Peripheral µ opioid receptor antagonists
As described above, one way of optimising the recovery of postoperative bowel function is to antagonise the peripheral opioid receptors without negating their central analgesic action. The main peripheral opioid antagonists used that do not cross the blood-brain barrier are alvimopan and methylnatrexone (figure1). Originally described in 1994 by Eli Lilly, alvimopan is a quaternary μ-opioid receptor antagonist with a high-molecular-weight zwitterionic form and polarity that restricts gastrointestinal absorption and prevents the drug from crossing the blood-brain barrier (Zimmerman et al., 1994; Schmidt, 2001). Alvimopan has an oral bioavailability of 6% resulting in predominantly gastrointestinal activity (Neary and Delaney, 2005). Since the early 2000s, randomised controlled trials have been conducted in North America on cohorts of patients who have undergone bowel resection and hysterectomy (Taguchi et al., 2001; Wolff et al., 2004; Viscusi et al., 2006; Ludwig et al., 2008; Delaney et al., 2012). Compared to placebo, patients treated with alvimopan had a significant reduction in time to transit recovery as evidenced by clinical functional signs such as first gas, first bowel movements or first stools (Jang et al., 2020). These results were confirmed by a combined analysis of three phase III trials (detailed in Table 2) with a significant reduction in the duration of hospitalisation and readmission to hospital in particular (Delaney et al., 2007). Alvimopan was approved by the FDA in 2008. It should be noted that adverse cardiovascular events have been reported, thereby limiting the indications for alvimopan (Erowele, 2008). A multicentre randomised clinical trial on a cohort of patients undergoing surgery after radical cystectomy also showed an improvement in the time taken to resume transit postoperatively (Lee et al., 2014). These encouraging results were not mirrored in a European clinical trial involving 70 hospitals in 10 European countries (Austria, Belgium, France, United Kingdom, Germany, Greece, Poland, Portugal, Spain and Sweden) and New Zealand. In fact, no significant improvement in transit recovery time was observed in the alvimopan group (Büchler et al., 2008). The medico-economic evaluation of alvimopan treatment in a retrospective national cohort of 7050 postoperative patients undergoing open and laparoscopic bowel surgery showed a significant reduction in direct costs (-$2345, p<0.0001)(Delaney et al., 2012). These results have recently been reviewed with the expansion of minimally invasive techniques and the progression of early rehabilitation protocols (Keller et al., 2016). The latest retrospective cohort studies on the cost and efficiency of alvimopan are inconsistent(Keller et al., 2016; Nemeth et al., 2017; Hyde et al., 2019).
Methylnatrexone was developed at the University of Chicago in the 1980s. It is a quaternary derivative of naltrexone. The addition of a methyl group to nitrogen increases polarity, reduces lipid solubility and reduces crossing of the blood-brain barrier (Russell et al., 1982). Methylnaltrexone antagonises opioid binding to the opioid receptors in order of decreasing affinity: µ receptor (median inhibitory concentration IC50 = 70 nmol/L), κ receptor (median inhibitory concentration IC50 = 575 nmol/L) and negligible for the σ receptor (Yuan and Israel, 2006). Despite its receptor antagonising properties, clinical trials, including a phase III trial, have not generated conclusive results (Table 2) (Yu et al., 2011; Viscusi et al., 2013).