A commonly used drug for stomach disorders can cause irreversible neurological damage in the brain, but many doctors seem to be disregarding these problems—challenging the concept that a drug’s benefits must outweigh its risks.

Metoclopramide (Reglan) is a widely prescribed generic drug available in tablets and by injection for nausea, gastroesophageal reflux disorder (GERD), and stomach disorders related to nerve damage in some patients with diabetes. It has other uses related to nausea, as well.

Reglan’s most troubling side effects are abnormal, often disfiguring movement disorders called dyskinesias. The movements may involve protruding tongue, lip smacking, eye rolling, and even repetitive movements of entire limbs. In time, the movements may become untreatable and irreversible, a condition called tardive dyskinesia.

Looking at FDA data from the first quarter of 2011 for our QuarterWatch program, we observed 63 cases of dyskinesia (or abnormal movements) and identified an additional 1,180 dyskinesia cases arising from lawsuits against the drug manufacturers for events that likely occurred over a longer period of time. QuarterWatch is an Institute for Safe Medication Practices program we use to identify drug risks and errors reported to the U.S. Food and Drug Administration (FDA) by healthcare practitioners and consumers.

While intended to improve emptying of the stomach, the drug also blocks the action of two chemicals in the brain, dopamine and serotonin, which are also involved in mood. Reglan’s mechanism of action is similar to that of the most powerful drugs for psychosis and schizophrenia and it shares the same risks. Over a year’s treatment, antipsychotic drugs are believed to cause irreversible neurological damage in 5 to 10 percent of those treated. Data are less clear for metoclopramide, but there are estimates of 1 to 10 percent, depending on the length of exposure.

The FDA conducted a study in a health insurance database in 2007 and discovered that doctors were frequently disregarding the principal safety measure for this drug: limiting the use of the drug to 12 weeks or less. The FDA study showed 20 percent of the prescriptions were for longer periods. The agency acted, escalating the warning for tardive dyskinesia in a boxed warning at the beginning of the prescribing information. The FDA also required that a plain-language Medication Guide be given to patents warning of the dangers of prolonged use. Nevertheless, metoclopramide is within the top 200 most frequently prescribed prescription drugs, according to IMS Health data, and these totals do not include the injected version of metoclopramide.

In the first quarter of 2011, we identified 77 serious adverse drug events for metoclopramide overall, including 18 patient deaths and the 63 tardive dyskinesia cases. That’s a higher toll than for 88 percent of the drugs we regularly monitor. We also identified an additional 1,208 case reports that indicated they originated from lawsuits. These cases included 180 patient deaths and 1,180 cases indicating dyskinesia. Notable was that 566/1,208 (47 percent) of the cases indicated “incorrect drug administration duration.”

Safer alternatives exist for all but one of the FDA approved uses for metoclopramide—the treatment of gastroparesis, a condition in which the nerves that control muscles in the stomach are impaired and the stomach does not empty normally. Apparently, metoclopramide is the only drug approved for this condition. But a recent review of this drug noted that the studies of this effect were small, short term, and showed only modest benefit and no benefit was recorded after one month. Given that gastroparesis is a chronic or long-term disorder, it appears that short-term benefits do not appear to justify the risk.

We believe substantial additional action should be taken to reduce brain damage caused by this widely used drug. The first step is a more systematic assessment of its risks, benefits and alternatives, given current therapeutic choices. Possible steps to be considered include outright safety withdrawal, highly restricted availability limited to a few weeks, and repeal of all its first-line indications. Its use in injectable form for nausea from surgery and chemotherapy should also be reassessed, given the presence of numerous safer alternatives.

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