delaney, M.D., Ph.D., Chief, Division of Colorectal Surgery, Director, Institute for Surgery and Innovation, and Professor of Surgery, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, USA.
Colorectal surgery is a common major operation, with around 300,000 bowel resections performed annually in the US alone. This surgery is complex, frequently associated with complications and typically involves a hospital stay of 10 days, and is an important area of focus for efforts to improve the quality and efficiency of health care.
One of the primary factors affecting the length of stay after surgery is post-operative ileus (POI), which delays hospital discharge until adequate oral hydration and nutrition can be tolerated. In severe cases, a nasogastric tube must be inserted, and patients may require intravenous nutrition. Some patients can be discharged from hospital, only to develop symptoms later, requiring readmission.
Alvimopan, recently approved by the FDA, has been extensively studied in patients undergoing abdominal surgery as a prophylactic oral medication to reduce the impact of POI. Pooled analysis of a series of prospective randomized controlled trials shows an acceleration of recovery of gastrointestinal function by 18 hours in patients undergoing open colectomy when managed by a standardized accelerated post-operative care pathway with the addition of 12 mg of alvimopan2. The time until the hospital discharge order was written was also significantly reduced, and readmission rates were reduced from 12% to 7%. These data suggest that the medication will be useful in patients undergoing elective open colectomy. Phase IV trials will probably involve patients with an ileostomy or colostomy, patients undergoing total colectomy and those undergoing proctectomy — populations that were excluded from the Phase III trials.
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In parallel with this research, over the past decade there has been increasing use of minimally invasive surgery to accomplish colectomy, which in recent reports may account for up to one-third of colon resections8. Laparoscopic colectomy has been shown to be oncologically safe, and is associated with a reduction in hospital stay of 1–2 days8. When combined with post-operative care pathways, hospital stays between 2.5–3.7 days can be achieved9. However, even with these excellent outcomes, 10% of laparoscopic colectomy patients have relatively delayed recovery, and close to 10% may require readmission to hospital. The similarity of these findings to those seen with open surgery suggests that alvimopan may provide a clinical benefit in patients undergoing laparoscopic colectomy, as well as those undergoing open surgery. Given the rapid increase in the volume of laparoscopic colon surgery, this population should be studied as soon as possible, and Phase IV trials are being planned. A further interesting population may be patients who develop POI who have not received alvimopan. It will be interesting to see whether there is a therapeutic benefit to the drug, similar to that seen with chronic opioid bowel dysfunction10.
In summary, multiple studies have now shown that alvimopan safely and effectively accelerates gastrointestinal recovery after open segmental colon resection. Further studies will help define subpopulations who will derive most benefit, and other potential populations who might benefit from this agent.
