Methylnaltrexone Versus Naloxone for Opioid-Induced Constipation in the Medical Intensive Care Unit

Design

Single-center, retrospective chart review

N= 100

Objective

To assess the effectiveness and safety of enteral naloxone versus subcutaneous methylnaltrexone for treatment of opioid-induced constipation (OIC) in the medical intensive care unit (MICU)

Study Groups

Naloxone (n= 52)

Methylnaltrexone (n= 48)

Inclusion Criteria

Received ≥ 1 dose of naloxone or methylnaltrexone for OIC, age ≥ 18 years, admitted to the MICU, received continuous fentanyl infusion, had no bowel movements (BMs) ≥ 72 hours

Exclusion Criteria

Active colitis, mechanical gastrointestinal obstruction, surgical abdomen, inability to receive naloxone orally, receipt of both naloxone and methylnaltrexone at any point during the study time period

Methods

The choice of the opioid antagonist was prescribed at the physician's discretion as both agents were on the formulary list at the study institution. 

Duration

January 2013 to August 2014

Outcome Measures

Primary outcome: time to first BM

Second outcomes: number of doses until first BM; total number of BMs within 48 hours; opioid requirements after treatment; change in heart rates, mean arterial pressures, and level of sedation after treatment

Safety outcome: evidence of gastric residuals, bowel perforation, ileus, or obstruction

Cost analysis: time to first BM

Post hoc subgroup analysis: time to first BM, total number of BMs, and number of doses to produce first BM for patients on vasopressors

Baseline Characteristics

Naloxone (n= 52)

Methylnaltrexone (n= 48)

Median age, years (interquartile range [IQR])

Male

Medications prior to admission

Opioid agonists

Bowel regimen

Number of bowel regimen agents per patient

0

1

2

3

16 (31%)

36 (69%)

-

2 (4%)

13 (27%)

14 (27%)

16 (31%)

19 (40%)

35 (73%)

-

0

8 (15%)

15 (31%)

12 (25%)

0.405

0.656

-

0.496

0.219

0.665

0.656

Category of ICU admission

Respiratory

Sepsis

Neurological

Cardiovascular

Gastrointestinal

22 (42%)

18 (34%)

6 (12%)

6 (12%)

0

12 (25%)

16 (33%)

4 (8%)

12 (25%)

4 (8%)

0.091

0.892

0.743

0.117

0.05

On vasopressors

42 (80%)

36 (75%)

0.822

Mechanical ventilation

50 (96%)

44 (92%)

0.423

Median fentanyl dose, μg/hour (IQR)

Median fentanyl dose 2 hours before treatment (IQR)

100 (50 to 195)

135 (81 to 200)

138 (100 to 175)

125 (100 to 156)

0.12

-

Receiving enteral nutrition

28 (58%)

0.142

Median laboratory parameters 2 hours before treatment (IQR)

Mean arterial pressure

Heart rate

83 (72 to 97)

86 (75 to 96)

73 (69 to 84)

87 (74 to 100)

-

-

Median Richmond Agitation Sedation Scale (RASS) 2 hours before treatment (IQR)

-2.5 (-3 to -1)

-2 (-3 to -1)

-

Results

Endpoint

Naloxone (n= 52)

Methylnaltrexone (n= 48)

p-value

Median time to first BM, hours

Median time to first BM with vasopressors, hours

30

29

24

24

0.165

0.426

Median total number of BMs within 48 hours (IQR)

Median total number of BMs on vasopressors (IQR)

1 (0 to 2)

1 (0 to 3)

1 (0 to 2)

1 (0 to 2)

0.779

0.958

Median total dose to produce first BM, mg (IQR)

Median number of doses to produce first BM

4 (4 to 8)

5 (2 to 9)

8 (8 to 12)

1 (1 to 1)

-

-

Median fentanyl dose (IQR)

1 hour after treatment

4 hours after treatment

8 hours after treatment

24 hours after treatment

100 (50 to 169)

100 (50 to 169)

100 (50 to 169)

100 (50 to 169)

100 (75 to 150)

100 (75 to 150)

100 (70 to 150)

100 (44 to 150)

-

-

-

-

Median mean arterial pressures (IQR)

1 hour after treatment

4 hours after treatment

8 hours after treatment

24 hours after treatment

77 (69 to 87)

83 (75 to 92)

80 (75 to 90)

80 (71 to 90)

81 (74 to 88)

77 (70 to 84)

76 (71 to 83)

73 (71 to 83)

-

-

-

-

Median heart rate (IQR)

1 hour after treatment

4 hours after treatment

8 hours after treatment

24 hours after treatment

87 (74 to 100)

