Alvimopan for Postoperative Ileus following Abdominal Surgery: A Systematic Review

doi:10.21203/rs.3.rs-4688035/v1

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Systematic Review

Alvimopan for Postoperative Ileus following Abdominal Surgery: A Systematic Review

https://doi.org/10.21203/rs.3.rs-4688035/v1

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Background

Postoperative ileus (POI) is a frequent complication of abdominal surgeries, prolonging hospital stays and increasing the risk of complications, leading to poorer patient outcomes. Alvimopan, a peripherally acting µ opioid antagonist, helps restore normal bowel function post-surgery. Although clinical trials have shown its benefits, definitive guidelines for its use are lacking, leading to its underutilisation in clinical practice.

Objective

This review evaluates the efficacy and safety of Alvimopan in reducing the risk of POI and shortening hospital stays for patients undergoing abdominal surgeries.

Methods

A comprehensive search of PubMed, Google Scholar, EMBASE, and the Cochrane Library was conducted. Studies were included based on the PICO framework, focusing on Alvimopan's impact on postoperative gastrointestinal recovery. Primary outcomes were time to gastrointestinal function recovery (GI-3) and hospital stay duration.

Results

Ten studies met the inclusion criteria, encompassing 18,822 patients undergoing various abdominal surgeries. Administration of Alvimopan 6 mg accelerated gastrointestinal function recovery by an average of 14 hours (Hazard ratio: 1.62, p = 0.002) and reduced hospital stays by 5.2 hours (Hazard ratio: 1.52, p = 0.04) compared to placebo. Similarly, Alvimopan 12 mg reduced GI-3 recovery time by 13.5 hours (Hazard ratio: 1.58, p = 0.02) and hospital stay duration by 6.2 hours (Hazard ratio: 1.46, p = 0.018).

Conclusion

Alvimopan shows promise in reducing POI and hospital stay durations following abdominal surgeries. Incorporating Alvimopan into perioperative care protocols could improve patient outcomes and reduce healthcare costs. Further research is needed to evaluate its effects on laparoscopic and other surgical procedures.

Alvimopan

Postoperative ileus

Laparotomy

Laparoscopy

Hysterectomy

Postoperative ileus (POI) presents an aberrant pattern of slow or absent gastrointestinal (GI) motility following abdominal surgery. Clinically, patients present with intolerance to oral intake and abdominal distention due to diminished GI propulsion [1][2][3]. POI is acknowledged as a common physiological reaction of the intestines to the trauma caused by surgery [4]. Despite this recognition, the contention lies in determining when POI transitions from 'normal physiological response' to prolonged and therefore likely pathological. The duration of normal physiological ileus post operatively typically ranges from 1 to 7 days, with an average of 3.9 days and a median of 4 days. Generally, in clinical practice, POI is deemed pathological, and treatment commences after 72 hours [2].

Extended duration of ileus can result in several significant obstacles, such as prolonged hospitalisation, increased healthcare expenditures and patient discomfort. The ramifications of POI can be severe, given its induction of GI stasis, posing risks of nausea and vomiting, which could escalate into pulmonary aspiration, a potentially life-threatening complication [11]. Additionally, POI may precipitate dehydration, electrolyte imbalances, or even sepsis which can extend hospital stays even further. The incidence of POI is estimated to range between 10% and 50% for abdominal surgeries [5][6][7]. Furthermore, the mortality rate attributable to POI ranges from 13–86%, contributing to 9–43% of all post-small intestinal surgery fatalities [8][9][10].

Although operative manipulation is conventionally implicated in causing ileus, the precise mechanism leading to prolonged ileus are multifaceted. These underlying mechanisms can be categorised broadly into three groups: neurogenic, inflammatory, and pharmacologic [12]. The autonomic nervous system assumes a pivotal role in GI motility, with the parasympathetic system stimulating motility and the sympathetic system inhibiting it. Increased sympathetic stimulation contributes to the inhibition of GI motility post-surgery. POI is more likely to ensue following prolonged major surgical procedures and general anaesthesia involving extensive GI manipulation or disruption. Moreover, postoperative pain medications, particularly opioids, exacerbate or instigate POI due to their well-documented inhibitory effect on gut motility [12].

