Naloxegol appears to reverse opioid-induced esophageal dysmotility in the same way as it does opioid-induced constipation, according to preliminary experience in two patients.

As naloxegol (Movantik, AstraZeneca) is a mu-opioid receptor antagonist, it is logical to assume that opioid-mediated dysmotility could be reversed wherever it occurs. Although naloxegol is now approved only for the management of constipation in patients taking opioids for pain, the benefit extended to severe coexisting esophageal motility disorders.

“The improvement was significant whether measured by symptoms or with manometry,” said Tarun Sharma, MD, of Advocate Aurora Health in Milwaukee, who conducted the study, and his Advocate colleague Megan Jacobson, PA.

In both cases, manometry was performed in patients before the administration of naloxegol. One patient, a 67-year-old man with dysphagia taking 30 mg of oxycodone twice daily, had jackhammer esophagus with a distal contractile integral value of 10,092 mm Hg/s/cm. The other, a 73-year-old woman with dysphagia and regurgitation taking 10 mg of oxycodone every six hours, had type III achalasia.

After five days on 25 mg of naloxegol, symptoms of jackhammer esophagus resolved, and manometry showed a significant relaxation, reaching 2,559 mm Hg/s/cm (P<0.05 vs. baseline), according to the investigators.

In the woman with achalasia, the manometry reading fell by half, reaching 2,887 mm Hg/s/cm from the baseline of 5,900 mm Hg/s/cm (P<0.05). The achalasia signature was changed to type II, suggesting lower spasticity. Although the improvement in dysphagia was mild, the decrease in regurgitation was substantial, according to the researchers, who presented the cases at the 2020 virtual meeting of the American College of Gastroenterology (abstract P1017).

Co-author Crista Ulteig, MD, acknowledged that an observational series with two patients does not confirm a benefit, but the improvement is consistent with naloxegol’s mechanism of action. Kristin Ciezki, PhD, another co-author and a researcher at the Advocate Aurora Research Institute, called for a larger prospective study evaluating the effect of the drug on esophageal dysmotility associated with opioids other than oxycodone.

Since the presentation of these data, a third patient with esophageal dysmotility has exhibited a similar response to naloxegol as the first two, strengthening the idea that naloxegol may have a role in reversing opioid-induced esophageal dysmotility. A larger study is planned.

David Johnson, MD, the chief of gastroenterology at Eastern Virginia Medical School, in Norfolk, called the concept for the study “novel” but cautioned that symptom relief in a few cases is just the start of a process needed to explore how and whether naloxegol provides benefit.

“It is reasonable to suspect that activation of peripheral opioid receptors is a mechanism, but we do not know that this is the cause of achalasia in patients taking opioids,” Dr. Johnson said. “It is even more of a reach to hypothesize that this explains jackhammer esophagus.”

To explore the underlying mechanism and benefit from naloxegol, controlled studies using appropriate methodology are needed, he said. “The real key is to evaluate the impact on symptoms using validated methods of measuring the clinical effect, such as the Eckardt score,” he said.

From a practical clinical point of view, he questioned whether other approaches to controlling opioid-associated achalasia might make more sense. These include changing the type of narcotic or stopping the opioids altogether. In the new study, the authors cited a reduction in achalasia class as a sign of benefit, but Dr. Johnson said he was not convinced that moving from type III to II would be clinically meaningful.

“Clinicians are routinely placed in the position of having to consider the benefit-to-risk ratio of nonstandard approaches in patients who have not improved,” Dr. Johnson said. “Naloxegol might be one option to discuss when making clear that it is not approved or well studied, but this is a clinical judgment that is very case-specific.”

—Ted Bosworth


Dr. Sharma reported no relevant financial disclosures. Dr. Johnson reported financial relationships with HyGieaCare and Pfizer.

This article is from the June 2021 print issue.