Peripherally acting μ-opioid receptor antagonists for recovery of bowel function after radical cystectomy: a systematic review and meta-analysis

Introduction

There were an estimated 3,121 new diagnoses of bladder cancer in Australia in 2023, with 1,061 estimated deaths (1). Radical cystectomy (RC) is the treatment of choice for muscle-invasive bladder cancer and some high-risk cases of non-muscle invasive disease (2). Despite advances in surgical technique and adoption of enhanced recovery after surgery (ERAS) protocols, post-operative complications can occur in 30–70% of patients, and 90-day mortality can be as high as 4.7% (3,4). Urinary diversion is frequently performed as a non-continent diversion in the form of an ileal conduit or an orthotopic neo-bladder, both techniques involving taking a segment of the small bowel and performing a primary anastomosis (5). Handling and resection of the bowel can result in a postoperative ileus (POI). POI can be defined as the interval from surgery until passage of flatus/stool and the tolerance of an oral diet (6). Some degree of POI is a normal physiological response to abdominopelvic surgery that usually resolves without serious complications (6). Prolonged POI can result in an increased length of hospital stay, decreased quality of life, and a higher burden to the healthcare service (6). It has been estimated that the incidence of developing a prolonged POI post-RC occurs between 1.6% and 23.5% (7). A recent study found that patients who experience POI after colorectal surgery have a significantly higher mean total cost of inpatient stay of AUD $7,868.13, a 26.4% increase over non-POI patients (8). While this data is not specific to RC patients, it exemplifies the need for further investigation into cost analysis and prevention strategies in this patient cohort.

Opioids have been the mainstay of management of post-operative pain in RC patients (9). Recent studies suggest epidural catheter placement, rectus sheath catheters and the pre-incisional wound infiltration with local anaesthetic have decreased post-operative levels of pain and prevented the over-use of opioid based analgesia (9). It is common for patients to still have an opiate requirement post-RC despite the clear evidence for the exacerbation of POI via activation of μ-opioid receptors in the gut. From this line of reasoning, it is prudent to study the effect of peripherally acting μ-opioid receptor antagonists (PAMORAs), as they can theoretically reduce the incidence of POI without compromising the analgesic effects of opiates. To our knowledge, there have been two systematic reviews conducted in 2016 and 2017 that have evaluated the efficacy of alvimopan in the reduction of POI (16,17). Since these reviews, further observational studies have been published that evaluated not only alvimopan, but other PAMORAs such as naloxegol and methylnaltrexone (12-21).

Alvimopan is a potent competitive PAMORA (22). Following its administration, alvimopan antagonises the peripheral effects of opiates by competitively binding to μ-opioid receptors in the gastrointestinal tract (22). Alvimopan does not cross the blood-brain barrier due to its moderately large molecular weight and low lipophilicity, and therefore it does not mitigate the central analgesic efficacy of opiates for the management of post-operative pain (22). Based on an RCT by Lee et al., which revealed positive results of decreased incidence of POI and length of stay (LOS) in hospital, alvimopan was approved by the FDA for the treatment of POI post-RC in 2014 (11). Naloxegol is a second PAMORA that has been approved for the treatment of opioid induced constipation in adult patients with non-cancer pain; however, it has had limited research conducted around its indication for short term treatment of opioid-induced constipation (18). A study has suggested that there is no significant difference between naloxegol and alvimopan in regard to outcomes of LOS or the incidence of POI (18). As naloxegol is significantly cheaper than alvimopan (at $14 per tablet in comparison to $192 per capsule of alvimopan), this could represent a significant cost savings in the pharmacological prevention of POI (18). Methylnaltrexone is a third PAMORA that is more commonly used for prevention of opiate induced constipation in palliative or cancer patients; however, it is showing promising results in the prevention of POI post-robotic-assisted RC cohort and has demonstrated significant cost savings and a potential for reduced LOS (19).