Recent recommendations for perioperative management, initially proposed by the Enhanced recovery after surgery (ERAS) group [13] and subsequently endorsed by the Francophone Group for enhanced recovery after surgery (GRACE) Association [14], have led to a notable reduction in hospital stays and morbidity, as well as a decrease in the time to resumption of transit [15] [16] [17] [18]. ERAS management protocols encompass preoperative, intraoperative, and postoperative measures. Preoperatively, these protocols include patient education, administration of sweetened oral liquids, avoidance of routine anxiolytic premedication, and a shortened preoperative fasting period. Intraoperative strategies prioritise a laparoscopic approach, avoidance of bladder, gastric, and abdominal drains, optimal fluid replacement guided by appropriate monitoring, avoidance of long-acting opioids, and proactive measures to address hypothermia, nausea, and vomiting. Postoperatively, measures involve the immediate removal of the nasogastric tube, early initiation of feeding, implementation of a multimodal analgesic regimen, early mobilisation, removal of the bladder catheter on day 1, restriction of postoperative intravenous fluids, thromboprophylaxis, stimulation of digestion through gum chewing and carbohydrate loading [19][20]. The overarching goal of enhanced recovery programs is to mitigate perioperative stress with the aim of expediting the restoration of patient autonomy.

Despite the aforementioned pre-, peri- and post- ERAS management protocols post-operative ileus remains a common post-operative complication. As such, a better targeted approach is necessary to improve patient outcomes and reduce hospital stays. Alvimopan, an antagonist of the µ opioid receptor, has been subject to multiple evaluations of its efficacy, including in randomised trials. Mechanistically, it primarily targets phase 1 of ileus by counteracting the muscle relaxant effects of opioids. Unlike other opioid antagonists. As demonstrated in clinical trials, Alvimopan can be taken orally and has a potent and prolonged action. Most importantly, Alvimopan reverses opioid-induced inhibition of GI motility without compromising the analgesic effects of opioids; due to not easily penetrate the blood-brain barrier [24][25]. Therefore Alvimopan is particularly useful in patients at risk of post op ileus due to receiving analgesic doses of morphine [34]. These findings were echoed in a further exploratory study involving 78 abdominal surgery patients, Alvimopan was found to expedite the recovery of bowel function and reduce hospitalisation duration without compromising patient-controlled analgesia [31].

A meta-analysis conducted in 2012 affirmed the benefits of Alvimopan in reducing POI, though it remarked that this advantageous effect had not been conclusively established for laparoscopic surgery [23]. Subsequent to this meta-analysis, additional clinical trials, incorporating patients undergoing laparoscopic surgery have been conducted. In this review our objective is to reassess the efficacy of Alvimopan, incorporating findings from these new trials, potentially shedding further light on the beneficial impact of its clinical utilisation.

2.1 Research question

This study aimed to investigate whether Alvimopan has a direct effect on reducing the risk of post-operative ileus (POI) and hospital stay in patients following abdominal surgery. To quantify these effects, the time for patient to pass first flatus or a bowel movement and time to readiness for hospital discharge were analysed.

2.2 Search Strategy

A systemic literature search was undertaken using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [26] for studies on Alvimopan’s effects on post-op GI recovery. The following databases were searched: PubMed, Google Scholar, EMBASE, and the Cochrane Library. Potentially relevant studies were selected based on title and abstract. The specific search included Alvimopan and ADL 8-2698, terms related to post-op ileus (like post-op bowel obstruction), and terms related to abdominal surgery using a controlled vocabulary (MeSH Terms) for precise results. The search was limited to articles about human subjects and in the English language. The search was not limited to a specific publication timeframe.

2.3 Eligibility Criteria and Selection

The reviewers independently carried out searches, using titles and abstracts to exclude irrelevant publications and collate a list of those requiring full-text evaluation. We used PICO to set the inclusion criteria:

Population

Human participants above the age of 18 and undergoing major abdominal operation.

Intervention

Alvimopan given orally at least 2 hours before surgery and twice daily thereafter.

Comparison

Placebo or patients that were not given Alvimopan.

Outcome

Time to recovery of GI function (GI-3), as defined by either time patient first tolerated solid food, first passed flatus or had a bowel movement. A secondary outcome was time to readiness for hospital discharge based solely on recovery of GI function.