90 (75 to 100)

92 (75 to 101)

84 (75 to 91)

86 (67 to 102)

84 (66 to 97)

82 (71 to 93)

87 (67 to 89)

-

-

-

-

Median RASS (IQR)

1 hour after treatment

4 hours after treatment

8 hours after treatment

24 hours after treatment

-2 (-3 to -1)

-2 (-3 to -1)

-2 (-3 to -1)

-2.5 (-3 to -2)

-2 (-3 to -1)

-2 (-3 to -1)

-2 (-4 to 0)

-2 (-3 to -2)

-

-

-

-

The authors reported there were no significant differences in opioid requirements, vital signs, or RASS compared to baseline values.

At the time of this study, methylnaltrexone every 48 hours cost $120.00, while naloxone 1 mg 4 times a day and 2 mg 4 times a day cost $158.40/day (1 mg/mL prefilled syringe). Methylnaltrexone was significantly more cost-effective for producing 1 BM compared to naloxone ($120.00 vs $197.90, p= 0.001).

Adverse Events

Common Adverse Events: No adverse events associated with the use of naloxone or methylnaltrexone occurred.

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

The time to the first BM was not significantly different between naloxone and methylnaltrexone. Subcutaneous methylnaltrexone may be as effective in treating OIC in critically ill patients as compared with enteral naloxone. Both agents appear to be safe for the treatment of OIC in the MICU. Finally, in terms of medication shortages, this study highlights a cost-effective alternative and equally efficacious option for the treatment of OIC.

InpharmD Researcher Critique

Safety of Enteral Naloxone for the Reversal of Opiate-Induced Constipation in the Intensive Care Unit

Design

Single-center, retrospective chart review

N= 24

Objective

To assess the safety of enteral naloxone in the intensive care unit (ICU) for the treatment of opiate-induced constipation (OIC)

Study Groups

Patients receiving enteral naloxone (N= 24)

Inclusion Criteria

Patients receiving at least one dose of enteral naloxone and receiving opiates (continuous infusion or intermittent boluses) ≥ 48 hours prior to initial naloxone dose

Exclusion Criteria

Richmond Agitation Sedation Scale (RASS) score not utilized, pharmacologically paralyzed, medical record indicated extubation planned within the following 24 hours

Methods

Each injectable naloxone solution dose was administered enterally. The administration of enteral naloxone to patients with known cirrhosis, acute hepatitis, or portal hypertension was discouraged at this institution. Patients were followed until the naloxone or opiate was discontinued or for five consecutive naloxone doses, whichever occurred first. If no RASS score was available for a particular naloxone dose, the RASS score for the next scheduled naloxone dose was used for analysis.

Duration

4 months

Outcome Measures

Baseline Characteristics

Patients receiving enteral naloxone (N= 24) 

Age, years

Female

Admitting diagnosis

Myocardial infarction

Acute respiratory distress syndrome

Cardiogenic shock/heart failure

Cardiac arrest

5 (21%)

4 (17%)

3 (12%)

2 (8%) 

Liver function tests

Alanine aminotransferase, U/L

Aspartate aminotransferase, U/L

Total bilirubin, mg/dL

Direct bilirubin, mg/dL

425 ± 977

587 ± 1,684

1.8 ± 2.2

1 ± 1.5

Fentanyl use prior to initial naloxone dose

Dose, mcg/hour

Duration, hours

213 ± 110

128 ± 71

Naloxone dose, mg

Frequency every 8 hours

3.6 ± 0.9

23 (96%)

Results

Endpoint

Patients receiving enteral naloxone (N= 24)

p-value

Vital signs

Heart rate, beats per minute (n= 88)

Mean arterial pressure, mmHg (n= 88)

Respiratory rate, breaths per minute (n= 87)

92 ± 22

79 ± 16

22 ± 7

92 ± 23

80 ± 15

23 ± 9

0.99

0.598

0.259

Pain presence (n= 78)

RASS score (n= 88)

Medication dosing

Fentanyl, mcg/hour (n= 88)

Propofol, mg/hour (n= 26)

Midazolam, mg/hour (n= 49)

229 ± 164

164 ± 100

4.4 ± 3.5

232 ± 170

173 ± 96

4.2 ± 3.4

0.601

0.38

0.42

These results are based on measurements taken around each evaluable naloxone dose.

Adverse Events

Study Author Conclusions

These results demonstrate that the administration of enteral naloxone to patients on intravenous opiates in the ICU setting was not associated with changes in sedation score, vital signs, fentanyl dose, midazolam dose, or propofol dose. Naloxone should be considered with other opiate antagonists (e.g., methylnaltrexone) in analyses designed to assess the efficacy and safety of opiate antagonists for the treatment of opiate-induced constipation in the ICU.