The role of PAMORAs, particularly alvimopan, in patients undergoing abdominal surgery has been extensively studied (23-25). However, there is a paucity of robust evidence that evaluates their use in RC patients, in whom the risk and incidence of POI rivals that of other intra-abdominal surgery (26). With this background, the aim of this review is to provide an overview of the use and efficacy of PAMORAs in the prevention of POI in RC patients. We present this article in accordance with the PRISMA reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0432/rc).

Methods

This review was conducted according to A Measurement Tool to Assess Systematic Reviews II guidelines (https://amstar.ca/Amstar_Checklist.php) and recent European Urology recommendations (27). The protocol was registered with PROSPERO (ID: CRD42024582954; https://www.crd.york.ac.uk/PROSPERO/myprospero).

Criteria for eligibility

Study design

Eligible studies included randomized controlled trials (RCTs) and non-randomized studies, including prospective and retrospective observational studies and case-control studies. Studies published in languages other than English were excluded. Studies were included regardless of their publication status (including abstracts) or year of publication.

Types of patients

Criteria for inclusion included (I) male or female patients undergoing RC for primary bladder cancer; (II) compared alvimopan, naloxegol, or methylnaltrexone vs. control (standard of care); and (III) reported on our primary or secondary outcomes in the review. Patients were included if the indication for cystectomy was for benign disease and regardless of histological subtype in initial transurethral resection. Other participants eligible for inclusion were those who undergo RC for non-muscle invasive cancer that has very high-risk features or persistent disease despite less invasive therapy, low-grade bladder cancer that is not amenable to complete transurethral resection, or bladder cancers that cause severe symptoms that cannot be managed endoscopically or medically. Exclusion criteria included patients who did not undergo a small bowel resection for concomitant urinary diversion or if they had received neoadjuvant radiotherapy for bladder cancer pre-operatively. Studies were included regardless of operative approach (open, laparoscopic, robot-assisted), whether they had undergone neoadjuvant chemotherapy, Bacillus Calmette-Guérin (BCG) therapy or previous transurethral resection.

Types of interventions

The intervention studied was the use of PAMORAs: alvimopan, naloxegol, and methylnaltrexone. Studies were included regardless of reported dose, frequency, and schedule. The intervention arm was compared to a control arm, which was standard of care or placebo. Studies that included co-interventions that comprise components of ERAS protocols were considered for inclusion if they were applied equally to the intervention and control group. Examples of co-interventions include early mobilisation, chewing gum, minimal opioid use, use of prokinetics, epidural placement.

Type of outcomes and measurement of treatment effect

Primary outcomes

• Time to flatus;
• Time to documented first bowel movement.

Secondary outcomes

• Length of hospital stay/time to hospital discharge;
• Initiation of total parenteral nutrition (TPN) or partial parenteral nutrition (PPN);
• Post-operative placement of nasogastric tube (NGT) or replacement after removal;
• Readmission to hospital;
• Major adverse events (Dindo-Clavien grades III to V).

Prior to data extraction, we determined our primary and secondary outcomes. For dichotomous outcomes (initiation of TPN or PPN, readmission to hospital, and adverse events), we documented odds ratios (ORs) with associated 95% confidence intervals (CIs). For continuous outcomes (length of hospital stay, time to flatus, and time to first bowel movement), we reported effect sizes of mean difference (MD) with an associated 95% CI.

Search methods

The search strategy was developed with the assistance of a librarian. An example of the search strategy can be found in Appendix 1. Variations of this search strategy were utilised for other databases (Appendices 2-4). Studies were included in the search regardless of their publication status. We searched the following databases for relevant studies: MEDLINE OvidSP, PubMed, Embase Ovid SP, and Cochrane Central Register of Controlled Trials (CENTRAL). Trial registries including the World Health Organisation International Clinical Trials Registry Platform (WHO ICTRP; https://www.who.int/tools/clinical-trials-registry-platform) and ClinicalTrials.gov (https://clinicaltrials.gov) were searched to identify unpublished studies. An integrated library of all retrieved articles was created using EndNote for ease of importation into Covidence.

