Abstract
Alvimopan is an US-FDA approved, peripherally acting mu opioid receptor antagonist which when started pre-operatively has been shown to hasten intestinal motility and reduce the duration of post-operative ileus. However the logistics involved in procuring, storing and dispensing the drug and the cost of the drug for fifteen doses as approved by FDA prohibits the use of it on a regular basis.
Keywords
Alvimopan; Ileus; Colorectal Surgery;
1. The trouble with post-operative ileus
Post-operative ileus is a distressing problem faced by patients after gastrointestinal (GI) surgeries. It leads to significant patient discomfort, prolonged hospital stay, unnecessary interventions and investigations which increases the overall cost of treatment. Length of hospital stay after GI surgeries is dependent on optimal bowel activity. The cause of ileus is usually multifactorial like bowel handling during surgery, resection and anastomosis of intestines, surgical stress, inflammatory mediators, electrolyte imbalances, systemic opioids either alone or together.1 Early initiation of enteral feeds is known to facilitate gut activity but it's not always possible especially after resection and anastomosis, gut ischaemia blunt injury abdomen etc.
Intravenous opioids are the mainstay of post-operative pain management after major bowel surgeries. Although an epidural catheter is usually placed for providing pain relief due to open surgeries, IV opioids are used as a part of pain relief round the clock or for breakthrough pain. Opioids bind to μ receptor in the gut leading to ileus.
2. Routine measures taken post-operatively
Post-operative ileus is a consistent problem after colorectal surgeries. Therefore, prophylactic measures are taken in the post-operative orders by using prokinetics like metoclopramide, levosulpiride, mosapride or itopride. IV neostigmine and lignocaine are used in resistant cases. Epidural analgesia is also known to enhance bowel motility. Aggressive ambulation and mobilization is usually practiced after such surgeries so as to facilitate gut functioning.2 Intravenous erythromycin was used extensively earlier which was supposed to relieve post-operative ileus owing to its prokinetic effects when used with a dose of 250 mg eight hourly, but the evidence is inconsistent.3
3. What is alvimopan?
Alvimopan is an orally available, peripherally acting μ receptor antagonist (PAM-OR) which has been found to be useful in counteracting post-operative ileus in several multicentre trials. Chemically it is a trans 3,4-dimethyl-4 (3-hydroxyphenyl)piperidine. ADL 08-0011 is a amide hydrolysis metabolite of alvimopan formed by the intestinal flora after oral administration. Both were found to be potent, highly selective, peripherally acting μ-receptor antagonist.4, 5, 6
Alvimopan was studied initially for opioid induced constipation in patients with opioid dependent chronic cancer pain. It has affinity for peripheral μ opioid receptors with less affinity for sigma and kappa opioid receptors. Alvimopan doesn't reverse the analgesia provided systemic opioids when administered intravenously, intramuscularly, subcutaneously or orally because it doesn't cross blood–brain barrier like naloxone.
4. The problem with the use of alvimopan
Studies conducted by Irving et al and Webster et al investigated the use of alvimopan in doses of 0.5 mg or 1 mg twice daily for a variable duration of 6 to 12 weeks.
In this study, early bowel movements was reported in non-cancer patients who suffered with opioid induced constipation. These patients used 1 mg twice daily of alvimopan. However, the drug was withhold for use as there was a significant incidence of cardiovascular events (myocardial infarction) noted in the patients on chronic alvimopan (0.5 mg/1 mg twice daily).7, 8
Later in 2008, US FDA approved the short term use of alvimopan for 15 doses, 12 mg preoperatively followed by 12 mg twice daily for not more than 7 days. The only approved indication of alvimopan now is for prevention of post-operative opioid induced ileus after bowel surgeries.
Owing to the cardiovascular adverse effects associated with its use after chronic use in patients taking it for opioid induced constipation, alvimopan is available for use to only those hospitals who are enrolled in EASE (Entereg Access Support and Education) Program and the drug is procured by REMS (Risk Evaluation and Mitigation Strategy) of US-FDA. The short term use was not associated with significant events. Therefore, procuring alvimopan requires a licence with the hospital with the drug getting available only on the prescription of designated physicians. Only hospitals performing high volume bowel resections are eligible for procuring, storing and getting approval for using it.9
5. Studies showing efficacy of alvimopan
Delaney et al did a pooled analysis of 3 randomized, double-blind, placebo-controlled, phase III, parallel-group, multicenter trials investigating the efficacy and safety of alvimopan after bowel resection surgeries. Patients were randomized to receive 6 mg, 12 mg alvimopan and placebo. They found significantly accelerated GI recovery in patients who received alvimopan, better in the group who received 12 mg compared to placebo.10 Traut et al analysed 39 RCTs which included 15 prokinetic drugs of different groups and 10 studies that involved comparison of prokinetic drugs. Frequently used drugs like erythromycin, cholecystokinin-like drugs, vasopressin, propranolol, cisapride etc had insufficient evidence to facilitate any benefit. IV lignocaine and neostigmine although found to be effective, lacked hardcore evidence. However, 6 RCTs supported the use of alvimopan. This was published in the Cochrane database systematic review in 2008.11 Poston et al conducted a retrospective cohort matched study involving 480 patients who received alvimopan compared to 960 matched control patients. On analysing the data, the authors found that the overall cost of hospitalisation and recovery from ileus was better in patients who received alvimopan.12
The cost of the drug is what prevents its use on a regular basis. The cost of 15 doses of alvimopan is around 250 times the cost of injection metoclopramide when used in a dose of 10 mg four times a day intravenously. On the other hand, alvimopan might not be really effective if it is used once ileus has set in. That's the reason why FDA insists starting its use preoperatively. Other supportive measures like optimization of electrolytes, mobilization, ambulation, early enteral feeds, laxatives should be continued. Non-selective opioid antagonists like naloxone also reverses the constipation due to systemic opioids but at the cost of antagonising the systemic analgesia as it tends to cross the blood–brain barrier which is not desirable post-operatively.
6. Conclusion
Alvimopan appears to be an excellent drug which can help in early recovery of post-operative bowel movements after colorectal surgeries. However, the cost of the drug and the logistics involved in procuring the drug is at present prohibiting clinicians from using it peri-operatively on a routine basis. Once made available easily and after reducing the price, it can be used as an agent that can reduce the suffering of patients undergoing abdominal surgeries.
Conflicts of interest
None.