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• Two Drug Classes Appear Effective for Gastroparesis Treatment

Two classes of drugs may be more effective than others for the treatment of gastroparesis, though the overall quality of evidence remains low to moderate and additional data are needed, according to a new report.

Oral dopamine antagonists and tachykinin-1 antagonists appear superior to placebo, finds the study. In addition, some drugs rank higher for addressing individual symptoms.

"Gastroparesis has a substantial impact on quality of life and societal functioning for patients, and the costs to the health service are high," Alexander Ford, MBChB, MD, a professor of gastroenterology and honorary consultant gastroenterologist at the Leeds Institute of Medical Research at St. James's, University of Leeds, England, told Medscape Medical News.

"There are very few licensed therapies, but some novel drugs are in the pipeline, some existing drugs that are licensed for other conditions could be repurposed if efficacious, and some older drugs that have safety concerns may be beneficial," he said. "Given the impact on patients and their symptoms, they may be willing to accept these safety risks in return for symptom improvement."

Only one drug, the dopamine antagonist metoclopramide, has US Food and Drug Administration approval for the treatment of gastroparesis, note Ford and colleagues. The lack of other recommended drugs or new medications has resulted in off-label use of drugs in other classes.

Investigating Treatments

To address the lack of evidence supporting the efficacy and safety of licensed and unlicensed drugs for the condition, the researchers conducted a systematic review and network meta-analysis of randomized controlled trials of drugs for gastroparesis dating from 1947 through September 2022. The trials involved more than dozen drugs in several classes.

They determined drug efficacy on the basis of global symptoms of gastroparesis and individual symptoms such as nausea, vomiting, abdominal pain, bloating, or fullness. They judged safety on the basis of total adverse events and adverse events leading to withdrawal.

The research team extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures. They reported efficacy as a pooled relative risk (RR) of symptoms not improving and ranked the drugs according to P-score.

The analysis included 29 randomized controlled trials with 3772 patients. Only four trials were at low risk of bias.

Overall, only two drug classes were considered efficacious: oral dopamine antagonists (RR, 0.58; P-score, 0.96) and tachykinin-1 antagonists (RR, 0.69; P-score, 0.83).

On the basis of 25 trials that reported on global symptoms, clebopride ranked first for efficacy (RR, 0.30; P-score, 0.99), followed by domperidone (RR, 0.69; P-score, 0.76). None of the other drugs were superior to the placebo. After direct and indirect comparisons, clebopride was superior to all other drugs except aprepitant.

After excluding three trials with a placebo run-in and a trial where only responders to single-blind domperidone were randomized, the researchers analyzed 21 trials with 2233 patients. In this analysis, domperidone ranked first (RR, 0.48; P-score, 0.93), followed by oral metoclopramide (RR, 0.54; P-score, 0.87). None of the other drugs were superior to placebo.

Among 16 trials, including 1381 patients, that confirmed delayed gastric emptying among all participants, only clebopride and metoclopramide were more efficacious than placebo. Clebopride ranked first (RR, 0.30; P-score, 0.95) and metoclopramide ranked third (RR, 0.48).

Among 13 trials with 785 patients with diabetic gastroparesis, none of the active drugs were superior to placebo. Among 12 trials recruiting patients with idiopathic or mixed etiology gastroparesis, clebopride ranked first (RR, 0.30; P-score, 0.93).

On the basis of trials that assessed individual symptoms, oral metoclopramide ranked first for nausea (RR, 0.46; P-score, 0.95), fullness (RR, 0.67; P-score, 0.86), and bloating (RR, 0.53; P-score, 0.97). However, the data came from one small trial. Tradipitant and TZP-102, a ghrelin agonist, were efficacious for nausea, and TZP-102 ranked second for fullness. No drugs were more efficacious than the placebo for abdominal pain or vomiting.

Among 20 trials that reported on the total number of adverse events, camicinal was the least likely to be associated with adverse events (RR, 0.77; P-score, 0.93) and prucalopride was the most likely to be associated with adverse events (RR, 2.96; P-score, 0.10). Prucalopride, oral metoclopramide, and aprepitant also were more likely than placebo to be associated with adverse events.

In 23 trials that reported on withdrawals due to adverse events, camicinal was the least likely to be associated with withdrawals (RR, 0.20; P-score, 0.87). Nortriptyline was the most likely to be associated with withdrawals (RR, 3.33; P-score, 0.16). However, there were no significant differences between any individual drug and placebo.

Urgent Need Remains

More trials of drugs to treat gastroparesis are needed, Ford said. "We need to consider the reintroduction of dopamine antagonists, if patients are willing to accept the safety concerns," he added. "The other important point is most drugs were not of benefit. There is an urgent need to find efficacious therapies, and these should be fast-tracked for licensing approval if efficacy is proven."

The study is "helpful for practicing clinicians since it provides a comprehensive review of clinical trials in gastroparesis," Anthony Lembo, MD, a gastroenterologist at Cleveland Clinic in Ohio, told Medscape Medical News.

Lembo, who wasn't involved with this study, has researched several drugs for gastroparesis, including relamorelin and TZP-102. He agreed that additional research is needed.

"There is a paucity of novel treatments currently in development," he said. "However, there is interest in developing a product similar to domperidone without cardiac side effects, as well as performing larger studies with botulinum toxin injection."

Gastroenterology. Published online. December 26, 2022. Full text


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