Data collection and analysis

Study selection and data extraction

Two review authors (E.P. and J.L.) screened titles and abstracts independently for eligibility through Covidence (https://www.covidence.org/). Covidence detected and removed duplicate studies. Full-text articles were screened by the same authors independently. Study eligibility was ultimately determined with discussion and consensus. The results of the search and selection of studies were summarized in a PRISMA flow diagram (Figure 1). A data extraction table was made using Covidence. The same authors independently extracted data onto the data extraction form. A comparison between the extracted data was made; disagreements were resolved after reviewing the full-text article; and the data were complete. The following study characteristics were extracted: study setting, year, methods, and funding. Population characteristics extracted included: inclusion criteria, exclusion criteria, total sample size, number of withdrawals, reason for withdrawal, intervention group sample size, and comparator group sample size. Baseline characteristics extracted included age, sex, American Society of Anaesthesiologists (ASA) score, body mass index (BMI), comorbidities, type of urinary diversion, surgical technique, prior treatment, and indication for RC. Data on intervention included the number of participants allocated to intervention and control, the dose, frequency, duration, time of initiation in relation to surgery, and components of ERAS. We attempted to contact authors to obtain missing key data. Characteristics of included studies can be found in Table 1.

Figure 1 PRIMSA diagram.

Assessment of risk of bias in included studies

The risk of bias was assessed by two reviewers (E.P. and J.L.) independently, and any disagreements were resolved and agreed upon by the two reviewers. Risk of bias for randomized trials was determined using the Risk of Bias 2 (RoB 2) Assessment Tool (28) (https://www.riskofbias.info/). The following domains were assessed to categorise the study as low risk of bias: allocation sequence, allocation concealment, baseline differences between intervention groups, blinding of participants and carers, appropriate analysis to assess the effect of the intervention, missing outcome data, measurement of outcome, selection of the reported result, and overall bias. We assessed risk of bias in included cohort studies using the Newcastle-Ottawa Scale (NOS) (Table 2), which evaluates selection, comparability, and outcome domains. The same two reviewers (E.P. and J.L.) independently scored each study; disagreements were resolved by discussion. Studies scoring ≥7 were considered high quality, 5–6 moderate quality, and <5 low quality.

Dealing with missing data

We attempted to contact study authors to obtain missing data but were unsuccessful. In the case of reports not providing mean and standard deviation (SD), we used endorsed statistical imputation methods. For studies that provided only median and interquartile range for continuous outcomes [Hamilton, Hanna, Packiam, and Tobis (15-17,29)], we calculated mean and SD using Wan’s formula (30). For studies that provided only median and range [Altobelli and Lenis (19,31)], we used Hozo’s formula (32). When only unadjusted ORs and CIs were reported [Huang (14)], the log OR and standard error were derived using the generic inverse-variance method, with approximate event counts inferred for contextual interpretation. For studies that only included data on sample size, mean, and associated P value [Swanson, Vora, and Manger (12,21,33)], we reconstructed arm-level SDs for time to flatus by converting the reported 95% CI of the between-group MD to a standard error and, under an equal-variance assumption, deriving a pooled SD (applied to both arms) to accompany the published group means. Sensitivity analyses were performed for the outcomes that included reconstructed data.

Assessment of heterogeneity

We assessed statistical heterogeneity using the I² statistic. In accordance with the Cochrane Handbook for Systematic Reviews of Interventions (34), I² values were interpreted as follows: 0–40% may represent unimportant heterogeneity; 30–60% may indicate moderate heterogeneity; 50–90% may reflect substantial heterogeneity; and 75–100% may denote considerable heterogeneity.

