The Efficacy and Safety of Methylnaltrexone for the Treatment of Postoperative Ileus

Background

Postoperative ileus (POI) is a known complication of surgery resulting in increased perioperative morbidity, length of stay (LOS), and hospital costs. ¹ It represents the physiological arrest of gastrointestinal (GI) transit in response to surgical stress identified by the presence of nausea or vomiting, enteral intolerance, absence of flatus, and abdominal distention. ² Inhibition of GI motility is multifactorial, explained by neurogenic, hormonal, and inflammatory changes in addition to endogenous and exogenous opioids.^1,2 Current enhanced recovery after surgery (ERAS) protocols focus on limiting surgical stress and prevention of POI via early enteral nutrition, mobility, and removal of nasogastric tube (NGT) postoperatively, opioid-sparing multimodal analgesia regimens, systemic laxatives, and appropriate fluid management. ²

The peripherally acting mu-opioid receptor (PAM-OR) antagonists methylnaltrexone (MNTX) and alvimopan were designed to combat GI side effects of opioids while preserving analgesia. ³ Randomized controlled trials have evaluated the efficacy of these agents for prevention of POI when added to ERAS protocols. Phase II and III trials with MNTX showed conflicting results, while alvimopan shortened time to GI recovery, discharge eligibility, and hospital LOS.^4-6 Thus, alvimopan is the only PAM-OR antagonist FDA approved for acceleration of GI recovery following small or large bowel surgery with primary anastomosis. ⁷

While the literature provides recommendations for prevention of POI, studies focused on treatment strategies are lacking.^4,5,8,9 Current POI treatment is limited to bowel rest with nutrition support, decompression of the stomach with a NGT, and laxatives including suppositories and/or enemas. ¹⁰ The purpose of our study was to determine if methylnaltrexone, in addition to usual care, is safe and effective for the treatment of postoperative ileus.

Methods

A single-center, retrospective cohort study was conducted at an academic medical center. This study was approved by the Vanderbilt University Medical Center institutional review board (IRB #191936). Surgical patients admitted from January 1, 2018 through June 30, 2019, who were ≥18 years of age, and diagnosed with a POI based on ICD-10 codes were included in the analysis. Patients were excluded if diagnosed with a mechanical GI obstruction, acute colonic pseudo-obstruction, or GI malignancy or if they received alvimopan, as it is used to prevent POI after small or large bowel resections and may confound time to ileus resolution. The intervention group consisted of patients who received MNTX in addition to usual care for POI treatment. Usual care included bowel rest with nutrition support consisting of maintenance intravenous fluids or total parenteral nutrition (TPN), gastric decompression via a NGT tube, and suppositories and/or enemas.

The primary outcome was time to ileus resolution, defined as return of bowel function and tolerance of enteral nutrition. ⁶ Return of bowel function was defined as first documented bowel movement or ≥ 100 mL of ostomy output after surgery. Tolerance of enteral nutrition was defined as a patient receiving a diet or tube feeds, the absence of emesis for ≥24 hours, and no need for TPN. Secondary outcomes included hospital LOS, time with NGT in place, TPN requirement, and incidence of GI perforations.

Results

Two hundred one patients were identified. Ninety-one patients were excluded, primarily due to lack of data confirming an ileus, use of MNTX for a different indication, or the ileus was not associated with an operation. One hundred ten patients were included in the analysis: 82 patients in the control group and 28 patients in the treatment group (Figure 1).

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Figure 1.

Study population.

The baseline characteristics are described in Table 1.

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Table 1.

Baseline Demographics.

Baseline characteristic	Control group (n = 82)	MNTX group (n = 28)	P-value
Age (years)	59 ± 13.2	47.5 ± 17.4	<.001
Sex (females)	33 (40.2)	6 (21.4)	.07
Weight (kg)	88.9 ± 20.1	86.8 ± 17.3	.62
Duration of surgery (hours)	4.81 ± 2.5	4.07 ± 2.1	.17
Estimated blood loss (mL)	483 ± 1525	421 ± 759	.84
Time from surgery to ileus (days)	4.1 ± 3	3.48 ± 2	.32
Number of bowel regimen agents	4.3 ± 1.8	5.8 ± 1.7	<.001
Neostigmine	28 (34.2)	5 (17.9)	.10
Opioids	78 (95.1)	28 (100)	.23
Lidocaine infusion	44 (53.7)	15 (53.6)	.99
Milligram morphine equivalent	141.2 ± 308	130.8 ± 168	.86
Surgery type			<.001
Abdominopelvic	45 (54.9)	11 (39.3)
Ortho/spine	6 (7.3)	11 (39.3)
Cardiothoracic	30 (36.6)	4 (14.3)
Cranial	1 (1.2)	2 (7.1)

Patients who received MNTX were younger (47.5 ± 17.4 years vs 59 ± 13.2 years, P < .001) and received more bowel regimen agents (5.8 ± 1.7 vs 4.3 ± 1.8 medications, P < .001). Patients who underwent an orthopedic or neurosurgical procedure were more likely to receive MNTX compared to those who underwent abdominopelvic or cardiothoracic operations (P < .001). There was no difference in the percentage of patients who received neostigmine (34.2% vs 17.9%, P = .10) or lidocaine infusion for pain control (53.7% vs 53.6%, P = .99) in the control and MNTX group, respectively. For patients who received MNTX, the median time from surgery to the first dose of MNTX was 4.15 days (IQR 3.2-6.7). Eighty-nine percent of patients received a 12mg dose and 75% received a one-time dose of MNTX. The median time to first bowel movement after MNTX administration was 13.6 hours (IQR 3.7-22.5) (Table 2).

