Doctors prescribe Reglan to treat gastrointestinal disorders. But the drug has also been linked to several serious, sometimes deadly, side effects, including tardive dyskinesia (TD) and neuroleptic malignant syndrome (NMS).
Reglan (metoclopramide) is prescribed for gastrointestinal disorders. However, the drug can interfere with a brain chemical called dopamine. Low dopamine levels can cause several serious side effects, including tardive dyskinesia (TD) and neuroleptic malignant syndrome (NMS).
TD causes involuntary body movements. NMS is a potentially deadly condition with a variety of symptoms.
While these side effects are sometimes reversible with the discontinuation of the drug, the conditions can also be permanent or lead to lasting injury or disability. If not immediately or properly treated, serious side effects of Reglan can also result in death.
The active ingredient in Reglan, metoclopramide, was found to cause tardive dyskinesia (TD) in some patients, especially those taking Reglan for longer than 12 weeks. The risk of developing TD, and the likelihood that the condition will become irreversible, increases with longer durations of Reglan treatment as well as total cumulative (increasing in quantity) dosage, according to drug labeling for the gastrointestinal medication.
TD is a disorder that involves potentially disfiguring involuntary movements of the face or tongue, and sometimes the trunk and extremities. Movements associated with the condition may appear as irregular migrating contractions or twisting and writhing. In addition to the typical facial movements that are a part of tardive dyskinesia, the condition can also involve twitching and rapid and uncontrolled movements in the patient’s arms, fingers, toes, legs, hips and torso.
These random body movements can be uncomfortable and painful as well as embarrassing, making it a social handicap as well. Severe cases of this disorder can be debilitating and make it difficult to perform simple tasks like talking, walking and eating. In some instances, patients even have trouble breathing.
Tardive means delayed and dyskinesia means abnormal movement. The “delay” is the time between the beginning of drug treatment and the onset of symptoms. TD can occur following the use of certain medications, such as Reglan or, more commonly, with the use of drugs called neuroleptics, or antipsychotics, used to treat mental problems. TD may result as an adverse reaction many months or years after beginning treatment, but sometimes the condition can occur after as little as six weeks.
Elderly patients, especially elderly women, are at an increased risk of developing TD with Reglan. Due to the risk of developing TD, patients should avoid using Reglan for longer than 12 weeks and elderly patients should consider a reduced dosage of the medication.
Reglan should not be used in patients with a history of TD or patients receiving other drugs that are likely to cause TD.
Most drugs associated with tardive dyskinesia (TD) are neuroleptics, which work by affecting the way the brain processes a chemical called dopamine. Dopamine controls the reward and pleasure centers of the brain and helps regulate movement and emotional response. Imbalances of this chemical are linked to diseases like Parkinson’s, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder (ADHD).
Most antipsychotic drugs lower a person’s level of dopamine activity by targeting and blocking D2 dopamine receptors. Because these drugs affect dopamine, they are also called dopamine antagonists.
Anyone who takes or has taken an antipsychotic medication is at risk of developing TD. The risk increases if you take the medication for several months or years, although there have been cases that occurred after just a few weeks of use. While older neuroleptic drugs are more likely to cause TD, there is also a risk with newer drugs.
These drugs are not used just for psychotic disorders, such as schizophrenia. They are also used to treat some digestive disorders, depression and other neurologic illnesses.
In one study, Reglan (generically called metoclopramide) was among three drugs, and one drug pairing, most commonly associated with the onset of TD. Reglan, while not a neuroleptic, is classified as a dopamine antagonist. By blocking certain dopamine receptors, Reglan is able to interfere with the part of the brain that controls nausea and vomiting, thereby alleviating such symptoms in patients.
Reglan itself may actually suppress, or partially suppress, the signs of tardive dyskinesia, masking the disease and making it difficult to pinpoint and diagnose. The effect of this symptomatic suppression on the long-term course of TD is unknown, according to drug labeling.
Depending on the person, TD symptoms may be mild and last for only a short time, or they may continue indefinitely.
If tardive dyskinesia is caught early, stopping Reglan or changing medications may be enough to relieve symptoms. Discontinuing the drug may result in reversal of the condition, either partially or fully, within several weeks to months after Reglan is stopped in some patients. In others, however, TD can be permanent.
When TD is mild or moderate, various medicines can be used to treat the condition and its symptoms. The FDA approved the first drug to treat TD, Ingrezza (valbenazine), in 2017. Patients in a clinical trial who took Ingrezza showed improvement in the severity of their symptoms.
The drug, manufactured by Neurocrine Biosciences, Inc., has its own potential serious side effects, however, including sleepiness and heart rhythm problems. According to the FDA, it should not be given to patients with certain heart conditions, and patients taking it should not operate heavy machinery or participate in other dangerous activities until the drug’s effects on them are known.
A second drug was also approved by the FDA for the treatment of TD in 2017. The drug, called Austedo (deutetrabenazine), is manufactured by Teva Pharmaceutical Industries Ltd., and it is also indicated to treat chorea (abnormal involuntary movement disorder) associated with Huntington’s disease. It is advertised as “the first and only medication approved to treat both” conditions.