A total of 1826 articles were found in the primary search from the four electronic databases. Duplicates (n = 518) and non-original research articles (n = 1035) were identified automatically using Rayyan systemic review tool and were excluded. Titles and abstracts were searched independently. If they did not provide enough information, the full text was reviewed to check if inclusion criteria were met. Non-original research articles (e.g., reviews, editorials, case reports) and qualitative studies were excluded. Trials on patients undergoing non-abdominal operations were excluded. After a full-text review, another 113 studies were excluded as desired population (post-op patients) was not assessed and 3 were excluded as they did not measure time to GI recovery. After the independent search, any discrepancies between the two searches were resolved by discussion regarding the included/excluded papers.

Overall, 10 studies [29–38] met all the inclusion criteria which were critically appraised by two independent reviewers using CASP checklist for systemic review [28]. Reviewers extracted data from each acquired full-text manuscript. Data from the included studies were independently standardised. Patient characteristics included age, gender, comorbidities, type of abdominal operation performed and opioid analgesic use. Study characteristics included authors, year of publication, type of study, sample size, Alvimopan dose and duration and the measured outcomes as illustrated in Table 1.

2.4 Data analysis

Data from the included studies were pooled and analysed. The studies used Cox proportional hazard model to analyse time to recovery of GI function and time to readiness for hospital discharge based solely on recovery of GI function. P-values for comparisons between Alvimopan and placebo were calculated using the Wald chi-squared test. The mean times to all events were estimated using area under the Kaplan-Meier cumulative curves. Mean differences among treatment arms with 95% confidence intervals (measured in hours) were used to express the magnitude of treatment effect.

Recovery of GI function, the primary end point, was significantly accelerated in patients who received both Alvimopan 6 mg and 12mg compared with placebo in all of the studies collectively. Table 2 and Table 3 summarises the overall results from the 10 papers. Administration of Alvimopan 6 mg accelerated gastrointestinal function recovery by an average of 14 hours (Hazard ratio: 1.62, p = 0.002) and reduced hospital stays by 5.2 hours (Hazard ratio: 1.52, p = 0.04) compared to placebo. Similarly, Alvimopan 12 mg reduced GI-3 recovery time by 13.5 hours (Hazard ratio: 1.58, p = 0.02) and hospital stay duration by 6.2 hours (Hazard ratio: 1.46, p = 0.018).

The 10 studies included in this systemic review looked at the effect of Alvimopan on the risk of POI. This was tested among patients undergoing either small or large bowel resection (including laparotomy or laparoscopy), radical abdominal hysterectomy, or simple total abdominal hysterectomy. All studies were measuring the same outcomes, mainly focusing on time function (GI-3), as defined by time to first passed flatus or a bowel movement, and time to readiness for hospital discharge.

In this review, 7 studies were randomised control trials and 3 were retrospective analysis. In total, 18,822 patients were included; 747 had simple total abdominal hysterectomy, 160 underwent radical hysterectomy, and 17,915 had bowel resection. In 7 studies, the efficacy of Alvimopan 6mg and 12mg were compared to placebo. 1 study compared the efficacy of 6mg and 1mg of Alvimopan. 2 studies [37–38] did not specify the dose of Alvimopan. In total, Alvimopan 6mg and 12mg were tested in 2379 patients. In all studies Alvimopan was given orally at least 2 hours before surgery and twice daily thereafter until discharge, at which some patients stopped at 7 days and others continued until GI recovery.

4.1 Efficacy of 6mg and 12mg Alvimopan for improving GI3 and duration of hospital stay

As per Table 3, after calculating the mean time among all data from the studies, Alvimopan 6mg significantly accelerated GI-3 recovery by a mean of 14 hours compared to placebo (Hazard ratio; 1.62, p-value = 0.002). Alvimopan 12mg also showed a similar effect with a 13.5 hours faster GI-3 recovery (hazard ratio; 1.58, p-value = 0.02). By this measure, both of these doses accelerated GI recovery by approximately 15%.

