Commercial and public payers concerned by prolonged hospital stays will be considering this μ-opioid antagonist
Passing gas has been, except for teenagers and the more obtuse movies, a social faux pas. However, for patients who have recently had abdominal surgery, passing gas is actually a landmark event, a sign that their bowel functions are resuming, a welcome event for both the patient and the health care provider. It is also a welcome event for payers because patients recovering from abdominal surgery cannot be discharged without demonstrating bowel function.
Bowel resection causes some of the worst post-operative ileus (POI). The trauma to the bowel, inhibitory sympathetic input, release of stress hormones and neurotransmitters, and the inescapable need for opioid analgesics combine to cause a long stay and hence, higher overall cost. POI can affect all segments of the gastrointestinal tract and may last more than five days. It is associated with bloating, abdominal distension, persistent abdominal pain, nausea, vomiting, an inability to eat or drink, and the accumulation of gas and fluids in the bowel, as well as delayed passage of flatus and defecation.
POI has long been treated with rapid ambulation, optimizing opioid use, decreasing nasogastric suction, and early challenge with clear liquids to “prime” the gut. Medication therapy has been all but ineffective. That has all changed with the recent, though twice delayed, approval of a new drug, alvimopan with the brand name of Entereg. It is the first drug with the FDA approved indication “to accelerate upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.”
Alvimopan is a selective, peripherally acting μ-opioid receptor antagonist. It works by competitively binding to μ-opioid receptors in the gut, selectively inhibiting the negative effects of opioid medications on gastrointestinal (GI) function and motility without affecting the central nervous system analgesic effects. It is given as a 12 mg capsule dose administered 30 minutes to five hours before surgery, followed by 12 mg twice a day for a maximum of seven days.
Plasma concentration peaks approximately two hours post ingestion. No significant accumulation occurs when dosed twice per day. A metabolite with μ-opioid receptor antagonistic properties also is present in the systemic circulation shortly after ingestion. This metabolite is the result of intestinal flora metabolism, not liver metabolism. It has no derogatory properties.
Alvimopan is cleared by biliary secretion in the feces and urine. The mean half-lives of alvimopan and its metabolite are approximately the same: 10–18 hours.
Alvimopan was evaluated in five multicenter, randomized, double-blind, parallel-group, placebo-controlled studies, four of which were performed in the United States.
Studies involved patients age 18 or older undergoing either of two types of abdominal surgery under general anesthesia — partial large or small bowel resection surgery with primary anastomosis, or total abdominal hysterectomy.
All U.S. patients were scheduled to receive intravenous patient-controlled opioid analgesia. Non-U.S. patients were scheduled to receive intravenous patient-controlled bolus parenteral opioid analgesia. The opioid used was left to the discretion of the treating physician. A standard accelerated postoperative care pathway was implemented: early nasogastric tube removal, early ambulation, early diet advancement and solids by the second day after surgery, as tolerated.
The primary endpoint for all studies was time to achieve resolution of postoperative ileus, a clinically defined composite measure of both upper and lower gastrointestinal recovery. The most objective measures of intestinal recovery are considered — tolerance to solid food and first bowel movement. Also recorded was time from surgery to time of discharge order.
The efficacy for those having an abdominal hysterectomy has not been established and is not in the FDA-approved indication. Thus the data collected will only be from those who had bowel resection.
A total of 1,877 patients who had a bowel resection were studied. The average age was 61, with equal proportions of men and women. The most common indications for surgery were GI cancer and diverticular disease. In each of the five studies, alvimopan accelerated the time to recovery of GI function and time to discharge order written as compared to placebo.
The mean treatment difference ranged from 10.7 hours to 26.1 hours. Across the studies, alvimopan recipients had their discharge orders written 13 to 21 hours earlier than comparable placebo recipients. There was no increased pain as measured by the visual analog scale pain intensity score, nor was there an increase in the amount of postoperative opioid administered.
Overall, the side effects in patients receiving alvimopan in short-term surgical clinical trials were mild and not significantly different from those in patients receiving placebo. Long-term use was studied at lower doses for as long as a year. Although a causal relationship was not established, in these studies, myocardial infarction was reported more often in those receiving active drug than in those receiving placebo.
Alvimopan is contraindicated in people who have taken therapeutic doses of opioids for more than seven consecutive days immediately before taking alvimopan.
Post-operative ileus lengthens the stay of patients undergoing abdominal surgery. Anything that promises to shorten stays in a cost-efficient manner is going to demand the attention of those at financial risk for these longer hospital stays. In the case of colon resections, both commercial payers and those at risk under the Medicare DRG system will be looking at alvimopan.
Entereg has a wholesale acquisition cost (WAC ) of $62.50 per dose. Assuming maximal use of 15 doses, the total cost, including administration, is about $1,000. Depending on the actual reduction in hospital length of stay and the actual incremental cost of the additional time, as well as payment methodology, alvimopan may or may not save money for hospitals or managed care organizations. Given that managed care commercial contracts commonly pay a full day charge for any part of a day that crosses midnight, a discharge order written a few hours earlier might in some cases save a hospital daily charge unit.
Hospitals may view this a bit differently for Medicare patients, as their costs are accumulating as the clock ticks because they are paid through diagnosis-related groups.
Patient experience is also sorely needed as there may be quality-of-life reasons to use this product. Although a case may be made for patient satisfaction and reduced discomfort, the manufacturer did not present quality-of-life data in the package insert.
Because of the safety concerns, the manufacturer has set up a restricted distribution process. It can only be purchased by hospitals that are now performing bowel resections and that have registered in the Entereg Access Support and Education (EASE) Program.
The EASE program is designed to maintain the benefits associated with short-term use of the product and to avoid diversion for patients and physicians searching for a solution to chronic bowel dysfunction related to chronic opioid use. The hospitals must have processes and systems that prevent more than 15 doses per patient per event.
Although the data shared in the PI is not compelling from a managed care or cost perspective, alvimopan is a breakthrough in the search for solutions to real problems facing patients undergoing bowel resection.