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).