Cardiovascular Safety of the Selective μ-Opioid Receptor Antagonist Naloxegol: A Novel Therapy for Opioid-Induced Constipation.

Abstract

BACKGROUND:

Naloxegol is a novel selective, peripherally acting μ-opioid receptor antagonist for treating opioid-induced constipation (OIC) in patients with chronic pain syndromes. We analyzed the cardiovascular (CV) safety of naloxegol based on data from its development program prior to approval by the US Food and Drug Administration in 2015.

METHODS:

Comprehensive CV safety analyses were performed in 4 clinical studies of naloxegol (12.5 and/or 25 mg) in patients with noncancer pain and OIC: two 12-week, double-blind, randomized studies; a 12-week, double-blind, extension study; and a 52-week, randomized, open-label study versus usual care. Evaluations of baseline CV risk were obtained from medical histories and clinical findings at the time of study initiation.

RESULTS:

Across the 4 studies (N = 2135), 68% of patients had ≥1 CV risk factor and 41% had a history of CV disease, diabetes, or ≥2 other CV risk factors. There were no increases in blood pressure, heart rate, or the rate-pressure product with naloxegol versus placebo. The rates of major adverse cardiovascular events (MACE) per 100 patient-years of exposure were 1.13 (95% confidence interval [CI], 0.31-2.89) for placebo/usual care and 0.75 (95% CI, 0.24-1.75) for naloxegol. The relative risk of MACE for all doses of naloxegol versus placebo was 0.67 (95% CI, 0.14-3.36).

CONCLUSION:

These data demonstrate that naloxegol has a CV safety profile comparable to placebo/usual care in patients with OIC. Although the observed number of events was low, the data show no CV signal in patients with OIC treated with naloxegol.

• Authors: William B White, Peter Kowey, Ulysses Diva, Mark Sostek, Raj Tummala
• Journal: Journal of cardiovascular pharmacology and therapeutics (J Cardiovasc Pharmacol Ther) Vol. 23 Issue 4 Pg. 309-317 (07 2018) ISSN: 1940-4034 [Electronic] United States
• PMID: 29504415 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Morphinans
• Narcotic Antagonists
• Receptors, Opioid, mu
• Polyethylene Glycols
• naloxegol

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Analgesics, Opioid (adverse effects)
• Cardiovascular System (drug effects, metabolism, physiopathology)
• Chronic Pain (drug therapy)
• Clinical Trials, Phase III as Topic
• Constipation (chemically induced, drug therapy, metabolism, physiopathology)
• Defecation (drug effects)
• Evidence-Based Medicine (methods)
• Female
• Humans
• Male
• Middle Aged
• Morphinans (adverse effects, therapeutic use)
• Narcotic Antagonists (adverse effects, therapeutic use)
• Polyethylene Glycols (adverse effects, therapeutic use)
• Randomized Controlled Trials as Topic
• Receptors, Opioid, mu (antagonists & inhibitors, metabolism)
• Recovery of Function
• Risk Assessment
• Risk Factors
• Signal Transduction (drug effects)
• Treatment Outcome
• Young Adult