InpharmD Researcher Critique

This study is limited by the inherent biases of a single-center, retrospective chart review and its small sample size. Based on the results, a mean enteral dose of 3.6 ± 0.9 mg enteral naloxone given every 8 hours can be administered safely with little changes in vital signs, RASS scores, and sedative dosing requirements.

Methylnaltrexone and Naloxone for Opioid-induced Constipation in the Critical Care Setting

Case report

A 52-year-old male with a past medical history significant for hypertension and type 2 diabetes reported to the emergency department after suffering a ground-level fall on his right hip. Patient was alert and oriented with a Glasgow Coma Scale of 15. Patient complained of severe pain, 10 on a scale of 10. Abdominal, lung and neurological exams were all normal. Patient's most recent bowel movement was the previous night. Blood pressure was 154/95, heart rate 108, respiratory rate 16, and O₂ saturation 85% with 4 L oxygen on nasal cannula. Patient was hyponatremic, hyperchloremic with metabolic acidosis, and no elevation in hepatic enzymes. Additionally, patient had an acute kidney injury with elevated creatinine and BUN, anemic with a hemoglobin of 8.5, and an INR of 1.3. Chest X-ray showed pulmonary congestion/edema with cardiomegaly. His right hip had suffered a nondisplaced femoral neck fracture. Patient was administered intravenous furosemide to control newly found congestive heart failure exacerbation, as well as heparin 5000 units every 8 hours. 

Patient was given 2 mg of morphine for intermediate pain and 4 mg of morphine for severe pain as needed Q4H, as well as a senna and docusate bowel regimen. Patient underwent total right hip arthroplasty seven days later. His pain was adequately managed throughout the rest of patient's stay with parenteral fentanyl and oral oxycodone as needed. Following surgery, however, he was no longer able to tolerate a regular carbohydrate diet, which resulted in nausea and vomiting. Patient felt bloating and had not had a bowel movement for 4 days after undergoing surgery. An X-ray revealed moderate colonic distension and he was given polyethylene glycol (17 g, two doses), senna (17.2 mg, three doses), senna-docusate (8.6-50 mg, three doses) orally, and two tap water enemas and bisacodyl (10 mg, one dose) rectally, none of which were effective. 

Patient was becoming nutrient-deprived and needed a one-time dose of vitamin K due to his INR increasing. He was determined to have opioid-induced constipation and was finally given 8 mg intravenous methylnaltrexone (MNTX). Three hours after MNTX patient had a large bowel movement and quickly experienced resolution of nausea, vomiting, and bloating. The authors noted he had been given 204 milliequivalents of morphine during his hospital admission. MNTX did not reverse the analgesic effect of opioids. Patient was discharged soon after to a rehabilitation facility. 

Opioid-induced constipation (OIC) is a common and often quickly resolving side effect of opioid use. However, in critically ill patients, it can progress insidiously. GI complications are on the more severe side of the spectrum and should be adequately managed. However, keeping a good balance between analgesia and the side effects of opioid administration is very crucial for patient satisfaction. Across the studies there seemed to be a consensus that MNTX an opioid antagonist which does not cross the blood-brain barrier would be a better cost-effective option. In our opinion, further good quality research is needed and should be directed towards the cost-effectiveness of administering opioid antagonists vs continuing with conventional laxation therapy for patients who are already being treated with opioids. The risks and benefits should also be assessed with regard to cost due to increased hospital stay and utilization of extra resources like imaging, staff, and cost of medications. MNTX can be a good first-line option for OIC in critically ill patients.

Methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients. Results from the MOTION trial

Design

Multi-center, double-blind, randomized placebo-controlled trial

N= 84

Objective

To test the efficacy of methylnaltrexone in relieving constipation in intensive care unit (ICU) patients whose sedative regimen included an opioid infusion

Study Groups

Methylnaltrexone (n= 41)

Placebo (n= 43)

Inclusion Criteria

Aged ≥ 18 years, ICU patients, mechanically ventilated and receiving opioids, constipated for ≥ 48 hours despite prior administration of regular laxatives, having already received at least one dose of laxative, scheduled to be enterally fed via nasogastric tube and to receive further opioid analgesics for at least 24 hours

Exclusion Criteria

Had diarrhea, undergone recent gastrointestinal tract surgery, signs of mechanical gastrointestinal obstruction or acute surgical abdomen, a history of inflammatory bowel disease, ileostomy or colostomy

Methods

Patients were randomized (1:1) to methylnaltrexone or placebo. Methylnaltrexone was dosed as follows: patients weighing 38–61 kg received 8 mg (0.4 mL) methylnaltrexone diluted in 50 mL of 0.9% saline; patients weighing 62–114 kg received 12 mg (0.6 mL) methylnaltrexone diluted in 50 mL of 0.9% saline. Placebo patients received saline. Drugs were infused over 15 min via an indwelling intravenous catheter. 