‘Summary of findings’ table

We summarized the certainty of the evidence for each outcome using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation), which evaluates confidence in effect estimates across five domains: study limitations, inconsistency, imprecision, indirectness, and publication bias. Because all included studies were either observational or mixed-design meta-analyses, particular attention was given to risks of bias and variability between studies. We generated a ‘risk of findings’ table using the GRADEpro Guideline Development Tool (35) (https://www.gradepro.org/), which provides a transparent overview of the magnitude and certainty of each effect estimate (Table 3).

Results

A total of 1,680 studies were identified. One hundred and twenty duplicates were removed. In total, 1,560 titles and abstracts were screened, and 1,479 were excluded. Full text was screened for 76 articles, and 62 were excluded. The total number of studies included in the review was 14 (Figure 1). A summary of included studies can be found in Table 1. Thirteen of the included studies were retrospective cohort studies, and there was one RCT. Given the lack of randomized evidence, pooled analyses incorporated both randomized and non-randomized studies. We considered a sensitivity analysis excluding observational studies and thereby reducing confounding and the risk of selection bias. However, only one randomized study was identified, making randomized-only meta-analysis infeasible and unlikely to provide additional insight. Most studies were single-centre and evaluated the use of alvimopan, with only one study assessing methylnaltrexone. Surgical approaches varied between studies, and several did not report technique. Common exclusion criteria included preoperative opioid use, prior major bowel surgery, and factors limiting postoperative data collection. Where reported, most studies incorporated ERAS protocols or compared ERAS vs. non-ERAS cohorts. Dosing regimens for alvimopan were largely consistent with standard perioperative protocols; however, some studies did not report information on dose. Overall, the studies demonstrated heterogeneous reporting practices but collectively evaluated the impact of PAMORAs on postoperative bowel recovery following RC. Although several studies reported incidence of POI, outcome definitions and reporting were vastly inconsistent across studies, and results were not pooled.

Meta-analyses were conducted to quantitatively synthesize evidence from randomized and observational trials that evaluate the efficacy of PAMORAs. One study, Faraj et al. (43) (Table 4), evaluated naloxegol, one of the PAMORAs we hoped to include in the review; however, it was excluded from the meta-analysis. The study compared naloxegol to alvimopan, yielding important and relevant results; however, it did not meet our criteria for inclusion of the comparison of a PAMORA to a control.

Forest plots were all generated using either a fixed (common) or random effect model, as appropriate, using R with the meta package. Pooled effect sizes were expressed as ORs for dichotomous outcomes and MDs for continuous outcomes, each accompanied by a 95% CI.

Primary outcomes

Time to flatus

Six studies were included comparing PAMORAs to control for time to first flatus (Figure 2). The pooled analysis of 1,119 participants (579 PAMORA and 540 control) demonstrated a significantly shorter time to flatus with PAMORA use, with an MD of −0.97 days (95% CI: −1.07 to −0.87; P<0.001). Both fixed- and random-effects models yielded identical estimates, and heterogeneity was minimal (I²=0%), indicating consistency across studies. This lack of heterogeneity likely reflects the high similarity among included trials, which investigated comparable interventions, measured the same outcome, and involved similar populations. The GRADE assessment rated the certainty of evidence for this outcome as very low, due to the non-randomized nature of all of the included studies and their inherent risk of confounding and selection bias, as well as the absence of a sufficiently large effect size to justify upgrading. Therefore, although results consistently favoured PAMORAs and demonstrated a reduction of approximately 1 day in time to first flatus, the true effect may differ substantially from the pooled estimate.

Figure 2 Time to flatus. CI, confidence interval; MD, mean difference; SD, standard deviation.

Only Bigley et al. (36) reported mean and SD. Given the paucity of raw data, we performed a sensitivity analysis (Figure 3) excluding the studies [Swanson and Vora (21,33)] that only included data on sample size, mean, and associated P values as the results, were estimates.

Figure 3 Sensitivity analysis for ‘time to flatus’. CI, confidence interval; MD, mean difference; SD, standard deviation.

