What are the risks of long-term promethazine (phenothiazine) use and its link to diseases such as tardive dyskinesia?

From the Guidelines

Long-term promethazine use is strongly associated with an increased risk of developing tardive dyskinesia (TD), a potentially irreversible movement disorder, and therefore, its use should be limited to short-term treatment whenever possible. The risk of TD with promethazine, a phenothiazine derivative, is similar to that of antipsychotic medications in the same chemical class, and it increases with the duration of use, higher doses, advanced age, female gender, and the presence of mood disorders or diabetes 1. Other significant risks of prolonged promethazine use include sedation, cognitive impairment, anticholinergic effects such as dry mouth, blurred vision, urinary retention, and constipation, as well as potential cardiac complications like QT prolongation 1.

Risks and Considerations

• The development of TD is a major concern, with up to 50% of patients on long-term neuroleptic therapy experiencing some form of tardive or withdrawal dyskinesia 1.
• Regular neurological examinations are crucial for patients requiring longer treatment to monitor for early signs of TD, such as tongue movements, lip smacking, or facial grimacing.
• Alternative medications with a lower risk of TD should be considered for chronic conditions requiring long-term treatment, especially in light of more recent guidelines that emphasize the importance of minimizing the risk of TD and other side effects in the treatment of schizophrenia and other conditions 1.

Recommendations

• Limit promethazine use to short-term treatment courses, typically not exceeding a few weeks, to minimize the risk of TD and other adverse effects.
• For patients requiring longer treatment, regular monitoring for signs of TD and other side effects is essential, along with consideration of alternative treatments that may have a more favorable side effect profile.
• The choice of medication should be guided by the most recent and highest-quality evidence, with consideration of the patient's specific needs, preferences, and risk factors for adverse effects 1.

Evidence Base

The most recent guidelines, such as those from the American Psychiatric Association 1, emphasize the importance of evidence-based treatment approaches that balance efficacy with the risk of adverse effects, including TD. These guidelines recommend careful assessment and monitoring, the use of antipsychotic medications with a lower risk of TD when possible, and consideration of non-pharmacological interventions to support overall patient health and well-being.

From the FDA Drug Label

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The EXTRAPYRAMIDAL SYMPTOMS WHICH CAN OCCUR SECONDARY TO PROMETHAZINE HYDROCHLORIDE TABLETS ADMINISTRATION MAY BE CONFUSED WITH THE CNS SIGNS OF UNDIAGNOSED PRIMARY DISEASE, e.g., ENCEPHALOPATHY OR REYE’S SYNDROME.

The main risks of long-term promethazine use include:

• Neuroleptic Malignant Syndrome (NMS): a potentially fatal symptom complex
• Extrapyramidal symptoms: which can occur secondary to promethazine administration and may be confused with CNS signs of undiagnosed primary disease
• Respiratory depression: which can be fatal, especially in pediatric patients
• Bone-marrow depression: leukopenia and agranulocytosis have been reported
• Lower seizure threshold: promethazine may lower seizure threshold, especially in persons with seizure disorders The link between long-term promethazine use and tardive dyskinesia is not explicitly stated in the provided drug labels, but extrapyramidal symptoms are mentioned as a potential risk 2, 2.

From the Research

Risks of Long-Term Promethazine Use

• Long-term use of promethazine, a phenothiazine derivative, has been linked to various movement disorders, including tardive dyskinesia, tardive dystonia, and tardive akathisia 3.
• Tardive dyskinesia is a movement disorder characterized by involuntary, repetitive movements of the face, trunk, and limbs, which can be permanent despite discontinuation of the offending medication 3.
• Promethazine, an antihistamine with antidopaminergic properties, can cause acute dystonia, especially in young children and pregnant women, but also in older adults, as reported in a case study where a 68-year-old female patient developed acute orofacial dystonia after promethazine treatment 4.

Link to Diseases

• The development of tardive syndromes, including tardive dyskinesia, is associated with the use of dopamine receptor blocking agents, such as promethazine, and can occur after chronic exposure or even rapidly after treatment initiation 3.
• Other diseases, such as generalized anxiety disorder, may be treated with promethazine, but careful assessment of the risk of developing acute dystonia is necessary, especially in older patients 4.
• Alternative antiemetics, such as ondansetron and granisetron, are available and do not pose a risk of movement disorders, highlighting the need for careful consideration of treatment options to minimize the risk of adverse effects 5.

Treatment and Management

• Discontinuation of the offending medication, such as promethazine, and treatment with alternative agents, such as botulinum toxin, may be necessary to alleviate symptoms of tardive syndromes 4.
• Carvedilol, a beta-blocker, has been reported to suppress intractable hiccups and tardive dyskinesia in a patient who failed other treatments, including promethazine 6.
• Patient safety organizations have recommended caution when using injectable promethazine due to the risk of rare but serious limb-threatening adverse effects, and the U.S. Food and Drug Administration has updated product labeling to reflect these concerns 7.