Naloxegol to Prevent Lower Gastrointestinal Paralysis in Critically Ill Adults Administered Opioids

Among the more than 5 million adults who are admitted to the ICU each year in the USA, most
have pain and thus receive a pain (analgesic) medication called an opioid. Opioid use in
critically ill adults continues to increase given the greater awareness of untreated pain in
the ICU and that an opioid-first approach be used to optimize patient safety and comfort and
improve tolerance with breathing machines (i.e. mechanical ventilation). Similar to
constipation, paralysis of the lower gastrointestinal (GI) tract is defined as the inability
to pass stool due to impaired gut movement, and is a common effect of opioid use in the
critically ill. Lower GI tract paralysis may lead to nausea, vomiting, aspiration, compromise
the ability to administer tube feeds (enteral nutrition), an increase abdominal pain,
delirium and delay getting off mechanical ventilation. One recent randomized study found that
aggressive use of laxatives to prevent lower GI tract paralysis in critically ill adults was
associated with lower daily organ dysfunction [as measured by the Sequential Organ Failure
Assessment (SOFA) score]. The lower GI tract paralysis that occurs in the critically ill
often responds poorly to laxative medication therapy (e.g., senna, bisacodyl, lactulose).
While stool softener medications like docusate are routinely administered to patients on
opioids, laxative-based protocols are frequently not initiated in the ICU until signs of
lower GI tract paralysis start to appear. There is therefore an important and unmet need for
a safe and efficacious medication to prevent lower GI tract paralysis in critically ill
adults who are initiated on opioid therapy. Naloxegol (Movantik) is a naloxone-like drug that
blocks the effect of opioids on the opioid µ receptor in the gut but is not absorbed in the
brain (and therefore does not block the pain effects of opioids). Naloxegol is currently
approved by the Food and Drug Administration (FDA) for the treatment of opioid-induced
constipation (OIC) in non-ICU patients receiving scheduled moderate to high dose opioids for
the treatment of chronic non-cancer pain. Naloxegol has a mechanism of action, efficacy,
convenience of administration, and safety profile that make it an ideal candidate for use as
a preventative medication for lower GI tract paralysis in critically ill adults receiving
scheduled opioid therapy. The investigators propose a pilot study in which they will test the
hypothesis that naloxegol (versus placebo) will reduce the time to the first spontaneous
bowel movement (SBM) that an ICU patient has, that it will prevent lower GI tract paralysis
in critically ill adults initiated on scheduled IV opioid therapy, and its use will not
result in side effects that are concerning to doctors or patients. The investigators will
randomize 36 critically ill ICU patients (18 in each arm) to receive naloxegol [25mg or
12.5mg (in patients with a creatinine clearance ≤ 60ml/min)] or placebo. This pilot study
will provide valuable information to help guide future, larger studies evaluating the role of
naloxegol in critically ill adults.

Inclusion Criteria:

- Age ≥ 18 years

- Admitted to an ICU

- Expected to require admission to an ICU for ≥ 48 hours

- Intravenous opioid administration in the prior 24 hours of ≥ 100 mcg fentanyl
equivalents

Exclusion Criteria:

- Scheduled use of an opioid ≥ 10 mg morphine equivalents per day in the week prior to
ICU admission

- History of constipation (≤ 2 SBM per week and current use of stool softener or
laxative therapy) prior to ICU admission

- Current scheduled use of a medication affecting gastric motility

- Current use of a medication known to be a strong CYP3A4 inhibitor

- History of a neurologic condition that may affect the permeability of the blood-brain
barrier

- Acute GI condition (e.g., clinical evidence of acute fecal impaction/complete
obstruction, acute surgical abdomen, acute GI bleeding)

- Condition affecting GI motility or function (e.g. inflammatory bowel disease requiring
immunosuppressive therapy, symptomatic Clostridium difficile, active diverticular
disease, surgery on the colon or abdomen within 60 days of ICU admission)

- Current use of total parenteral nutrition

- Administration of enteral nutrition through a jejunal tube

- Severe hepatic dysfunction

- Endstage renal disease defined as either i. calculated creatinine clearance ≤ 10ml/min
or ii. Any current use of renal replacement therapy

- Inability to enroll in study and initiate study medication within 48 hours of the
patient begin first initiated on scheduled IV opioid therapy after ICU admission

- Unreliable method for enteral, gastric and/or oral medication administration (e.g., no
feeding tube, nasogastric tube is on suction)

- Current or previous use of an opioid antagonist agent (e.g., naloxegol,
methylnaltrexone) in the past 30 days

- Pregnant or actively lactating females

- Current participation in another interventional clinical study

- Inability to obtain informed consent