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Table 2.

Characteristics of Methylnaltrexone Administration.

Outcome	MNTX group (n = 28)
Time from surgery to MNTX dose (days)	4.15 (3.2-6.7)
12 mg MNTX dose received	25 (89)
Receive one-time dose	21 (75)
Time to bowel movement after MNTX dose (hours)	13.6 (3.7-22.5)

The primary outcome of time to resolution of ileus was 9.9 ± 6.8 for the MNTX group and 11.4 ± 8.1 days for the control group (P = .38) (Table 3). For the multivariate linear regression, there was no difference in time to resolution of ileus (P = .78). There was also no difference in duration of NGT (4.6 ± 4.2 days for MNTX vs 4.2 ± 6 days for control, P = .71), LOS (19.9 ± 13.6 days for MNTX vs 19.7 ± 21 days for control, P = .96), or percent of patients requiring TPN (17.9% for MNTX vs 22% for controls, P = .65). No GI perforations occurred in either group.

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Table 3.

Primary and Secondary Outcomes.

Outcomes	Control group (n = 82)	MNTX group (n = 28)	P-value
Time to ileus resolution (days)	11.4 ± 8.1	9.9 ± 6.8	.38
Time with nasogastric tube (days)	4.2 ± 6	4.6 ± 4.2	.71
Length of stay (days)	19.7 ± 21	19.9 ± 13.6	.96
TPN requirement (%)	18 (22)	5 (17.9)	.65

Discussion

Although MNTX has been studied in randomized and retrospective trials for prevention of POI, data for use as a treatment of POI are limited to a single retrospective study of 86 surgical patients comparing MNTX dosing regimens and time to first bowel movement.^4,5,8,9 In our single-center, retrospective cohort study, we compared the time to POI resolution in patients who received usual care vs those administered MNTX in addition to usual care for the treatment of POI. Time to resolution of ileus did not differ significantly for patients receiving MNTX.

Patients who received MNTX were younger and received more laxatives. Given that MNTX is considered last line for treatment of POI at our institution, it is not surprising more laxatives were used in this cohort. Patients in the MNTX group were also less likely to have undergone an abdominopelvic operation. This was expected due to case reports of bowel perforations with MNTX leading to cautious use of this medication in a patient with possible decreased integrity of the GI tract. In addition, some surgeons may consider opioids a less likely cause of POI after an abdominopelvic operation versus neurosurgical or orthopedic operations and conclude that MNTX may not be effective in these patients.

The median MNTX dose in our study was .14 mg/kg/dose, with 75% of patients only receiving 1 dose. Different dosing strategies have been reported in the literature with variations in dose, route, and frequency. In the study by Gathers et al, the median dose of subcutaneous MNTX for POI treatment was .15 mg/kg with 63% of patients receiving one-time doses. ⁸ They did not find a correlation between dose and efficacy. Two retrospective studies analyzing subcutaneous MNTX use for opioid-induced constipation (OIC) in critical care patients also used one-time doses, but 1 study administered .15 mg/kg/dose while the other study used the weight-based dosing algorithm described for OIC with advanced illness.^7,11,12 A randomized trial of subcutaneous MNTX vs standard care for OIC after orthopedic surgery administered a standardized dose of 12 mg daily for 4-7 days. ¹³ The randomized trials assessing MNTX for prevention of POI administered .3 mg/kg, 12 mg, or 24 mg intravenously every 6 hours.^4,5 Our institution’s computer order entry dosing advisor recommends the following weight-based dosing: 8 mg for a weight of ≤ 61 kg, 12 mg for a weight of 61-114 mg, and .15 mg/kg for a weight ≥115 kg. The institution restricts MNTX administration to the subcutaneous route. This explains the dosing and route used in our study. It is unknown if administering MNTX intravenously, more frequently, or for a longer duration would lead to faster resolution of POI.

The median time to first bowel movement after administration of MNTX was 13.6 hours (IQR 3.7-22.5). This is comparable to the 14.5 hours reported in a retrospective study describing the use of MNTX use for POI treatment. ⁸ Studies of MNTX use for postoperative and critical illness OIC report similar times to laxation (12-30 hours).^11-14 Our study adds to the evidence that MNTX can lead to laxation within 24 hours of administration.

There have been case reports of GI perforations associated with MNTX administration, but MNTX was found to be safe and well-tolerated in randomized and retrospective studies and case reports.^4,5,8,11-18 In our study, no GI perforations were observed. This addresses an important concern with use of this medication and sheds further light on its safety in this patient population

Our study has several limitations. This was a single-center retrospective study. Due to the retrospective design, data collection relied on chart review to determine ileus resolution. Prior MNTX and alvimopan studies defined tolerance of food by absence of nausea and vomiting within 1 to 4 hours after meal consumption.^4,6 Timing and quantity of enteral intake and nausea and vomiting are rarely documented accurately. Therefore, nutrition tolerance was defined as lack of emesis for ≥ 24 hours in our study. This may have caused longer times to ileus resolution in both cohorts. A prospective trial is warranted to better determine the role of MNTX for the treatment of postoperative ileus.

Conclusion

In this retrospective study, methylnaltrexone for treatment of postoperative ileus did not significantly reduce time to resolution. In addition, there was no impact on hospital length of stay, duration of nasogastric tube, or need for TPN. However, there were no GI perforations observed in either group, meaning that MNTX can be safely used in these patients. Prospective studies are needed to further elucidate the role of MNTX in the treatment of POI. To our knowledge, this is the first study comparing the use of methylnaltrexone for treatment of postoperative ileus to usual care.