Patients were administered study drugs at the same time each day until the patient was free of opioids for 24 hours or at 28 days. If a patient in either group was unable to have a bowel movement within 72 hours of receiving the study drug, they were given rescue laxatives (combination of 5 mg sodium picosulfate and two 4 gm glycerin suppositories).

Primary endpoint of significant laxation was defined as a stool volume of > 100 mL, estimated by nurses. Secondary endpoint of tolerance of enteral feeds was defined by daily assessment of the percentage of patients achieving a full target of enteral feeding. 

Duration

Follow-up: 28 days

Outcome Measures

Primary: time to significant rescue-free laxation following randomization

Secondary: gastric residual volume every 4 hours and totaled over 24 hours, tolerance of enteral feeds, the requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, and sedation, incidence of ventilator-associated pneumonia, incidence of diarrhea and Clostridium difficile infection, 28 day ICU and hospital mortality

Baseline Characteristics

Methylnaltrexone (n= 41)

Placebo (n= 43)

Age, years

Male

Ethnicity

Caucasian

Asian

Black

24 (58.6%)

12 (29.3%)

3 (7.3%)

28 (71.8%)

9 (23.1%)

2 (5.1%)

Body mass index, kg/m² (Interquartile range [IQR])

Males

Females

24.5 (23.1 to 29.4)

25.4 (22 to 29.5) 

25.3 (22.7 to 27.7)

24.3 (22.7 to 34.8)

Reason for ICU admisssion:

Medical (non-operative)

Surgical, emergency (operative)

Surgical, elective (operative)

31 (75.6%)

10 (24.4%)

0

34 (79.1%)

6 (14%)

3 (7%)

Type of opioid at randomization

Fentanyl

Remifentanyl

Morphine

None

29 (70.7%)

9 (22%)

2 (4.9%)

1 (2.4%)

35 (81.4%)

8 (18.6%)

0

0

Results

Endpoint

Methylnaltrexone (n= 39)

Placebo (n= 43)

p-value

Rescue-free laxation within 96 hours

0.22 (hazard ratio 1.42, 95% confidence interval 0.82 to 2.46)

Gastric residual volume (IQR)

Full enteral feed achieved, proportion of patient days

Requirement for rescue laxatives (at least once)

Requirement for prokinetics (at least once)

Metoclopramide

Erythromycin

Median number of bowel movements per day (IQR)

Days 1-3

Days 4-28

0.67 (0 to 1)

1.38 (1 to 2)

0.67 (0 to 1.67)

2 (1.54 to 2.5)

0.58

0.01

Escalation of opioid dose

Fentanyl

< 100% increase

≥ 100% increase

Remifentanyl

< 100% increase

≥ 100% increase

0

3 (11.5%) 

1 (11.1%)

0

3 (9.1%)

0

1 (20%)

1 (20%)

Ventilator-associated pneumonia (Clinical Pulmonary Infection Score > 6)

Baseline

Day 1

Day 4

Day 7

11 (26.8%)

12 (30.8%)

13 (35.1%)

14 (48.3%) 

10 (23.3%)

9 (20.9%)

16 (37.2%)

14 (35.9%) 

N/A

Diarrhea (at least once)

Positive for Clostridium difficile infection

23 (59%)

3 (7.7%)

36 (83.7%)

7 (16.3%)

0.02

0.32

28 day ICU and hospital mortality

Adverse Events

Common Adverse Events: diarrhea (20.5% methylnaltrexone vs. 26.8% placebo), skin rash (2.6% vs. 0)

Serious Adverse Events: respiratory (5.1% vs. 0), cardiovascular/circulatory (0 vs. 7.7%), digestive (0 vs. 7.7%)

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

We found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients, however, the confidence interval was wide, and a clinically meaningful difference cannot be excluded.

InpharmD Researcher Critique

A possible reason no significant difference was seen between groups may have been due to a change in clinical practice to favor lighter levels of target sedation. As a result, daily sedation holds reduced the duration of opioid dosing, thus lessening the impact of opioids on constipation and diminishing the possible rescue effect of methylnaltrexone.