Austedo’s drug labeling includes a safety warning that treatment with the medication can cause depression, suicidal thoughts and/or suicidal actions, as well as irregular heartbeat, restlessness, sleepiness, diarrhea and dry mouth.
When TD is very severe, treatment with various medications may not be enough. In such cases, a procedure called deep brain stimulation (DBS) can be attempted. DBS uses a device called a neurostimulator to deliver electrical signals to the areas of the brain that control movement.
Involuntary movements associated with TD can also worsen over time in some patients whose symptoms are not reversed after stopping the causal drug.
Metoclopramide, the active ingredient in Reglan, may cause a potentially deadly symptom complex called neuroleptic malignant syndrome (NMS) in patients being treated by the gastrointestinal drug. NMS has also been reported in patients taking metoclopramide with another drug associated with NMS and in cases of Reglan overdose. NMS is a life-threatening reaction to Reglan or, more commonly, antipsychotic drugs.
Autonomic dysfunction can affect the proper functioning of the patient’s heart, bladder, intestines, sweat glands, pupils and blood vessels.
NMS typically presents shortly after the initiation of treatment with the causal drug, or following dose increases. Some patients can develop NMS within hours or days after taking Reglan, with the mean onset of symptoms occurring within two weeks. Nearly all patients who will be affected by NMS, will exhibit symptoms within 30 days of beginning treatment with Reglan.
Patients taking other drugs associated with NMS, including all antipsychotic medications, should avoid taking Reglan.
The first reported case of neuroleptic malignant syndrome (NMS) surfaced in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (thorazine). Additional reports quickly followed, and in 1960, during a study, French clinicians gave NMS its name.
The primary trigger of NMS has been linked to dopamine receptor blockades, such as Reglan and antipsychotic medications. The stronger the drug’s dopamine-blocking properties, the greater its potential to cause NMS.
The interference of dopamine receptors in the hypothalamus of the brain and/or the spinal cord likely lead to increased muscle rigidity in patients affected by NMS. Dopamine receptors affected in the hypothalamus are also likely responsible for a rise in body temperature as well as uncontrolled blood pressure.
Some researchers suggest that NMS may be related to a certain genetic disorder called malignant hyperthermia, which is characterized by an abnormal reaction to anesthesia drugs.
NMS has also been found to occur in patients treated by anti-Parkinson medication who abruptly stop treatment. This sudden medication withdrawal is shown to decrease dopamine activity in the brain.
While researchers have identified several risk factors for NMS, the rarity of the condition and difficulty in its controlled, prospective study, make the adverse reaction hard to completely understand.
The National Institutes of Health (NIH) published a review of neuroleptic malignant syndrome (NMS), originally appearing in the journal The Neurohospitalist, that summarizes information associated with the rare but serious syndrome found through observations, case studies, other research and evaluations, and reports.
Various case studies determined some known risk factors that may contribute to the development of NMS in patients taking neuroleptics and other dopamine antagonists.
Some research indicates that males under 40 may be at a greater risk of developing NMS, although this elevated risk might just be due to the increased incidence of neuroleptic use in the specific population. Postpartum women are also believed to be at a slightly higher risk of developing NMS.
Some reports indicate that there may be a genetic risk factor associated with the development of NMS as well. This is possibly due to a genetically associated reduction in the function of certain dopamine receptors.
NMS occurs only after exposure to a certain drug, such as Reglan. Onset, on average, is within four to 14 days after the initiation of treatment. Most cases that develop (90 percent) are symptomatic within 10 days, but some cases of NMS can occur years into treatment with the offending drug.
Once symptoms of NMS appear, the condition can progress very quickly, reaching its peak intensity in as little as three days.
Patients with neuroleptic malignant syndrome (NMS) will be hospitalized for treatment as the condition is considered a neurologic emergency. A delay in treating NMS, or the withholding of any available therapeutic measures for the condition, can potentially lead to serious, possibly permanent, injury or death. Because of its severity, if signs and symptoms of NMS are present, a health care provider may choose to treat the patient for NMS even without an official diagnosis.
Treatment with Reglan should be immediately stopped in patients diagnosed with NMS. Treatment of NMS is solely supportive, focused on managing symptoms and monitoring the patient’s condition to prevent further complications. Patients will also be given various medications or other treatments that are available for any serious medical problems occurring along with NMS, including kidney failure, low blood oxygen levels and other metabolic abnormalities.
Some medications, such as dantrolene and bromocriptine, are available to treat muscle contractions and decreased dopamine activity, respectively. When patients do not respond to these drug therapies, electroconvulsive treatments have also been used with mixed results.
Although NMS is considered an idiosyncratic reaction, meaning it’s rare and unpredictable, physicians are reluctant to restart the patient on the same medication that caused the initial reaction. Recurrences of NMS do occur when patients are restarted on the medication, especially at a high potency, too quickly. Reintroduction of medications should be done very slowly, usually after a two-week waiting period, and dosages should be started low and gradually increased.
Once patients have fully recovered from NMS, typically within one to two weeks, although some patients’ recovery time can take as long as a month, about 87 percent will be able to tolerate the same type of drug that caused their initial reaction in the future.
Initial reports of death by NMS were over 30 percent, according to the NIH, but over time that number has decreased to about 10 percent with increased physician awareness and the introduction of newer medications, specifically neuroleptics, with less side effects.
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