In the sensitivity analysis (Figure 3), there was a total of 981 participants (520 PAMORA and 461 control). The pooled MD remained virtually unchanged at −0.97 days (95% CI: −1.12 to −0.81; P<0.001), confirming that exclusion of these studies did not materially influence the overall effect size. The sensitivity analysis continued to show no evidence of heterogeneity (I²=0%; P=0.48), indicating that the variation in study results was fully attributable to chance rather than genuine differences between trials. This lack of heterogeneity could reflect the high degree of similarity among the included studies. However, it should be interpreted with caution, as there remains three studies in which the means and SD were reconstructed. This could have resulted in an inherently smooth inter-study variability, as they are based on distributional assumptions as opposed to raw patient-level data.

Time to first bowel movement

Nine studies were included evaluating the effect of PAMORAs on time to first bowel movement (Figure 4). Across a total of 1,738 participants (824 PAMORA; 914 control), PAMORA use was associated with a significantly earlier return of bowel function. The pooled MD was −1.32 days (95% CI: −1.37 to −1.28) under a fixed-effect model and −1.30 days (95% CI: −1.81 to −0.79) using a random-effects model, both indicating a clinically meaningful reduction in time to first bowel movement. Heterogeneity was substantial (I²=84%), reflecting variability in study design and effect sizes; however, the direction of effect consistently favoured PAMORAs across all studies.

Figure 4 Meta-analysis and forest plot for ‘time to first bowel movement’. CI, confidence interval; MD, mean difference; SD, standard deviation.

The certainty of evidence for time to first bowel movement was judged to be very low (Table 2). This was primarily due to the inclusion of mostly non-randomized studies and the presence of substantial heterogeneity across studies (I²=84%). Although the pooled analysis demonstrated a consistent direction of benefit favouring PAMORAs and suggested a reduction of approximately 1.3 days, the magnitude of effect did not meet thresholds for upgrading. Therefore, the true effect may differ from the pooled result despite the overall trend towards earlier time to first bowel movement with PAMORA use.

A sensitivity analysis was conducted to assess the robustness of the pooled results by excluding the Swanson and Vora studies (21,33), with their small sample sizes and reconstructed data potentially contributing to heterogeneity (Figure 5). Seven studies were included. The pooled MD in length of hospital stay remained −1.30 days (95% CI: −1.97 to −0.63; P=0.003) in favour of PAMORA treatment, confirming a statistically significant reduction compared with control. Heterogeneity remained high (I²=87.9%; τ²=0.0797; P<0.001), suggesting persistent variability across trials, likely due to differences in surgical context, PAMORA type, and study size. Exclusion of these two studies did not materially change the findings.

Figure 5 Sensitivity analysis for ‘time to first bowel movement’. CI, confidence interval; MD, mean difference; SD, standard deviation.

Secondary outcomes

LOS

Eleven studies analysed the outcome of LOS, comprising 1,912 participants (899 PAMORA and 1,013 control). The pooled analysis (Figure 6) demonstrated a significant reduction in LOS among patients treated with PAMORAs, with a MD of −1.37 days (95% CI: −2.08 to −0.65; P=0.002), indicating shorter hospitalization compared with controls. Heterogeneity was substantial (I²=78.8%; τ²=0.5797; P<0.001).

Figure 6 Meta-analysis and forest plot for ‘LOS’. CI, confidence interval; LOS, length of stay; MD, mean difference; SD, standard deviation.

Requirement for NGT

Figure 7 shows the effect of PAMORA use on postoperative NGT placement. The three studies included 931 in total (470 in the experimental group and 461 in the control group). The analysis reported a pooled OR of 0.31 (95% CI: 0.21–0.46), indicating significantly lower odds of events in the experimental group. The heterogeneity was 0% (I²=0%), indicating no detectable variability in effect sizes between the included studies. This suggests that the observed differences among studies are likely due to random sampling error rather than true differences in treatment effect. Given the small number of studies and the overlapping CIs for individual ORs, statistical power to detect heterogeneity was limited. Therefore, while the data appear consistent, the absence of heterogeneity should be interpreted cautiously.