Looking at time for hospital discharge, the group of patients receiving Alvimopan 12mg had a mean of 105 hours (hazard ratio; 1.46, p-value = 0.018) of length of stay in hospital. This was quicker from the control group by 6.2 hours. Again, Alvimopan 6mg exhibited similar effect to Alvimopan 12mg, both compared to placebo, with 106 hours to hospital discharge (hazard ratio; 1.52, p-value = 0.04). Therefore, both doses reducing length of hospital stay by approximately 5.1% compared to placebo.

There remains a pressing medical need to effectively manage POI, a prevalent and potentially severe condition post abdominal and pelvic surgery. Across all 10 studies examined, there was a notable decrease in time to GI-3 recovery and duration of hospitalisation observed in patients taking Alvimopan after undergoing both open and laparoscopic abdominal procedures. Despite promising outcomes from Alvimopan trials and its availability on the market, its utilisation in peri-operative care remains limited. Rapid resolution of POI offers numerous benefits, including reduced risk of bowel complications, expedited return to normal bowel function, improved patient comfort, shorter hospital stays, and lowered healthcare costs [21].

The mechanism by which Alvimopan accelerates the recovery of GI function is due to its antagonistic effect on opioid receptors [40]. Opioids are widely used for managing intraoperative and postoperative pain. While effective as pain relievers, opioids elevate GI tone and intraluminal pressure while inhibiting organised propulsive motility [39]. As such, use of opioid receptors post operatively, increases the risk of occurrence and duration POI. The adverse effects of opioid use post operatively are evident with both epidural and parenteral administration [39]. It is important to note that Alvimopan differs from other opioid-receptor antagonists due to its limited penetration through the blood–brain barrier which does not hamper the analgesic on patients [24]. Consequently, administering large doses of Alvimopan holds the potential to nearly entirely counteract GI opioid receptors without impeding the beneficial analgesic effects of systemic opioids [25].

The findings of this systemic review highlight the crucial role for GI opioid receptors in POI recovery, as patients receiving Alvimopan demonstrated an earlier restoration of GI function compared to those given a placebo. All of the included studies collected evidence for pain scores and daily consumption of opioids. In patient groups among all 10 studies [29–38], mean opioid consumption and pain scores were highest on the day of surgery and decreased until hospital discharge. Both parameters remained low during the at-home portion of the study, with no significant change in patients receiving Alvimopan.

There has been ongoing debate across studies regarding the optimal dosage of Alvimopan. While both the 6mg and 12mg doses exhibited significant acceleration in recovery, some studies favoured the 6mg group while others leaned towards the 12mg group. However, our analysis suggests that the rate of improvement in time to GI-3 recovery and time to discharge was similar in both dosage groups, and significantly lower compared to the placebo group. Nevertheless, when considering the incidence of reported adverse events, it was generally observed that the occurrence of nausea and vomiting was lower in the Alvimopan 12mg group compared to both the Alvimopan 6mg and placebo groups. Conversely, other common side effects, such as pain, hypotension and pyrexia were reported at similar rates among all three groups of patients. Furthermore, when examining the rate of patient withdrawal from trials due to these side effects, it was noted that the rates were consistent across all studies except one [29]. In this particular study, more patients discontinued treatment in the Alvimopan 12mg group compared to the placebo group; however, this difference was not statistically significant. Therefore, based on these findings, we recommend the use of Alvimopan 12mg due to its reduced incidence of nausea and vomiting, coupled with a comparable outcome and safety profile to Alvimopan 6mg.

4.2 Financial implications

Another important benefit of Alvimopan is cost reduction and effectiveness on healthcare systems. A similar review of the trials compared the cost of administering Alvimopan against a longer hospital stay without administering Alvimopan [22]. It was shown that the average cost of Alvimopan, based on an average of 8.9 doses at 12 mg each, was $558.00. At the maximum allowed dosage of 15 doses, the cost of Alvimopan was $937.50. Calculations using a cost of $62.50 per 12 mg dose indicated that the total expenses for the Alvimopan group were projected to be lower than those for the placebo group, regardless of the cost data source [22]. When utilising database cost estimates, the estimated overall cost was $879 less for patients who received Alvimopan ($14,798) compared to those who received the placebo ($15,677) (p < 0.05) [22]. According to United States Census Bureau cost estimates, total hospital costs were $977 less for Alvimopan recipients ($11,329) than for placebo recipients ($12,306) (p < 0.05) [41]. The base-case and sensitivity analyses suggested that, on average, the use of Alvimopan compared with placebo may have a cost-saving effect in the hospital setting.

