Naloxegol is a peripherally acting opioid antagonist which is used to treat constipation caused by chronic opioid use. Naloxegol has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury.
Naloxegol (nal ox' ee gol) is a pegylated, semisynthetic opiate receptor antagonist which is similar structurally to naltrexone, but is peripherally restricted and thus has few if any effects on the central nervous system. Naloxegol is a polyethylene glycol (PEG) derivative of alpha-naloxol, an opiate antagonist. The addition of the large PEG molecule to naloxol does not block its engagement with opioid receptors, but does prevent the drug from crossing the blood brain barrier. As a consequence, the opioid antagonist reverses the peripheral but not the central nervous system effects of opiates, such as pain relief and euphoria. In large, preregistration trials, naloxegol was found to increase spontaneous bowel movement frequency and reduce constipation related side effects of opiates used for analgesia in patients with chronic pain. Naloxegol was approved for use in the United States in 2014 and is available as tablets of 12.5 and 25 mg under the brand name Movantik. The recommended dosage is 25 mg once daily, reducing the dose to 12.5 mg daily for intolerance. Side effects include abdominal pain, diarrhea, nausea, flatulence, anxiety, restlessness and sweating. Withdrawal symptoms can occur, but are rare. In persons not taking opioids, naloxegol has minimal effects on constipation.
Therapy with naloxegol has not been linked to serum enzyme elevations or to clinically apparent liver injury. In preregistration studies, liver test abnormalities arose in less than 1% of treated patients but were transient, mild and not associated with symptoms. There were no reported cases of liver injury with jaundice or symptoms. Since its approval and more widescale use, there have been no published reports of hepatotoxicity attributed to naloxegol.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism by which naloxegol might cause liver injury is not known. Naloxegol is extensively metabolized in the liver, largely by CYP 3A4 and it is susceptible to drug-drug interactions with agents that induce or inhibition CYP 3A activity. Most opioid-antagonists appear to have little intrinsic hepatotoxicity.
REPRESENTATIVE TRADE NAMES
Naloxegol – Movantik®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 20 April 2017
Zimmerman HJ. Narcotic analgesics. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 710-11. (Expert review of hepatotoxicity published in 1999; mentions that trials of naltrexone have reported serum aminotransferase elevations in up to 30% of recipients, an effect that appeared to be partially dose dependent; naloxegol not discussed).
Larrey D, Ripault MP. Illegal and recreational compounds. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 456-7. (Review of hepatotoxicity discusses buprenorphine, an orally available morphine analogue, which has been linked to cases of severe acute liver injury, usually as a result of intravenous administration; naloxegol not discussed).
Yaksh TL, Wallace MS. Opioids, analgesia, and pain management. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 481-525. (Textbook of pharmacology and therapeutics).
Webster L, Dhar S, Eldon M, Masuoka L, Lappalainen J, Sostek M. A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. Pain 2013; 154: 1542-50. PubMed Citation (Among 207 patients with opioid-use related constipation treated with naloxegol [5, 25 or 50 mg once daily] or placebo for 4 weeks, spontaneous bowel movements increased with higher doses of naloxegol, while side effects included abdominal pain, diarrhea and nausea, but there were “no clinically relevant changes in serum chemistry”).
Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014; 370: 2387-96. PubMed Citation (Among 1362 patients with opioid induced constipation treated in two controlled trials with naloxegol [12.5 or 25 mg daily] or placebo, spontaneous bowel movements were more frequent with naloxegol, particularly with a 25 mg dose, and adverse events were largely mild gastrointestinal intolerance without change in pain scores or opioid dose; no mention of ALT elevations or hepatotoxicity, but there were no liver related serious adverse events).
Webster L, Chey WD, Tack J, Lappalainen J, Diva U, Sostek M. Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation. Aliment Pharmacol Ther 2014; 40: 771-9. PubMed Citation (Among 804 patients with opioid induced constipation treated with naloxegol [25 mg daily] or placebo for 52 weeks, adverse events that were more frequent with naloxegol included abdominal pain [18% vs 3%], diarrhea [13% vs 6%], nausea [9% vs 4%], headache [9% vs 5%], and flatulence [7% vs 1%]; no mention of ALT elevations or hepatotoxicity).
Leonard J, Baker DE. Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother 2015; 49: 360-5. PubMed Citation (Review of the pharmacology, clinically efficacy and safety of naloxegol; discusses common mild gastrointestinal side events and lack of evidence for increase in cardiovascular complications or withdrawal symptoms with naloxegol; no mention of ALT elevations or hepatotoxicity).
Naloxegol (Movantik) for opioid-induced constipation. Med Lett Drugs Ther 2015; 57 (1478): 135-7. PubMed Citation (Concise review of the mechanism of action, efficacy and safety of naloxegol shortly after its approval for use in the US; mentions dose related gastrointestinal side effects, but not ALT elevations or hepatotoxicity).
Eldon MA, Kugler AR, Medve RA, Bui K, Butler K, Sostek M. Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol. Clin Pharmacol Drug Dev 2015 4: 442-8. PubMed Citation (Among 32 healthy volunteers given increasing doses of naloxegol or placebo for 7 days, minor gastrointestinal side effects occurred with the highest doses, but there were no serious adverse events or discontinuations because of side effects; no mention of ALT levels or hepatotoxicity).
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