◊ SUMMARY:
Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed.
◊ Reviewed by L.J. Lang, MD
Team member of Prof Stein
Research associate, Department of Anesthesiology,
Charité, Campus Benjamin Franklin,
Berlin, Germany
This review was supported, funded, and assisted by Adolor Corporation and Glaxo-SmithKline as shown in the financial disclosure. Most authors have a longstanding and intense affiliation to either, Adolor Corporation (alvimopan) or Wyeth/ Progenics (methylnaltrexone) or both, including grant and research support, stockholding and patent rights. Some are currently (or were in the past) employed by Adolor, others are serving as consultants and advisors. Some were pivotal in performing phase III trials. Given this intense involvement in their development and investigation, authors probably know best about potential and shortcomings of these drugs. This is well reflected in the summaries on enteric neurophysiology and on opioids in the CNS and enteric nervous system. Still, due to their financial involvement they are also most vulnerable to biased presentation of drug and trial data.
One may want to be careful in sharing the optimism about the outstanding potential of peripherally acting mu-opioid receptor (PAM-OR) antagonists in the management of postoperative ileus (POI). Most studies were conducted in patients with bowel resection (BR) and hysterectomies. There was no benefit after hysterectomy to accelerate GI recovery and mixed results for bowel resection. The authors’ brief statement that "therefore, results are only reported for the BR patient population” is no longer appropriate in times where publication of negative results is becoming mandatory. Two out of four clinical trials showed no significantly accelerated GI recovery compared with placebo. Adjustment for covariates and post-hoc analysis of subgroups are not adequate to prove clinical efficacy in double-blind, randomized, controlled trials. Such analyses should be seen as exploratory tools and may prompt further trials.
The development of POI is complex. A potential treatment option targeting a single underlying patho-physiological pathway (opioid-induced impairment of bowel function) should always be seen in the context of other treatment options and peri-operative pathways, even though statistically significant differences between treatment groups may have been shown. In the case of PAM-OR antagonists this becomes obvious in Buechler’s trial of 2008. Alvimopan increased GI recovery time by 8.5 hours compared to placebo (84.2 vs. 92.6 hours) (Buchler et al. 2008). However, in this non-American trial, patients were allowed to receive opioids either by the nursing team or by self-administration via PCA. Simply not using the PCA reduced GI recovery time by 12.3 hours (85.9 vs. 98.2 hours non-PCA vs. PCA group). This underlines the impact of simple and cost-effective changes in peri-operative protocols on post-operative GI recovery, questions the amount of opioids administered, and makes the absolute benefit of PAM-OR antagonists debatable.
It is also not helpful to question epidural analgesia with reference to modern peri-operative thrombo-embolism prophylaxis. This does not reflect state-of-the-art anaesthesia. Epidural analgesia remains a powerful tool in a multimodal approach of anaesthesiologists in the management of POI.
The impact of PAM-OR antagonists on pain relief (analgesia) has not been systematically investigated or discussed in any of the cited trials. Therefore conclusions on analgesia should be handled with caution. So far, most authors have ignored that analgesic and anti-inflammatory effects of opioids can be mediated to a significant degree through peripheral opioid receptors, both in animals and in humans. If peripheral opioid receptors are blocked by PAM-OR antagonists, one might expect an increased demand for centrally acting opioid analgesics to compensate for the loss, resulting in increased centrally mediated side effects. Indeed, in the alvimopan phase III trial of 2005, Delaney presented a graph showing an obvious difference in opioid consumption during the first 2 post-operative days. However, by cumulating opioid demands over 7 postoperative days, these differences were lost in the statistical analysis.
Reading this article is definitely worthwhile to upgrade knowledge on opioids and POI and to sharpen one’s awareness of potentially biased reporting. However, one must take into account that vested interests of authors are destined to bias their conclusions.
◊ References
[1] Buchler, M. W., C. M. Seiler, et al. (2008).
"Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study." Aliment Pharmacol Ther 28(3): 312-25.
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