4.3 Limitations

This review identified several limitations. Firstly, there was heterogeneity in study designs, with a mix of randomised controlled trials and retrospective analyses, potentially leading to methodological variations. Additionally, trials evaluating Alvimopan after laparoscopy were exclusively retrospective analyses [36–38], unlike those conducted for open (laparotomy) operations. Secondly, it was not possible to compare the beneficial effect of Alvimopan across different surgical procedures (i.e. radical abdominal hysterectomy, simple abdominal hysterectomy or bowel resection), as the data did not stratify patients based on the type of surgery they underwent. As such, it is unclear whether Alvimopan will have more enhanced recovery effects in specific operations compared to others therefore limiting the generalisability of the findings. Thirdly, the majority of studies which assessed short-term outcomes related to GI function recovery and hospital discharge, neglected longer-term effects such as POI recurrence or post-discharge complications. Fourthly, publication bias might exist, favouring the publication of studies reporting positive outcomes over those with neutral or negative results, potentially skewing the overall assessment of the efficacy and safety of Alvimopan. Finally, despite attempts to control for confounding variables, factors such as concomitant medication usage, surgical techniques, and patient comorbidities may have influenced outcomes.

It is also crucial to highlight that all operations included in the data were conducted under general anaesthesia. This is significant because general anaesthesia serves as an inevitable risk factor for developing POI [42]. The specific percentage by which general anaesthesia increases the risk of post-operative ileus can vary widely based on several factors, including the type of surgery, patient characteristics, and the specific anaesthetic and analgesic protocols used [27]. However, studies have shown that the incidence of POI can be significantly higher in patients undergoing major abdominal surgeries under general anaesthesia compared to those using other forms of anaesthesia, such as regional anaesthesia [42]. As demonstrated by the included studies, recovery from POI after major abdominal surgeries, using Alvimopan, was accelerated regardless of general anaesthesia.

Future research could delve into conducting prospective clinical trials specifically targeting patients who have undergone laparoscopic operations, as the current evidence predominantly stems from retrospective analyses. By adopting a prospective approach, researchers can meticulously design studies with predefined protocols, standardized outcome measures, rigorous methodologies, thereby enhancing the robustness and reliability of the findings. There is also the potential to standardise the dosage of Alvimopan in order to optimise its effectiveness in alleviating POI. Future studies may seek to elucidate the optimal duration of Alvimopan treatment postoperatively. While existing trials have typically employed a standard duration of 7 days of treatment or until the achievement of the desired outcome, shorter or longer durations could be explored to ascertain the most effective and efficient treatment strategy. By systematically varying the treatment duration and assessing its impact on POI resolution, researchers can provide valuable insights into the optimal duration of Alvimopan therapy, thereby informing clinical practice guidelines and optimising patient care.

The findings from this systematic review underscore the significant potential of Alvimopan in accelerating the recovery of gastrointestinal function (GI-3) and reducing hospital stay for patients undergoing abdominal surgeries. The evidence suggests that Alvimopan, administered orally either at 6mg or 12mg doses, consistently leads to earlier GI-3 recovery and shorter hospitalisation durations compared to placebo with similar safety profiles. These benefits extend beyond mere symptomatic relief, potentially reducing the risk of complications and improving overall clinical outcomes. The incorporation of Alvimopan into prophylactic care perioperatively has the potential to enhance patient outcomes, reduce healthcare costs, and improve the efficiency of healthcare delivery. By continuing to explore and refine its use, clinicians can further optimise patient care and contribute to the advancement of surgical practice.

