The Effect of Naloxegol on Refractory Constipation in the Intensive Care Unit

Constipation is often defined as the absence of a bowel movement for 3 consecutive days. The
incidence of constipation in critically ill patients is estimated to be 50-80%. Constipation
in the ICU is associated with various undesirable clinical outcomes, including: increased
rate of infections, prolonged duration of mechanical ventilation, greater hospital length of
stay, worsening of organ dysfunction, and even higher mortality.

Typical first-line agents for the management of ICU constipation include stool softeners
(e.g. docusate) and bowel stimulants (e.g. senna glycol or bisacodyl), and these are often
used prophylactically in critically ill patients. However, a significant proportion of
patients require additional therapy to promote laxation , the most common being osmotic
agents such as propylene glycol or lactulose. Often, multiple doses of osmotic agents over
several days are required to achieve acceptable laxation rates during critical illness. As
such, this has prompted the need for targeted therapy to improve constipation in the ICU.

Among major risk factors for constipation in the ICU are the lack of bowel stimulation via
nutrition and exposure to high doses of continuous opioids . Indeed, clinical data suggests
that early enteral nutrition promotes laxation in ICU patients. And recently,
methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, has shown promising
results in its ability to reverse opioid-induced constipation. However, methylnaltrexone is
delivered via subcutaneous injection and its absorption is likely to be variable in
critically ill patients who often receive aggressive fluid resuscitation and have
significant peripheral edema. The US Food and Drug Administration recently approved the use
of naloxegol, a μ-opioid receptor antagonist available in tablet form, for the management of
opioid-induced constipation in non-cancer chronic pain patients.

Inclusion Criteria:

1. Age ≥18 years

2. Admitted to an ICU at Massachusetts General Hospital (MGH)

3. Received ≥72 hours of continuous opioid infusion

4. Anticipated to require ≥48 hours of additional care in the ICU

5. Did not have a bowel movement in ≥72 hours

6. Allowed to receive (and tolerating) medications via nasogastric, orogastric, gastric,
gastrojejunal, or oral route

7. Receiving at least trophic (10 mL/hr) of enteral nutrition

Exclusion Criteria:

1. Unable to provide informed consent or unavailable healthcare proxy

2. Not expected to survive >48 hours from time of enrollment

3. "Comfort measures only" status (i.e. palliative care)

4. Received medication other that docusate and senna glycoside for laxation

5. Had abdominal surgery that is expected to cause significant ileus

6. Mechanical bowel obstruction

7. Total bowel rest/exclusively receiving total parenteral nutrition

8. History of chronic constipation unrelated to opioid use

9. Compromised blood-brain-barrier

10. Current diagnosis of solid organ or hematologic cancer

11. On moderate/strong CYP3A4 inhibitors or strong CYP3A4 inducers

12. On other opioid antagonists

13. Pregnant or lactating females