Figure 7 Meta-analysis and forest plot for ‘requirement for NGT’. CI, confidence interval; NGT, nasogastric tube; OR, odds ratio.

Readmission

There was a total of 2,664 participants evaluating the readmission rate post-RC (1,263 PAMORA and 1,401 control) with 519 total readmission events (Figure 8). The pooled OR was 0.77 (95% CI: 0.55–1.08), directionally toward reduced readmission with alvimopan, though this result did not reach statistical significance (z=−1.53; P=0.13). Moderate heterogeneity was observed (I²=53.2%; P=0.040), indicating some variability among studies.

Figure 8 Meta-analysis and forest plot for ‘readmission’. CI, confidence interval; OR, odds ratio.

Adverse events

Data from three studies were pooled to evaluate the effect of PAMORA on adverse events (Figure 9), including 7,796 participants (3,546 PAMORA and 4,250 control) and 1,144 total events. The analysis showed an association between alvimopan use and decreased incidence of adverse events (OR =0.63; 95% CI: 0.55–0.72; z=−6.83; P<0.001). No significant heterogeneity was observed (Q=0.78; P=0.68; I²=0%), indicating consistent results across studies.

Figure 9 Meta-analysis and forest plot for ‘adverse events’. CI, confidence interval; OR, odds ratio.

Initiation of TPN

Figure 10 shows an analysis of two studies that analysed the effect of PAMORAs on the initiation of TPN, comprising a total of 651 participants (331 PAMORA and 320 control group). The pooled estimate demonstrated a statistically significant reduction in the need for TPN among patients treated with alvimopan, with a pooled OR =0.41 (95% CI: 0.26–0.63; P<0.001). Although only two studies were available, moderate heterogeneity was observed (I²=67.6%; P=0.079), suggesting some variability in study results.

Figure 10 Meta-analysis and forest plot for ‘initiation of TPN’. CI, confidence interval; OR, odds ratio; TPN, total parenteral nutrition.

Risk of bias

The risk of bias for randomized studies has been summarized in Figure 11. Only one randomized trial was included in the review, and the overall risk of bias was considered ‘some concerns’ due to insufficient reporting of allocation concealment in the randomization process (11).

Figure 11 Risk of bias assessment utilizing RoB 2. RoB 2, Risk of Bias 2.

We assessed risk of bias in included cohort studies using the NOS (Table 2). Overall, 13 studies were included. The quality ranged from 7 to 9, with a median of 8. The domain that consistently introduced the most bias ‘comparability’, in which confounding bias was introduced in studies that failed to control for confounding variables such as age, BMI, smoking, and comorbidities.

Discussion

Summary of evidence

Across the included studies, PAMORA therapy was consistently associated with improved postoperative gastrointestinal recovery following RC. Six observational studies (n=1,119) demonstrated that PAMORAs reduced time to first flatus by approximately one day (MD =−0.97 days; 95% CI: −1.07 to −0.87), with no detectable heterogeneity (I²=0%). Nine non-randomized studies (n=1,738) also showed a reduction in time to first bowel movement (MD =−1.30 days; 95% CI: −1.81 to −0.79), although heterogeneity was substantial (I²=84%). For LOS, 11 studies involving 1,912 participants reported a mean reduction of 1.37 days (95% CI: −2.08 to −0.65), again with considerable heterogeneity (I²=79%). Three studies (n=931) evaluating NGT placement found a large and consistent reduction with PAMORA use (OR =0.31; 95% CI: 0.21–0.46; I²=0%). Three studies (n=7,796) demonstrated fewer adverse events with PAMORAs (OR =0.63; 95% CI: 0.55–0.72; I²=0%). This result may be influenced by residual confounding given only three studies were included. Furthermore, post-operative adverse events can be affected by patient characteristics, surgical approach, and peri-operative care pathways. Evidence for readmission was less certain. Across eight studies (n=2,664), the pooled estimate did not demonstrate a statistically significant association between PAMORA therapy and readmission (OR =0.77; 95% CI: 0.55–1.08), with moderate heterogeneity (I²=53%). Two studies assessing need for postoperative TPN/PPN (n=651) showed a substantial reduction in risk (OR =0.41; 95% CI: 0.26–0.63), although heterogeneity was moderate (I²=68%). Overall certainty of evidence was generally rated very low for most outcomes due to non-randomized designs, residual confounding, and inconsistency, except for NGT placement, which was supported by moderate evidence owing to a large, consistent effect and absence of heterogeneity.