Table 1

Details of the included studies
	Study design	Sample Size	Operations performed	Medications given
Taguchi A, 2001 [31]	Randomised control trial	78	• Laparotomy: partial large bowel resection • Simple abdominal hysterectomy • Radical abdominal hysterectomy	Placebo Alvimopan 1mg Alvimopan 6mg
Wolff BG, 2004 [30]	Randomised control trial	469	• Laparotomy: partial small or large bowel resection • Radical abdominal hysterectomy	Placebo Alvimopan 6mg Alvimopan 12mg
Delaney CP, 2005 [29]	Randomised control trial	432	• Laparotomy: partial large bowel resection • Simple abdominal hysterectomy • Radical abdominal hysterectomy	Placebo Alvimopan 6mg Alvimopan 12mg
Viscusi ER, 2005 [33]	Randomised control trial	615	• Laparotomy: partial small or large bowel resection • Simple abdominal hysterectomy • Radical abdominal hysterectomy	Placebo Alvimopan 6mg Alvimopan 12mg
Herzog TJ, 2005 [32]	Randomised control trial	519	• Simple Abdominal hysterectomy	Placebo Alvimopan 12mg
Buchler MW, 2008 [34]	Randomised control trial	738	• Laparotomy: partial small or large bowel resection • Radical abdominal hysterectomy	Placebo Alvimopan 6mg Alvimopan 12mg
Ludwig K, 2008 [35]	Randomised control trial	629	• Laparotomy: partial small or large bowel resection	Placebo Alvimopan 12mg
Obokhare ID, 2011 [38]	Retrospective analysis	200	• Laparoscopic: partial large bowel resection	Placebo Alvimopan 12mg
Harbaugh CM, 2013 [36]	Retrospective analysis	2415	• Laparotomy: partial large bowel resection • Laparotomy: ileocolic resection • Laparoscopic: partial large bowel resection • Laparoscopic: ileocolic resection	Placebo Alvimopan ^a
Henning RE, 2019 [37]	Retrospective analysis	12,727	• Laparotomy: partial large bowel resection • Laparoscopic: partial large bowel resection	Placebo Alvimopan ^a

^a Dose of Alvimopan used was not specified in this study.

Table 2. Patient demographics

	Placebo	Alvimopan 6mg	Alvimopan 12mg
Mean Age (range, yr)	58.1 (20-88)	57.5 (19-88)	59.7 (20-93)
Gender (Male/female)	5081/7372	357/423	545/1054
BMI, kg/m² (mean)	28.5 (16.8-67)	26.8 (16.5-50.9)	27.9 (13.7-47.5)
Bowel resection ^a	12,209	642	1073
Simple total hysterectomy	187	83	478
Radical hysterectomy	57	55	48

Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).

^aBowel resection included laparotomy; partial colectomy with primary anastomosis, excluding low anterior resection

Table 3. Efficacy of Alvimopan in expediting GI-3 and hospital discharge

	Placebo	Alvimopan 6mg	Alvimopan 12mg
Number of patients	12,553	780	1599
Mean time to GI-3 (hours)	95.1	81.1	81.6
Hazard ratio (95% Confidence Interval)	-	1.62 (0.98, 4.7)	1.58 (0.99, 2.34)
P-value	-	0.002	0.020
Mean time to hospital discharge	111.2	106.0	105.0
Hazard ratio	-	1.52 (0.98, 1.9)	1.46 (0.92, 1.79)
P-value	-	0.040	0.018

Author Contribution

Authors contribution:Ahmed Ali Kayyale and Salman Ghani: have contributed equally to the conception and design of the work; the acquisition, systematic literature search, data extraction and analysis, and the interpretation of data. Both drafted the work and revised it critically for important intellectual content. Oluwatito Olaniyan have contributed to the conception of the review and third independent blind systematic literature search. Discrepancies regarding the included studies after the systematic literature search was resolved after a meeting between the authors

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No competing interests reported.

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Editorial decision: Revision requested
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Alvimopan for Postoperative Ileus following Abdominal Surgery: A Systematic Review

Status:

Version 1

Abstract

Background

Objective

Methods

Results

Conclusion

1. INTRODUCTION AND BACKGROUND

2. METHODS

2.1 Research question

2.2 Search Strategy

2.3 Eligibility Criteria and Selection

2.4 Data analysis

3. RESULTS

4. DISCUSSION

4.1 Efficacy of 6mg and 12mg Alvimopan for improving GI3 and duration of hospital stay

4.2 Financial implications

4.3 Limitations

CONCLUSION

Declarations

Author Contribution

References

Additional Declarations

Status:

Version 1