Clinical implications

POI is a common complication post-RC that causes increased morbidity, hospital LOS, hospital costs, and decreased patient satisfaction. The inclusion of PAMORAs in an established ERAS pathway may reduce the burden of POI after RC in this vulnerable patient cohort. This study has shown that alvimopan accelerates gastrointestinal recovery, with limited published evidence to support the use of methylnaltrexone and naloxegol.

Alvimopan

There are three key barriers to the implementation of alvimopan in standard post-operative recovery protocols: cost, side effect profile, and limited evidence to suggest its efficacy in robotic-assisted surgeries. One of the most salient adverse effects of alvimopan is its previously documented association with increased cardiovascular adverse events (CV AE). This is documented in the 2013 FDA approval for alvimopan in RC patients and lies on the basis of increased association of myocardial infarction in patients with prolonged use of alvimopan (37). There is no reference to the clinical trial in the FDA document. It presumably relates to a phase 3 randomized trial by Irving et al. in 2008. This study demonstrated in a 12-month clinical trial that showed a greater incidence of myocardial infarction in alvimopan-treated patients (n=538) compared to placebo (n=267) in patients with chronic non-cancer pain, although a causal relationship was not established. 2.6% of patients treated with 12 months of alvimopan 0.5 mg BD in comparison to 1.12% for placebo patients suffered myocardial infarction (38). The only randomized study included in this review demonstrated that the overall incidence of CV AEs was 8.4% in the alvimopan group and 15.3% in the control group, which was similar to other studies in the colorectal cohort (11,39). This is the only published randomized trial of the usage of alvimopan in RC patients that suggests the FDA label of increased association of alvimopan with myocardial infarction may not be justified. Another factor that supports the use of alvimopan is its cost-effectiveness. Although economic analysis was not included in the review, studies have shown reduction in total costs associated with RC, ranging from USD $700–2,640 (12,40,41). Concerns regarding cost per capsule (~$60) may influence surgeons to trial other, cheaper PAMORAs, although their evidence base is less robust. There was inconsistent surgical approach across the included studies, which supports the evidence of alvimopan regardless of laparoscopic or robot-assisted surgical technique. A recent retrospective study has commented on the effectiveness of alvimopan in the robotic compared to the open approach (42). It suggests that alvimopan use provides less benefit in the RARC cohort; however, this is not substantiated on a randomized basis.

Methylnaltrexone

Only one study was identified that analysed the use of methylnaltrexone in this cohort (19). This yielded promising results, demonstrating a statistically significant reduction in LOS and reduced gastrointestinal complications. It reported a decrease in time to flatus and time to first bowel movement; however, these outcomes were not statistically significant. Authors hypothesized that methylnaltrexone, while not decreasing time to flatus consistently, decreased abdominal discomfort. Like alvimopan, methylnaltrexone demonstrated a large per-patient cost savings of $USD 10,575.51, which can be accounted for by the decreased LOS (19). The findings of this study should only be applicable in the robotic-assisted cohort, as there was no inclusion of open or laparoscopic-assisted approaches.

Naloxegol

No studies were identified that matched our PICO criteria (Population, Intervention, Comparison, and Outcome) for inclusion that compared naloxegol to a control group. Nevertheless, we identified a retrospective cohort study that compared the use of naloxegol to alvimopan that warrants discussion (43).

The Faraj et al. study (43) was not included in the pooled meta-analysis due to differing study design and comparison agents; however, it provides relevant contextual information (Table 4). In this study, outcomes were reported separately for patients receiving alvimopan and naloxegol. The median time to first bowel movement was 3 days [interquartile range (IQR), 2–3 days] in the alvimopan group and 2 days (IQR, 2–3 days) in the naloxegol group. The median LOS was 6 days (IQR, 5–7 days) for both treatment groups. The need for NGT insertion occurred in 18 of 278 patients (6.5%) receiving alvimopan and 7 of 57 patients (12.3%) receiving naloxegol. Readmission rates were 61 of 278 (21.9%) for alvimopan and 17 of 57 (29.8%) for naloxegol. Overall, both PAMORAs were associated with similar recovery timelines; however, the naloxegol group exhibited slightly higher rates of NGT insertion and readmission. These findings complement the meta-analysis results and underscore the consistent benefit of PAMORAs in facilitating postoperative bowel recovery. Further studies could be designed that randomize patients to either naloxegol or alvimopan that explore whether the cost benefits and more favourable safety profile of naloxegol are forfeited by its reduced efficacy in comparison to alvimopan.

Limitations

A key limitation of this study was the inclusion of 13 non-randomized studies, leading to an overall low certainty of evidence. Although the pooled analysis suggests improvements in bowel recovery outcomes with PAMORA use, these findings should be interpreted with caution until further randomized studies become available. Many of the studies had inconsistent reporting of key variables such as the dosing and frequency of PAMORA, diversion technique, and particular aspects of ERAS that were employed.

Substantial heterogeneity was observed for several outcomes. Potential contributors include differences in surgical approach, urinary diversion type, PAMORA dosing regimens, study period, and implementation of ERAS protocols. These factors were inconsistently reported across studies, limiting our ability to explore their contribution through subgroup analyses or meta-regression. Consequently, pooled estimates for these outcomes should be interpreted with caution.

Only three studies commented on the incidence of POI, with substantial variation between definitions and PAMORA type, limiting meaningful quantitative synthesis. Definitions varied from clinical criteria to radiographic evidence of ileus, administrative coding diagnosis or undefined measurements. We consequently relied on measures of gastrointestinal recovery (time to flatus, time to first bowel movement, NGT insertion) to assess response to PAMORA.

A second limitation of this meta-analysis is the reliance on reconstructed summary statistics for several included studies in which means and SDs were not directly reported. Although established methods [Hozo et al. and Wan et al. (30,32)] were used to approximate these values, such reconstructions introduce inherent uncertainty and rely on assumptions of normal data distribution. The use of reconstructed data may attenuate genuine variability between studies, leading to spuriously low heterogeneity estimates. While sensitivity analyses excluding studies with reconstructed data demonstrated stable pooled estimates, suggesting robustness of the main findings, there is still potential for underestimation of between-study heterogeneity.

A further limitation of this review is the potential confounding introduced by ERAS pathways. Several included studies compared cohorts from different time periods, including before and after the implementation of alvimopan and/or ERAS protocols. Consequently, improvements in postoperative bowel recovery may be attributable not only to PAMORA administration but also to concurrent changes in perioperative care, including reduced opioid exposure, early mobilization, early enteral feeding, multimodal analgesia, and other ERAS components. Furthermore, the content and degree of adherence to ERAS protocols were inconsistently reported across studies, limiting our ability to determine the independent effect of PAMORA therapy. Therefore, while PAMORA use was consistently associated with improved gastrointestinal recovery, causality cannot be confidently attributed to PAMORA use alone.

Conclusions

In summary, the use of PAMORAs has consistently demonstrated improved post-operative outcomes post-RC. PAMORAs have consistently shown decreased time to flatus and bowel movement and reduced in LOS. However, the certainty of the evidence remains low due to the predominance of non-randomized trials and heterogeneity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0432/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0432/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0432/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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