Tetrabenazine and Trihexyphenidyl Can Cause Fever
Yes, both tetrabenazine and trihexyphenidyl can cause fever through different mechanisms, with tetrabenazine potentially causing neuroleptic malignant syndrome (NMS) and trihexyphenidyl causing anticholinergic-induced hyperthermia. 1, 2, 3
Tetrabenazine and Fever
Mechanisms of Fever
- Tetrabenazine can cause fever through a potentially fatal symptom complex known as Neuroleptic Malignant Syndrome (NMS) 1
- NMS occurs because tetrabenazine reduces dopaminergic transmission in the brain 1
- Simple drug-induced hypersensitivity fever can also occur with tetrabenazine, typically developing after several days of drug administration 4
Clinical Manifestations
- NMS presents with hyperpyrexia (elevated temperature), muscle rigidity, altered mental status, and autonomic instability 1
- Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure 1
- Severe hyperthermia (temperature above 41°C) with intense rhabdomyolysis has been reported with tetrabenazine therapy 5
- The lag time between initiating a drug and fever development averages 21 days (median 8 days) 6, 7
Management
- Immediate discontinuation of tetrabenazine if NMS is suspected 1
- Intensive symptomatic treatment and medical monitoring 1
- Treatment of any concomitant serious medical problems 1
- Fever typically resolves within 1-3 days after drug discontinuation but may take up to 7 days 6, 7
Trihexyphenidyl and Fever
Mechanisms of Fever
- Trihexyphenidyl has anticholinergic properties that can interfere with heat dissipation 2
- It can cause anticholinergic syndrome with hyperthermia as a feature 6
- Malignant hyperthermia has been reported as a rare adverse reaction to trihexyphenidyl 3
Clinical Manifestations
- Anticholinergic syndrome presents with hyperthermia, hot/dry/erythematous skin, mydriasis, dry mucous membranes, and hypoactive bowel sounds 6
- Patients may develop tachycardia, mild hypertension, agitated delirium, and tachypnea 6
- Trihexyphenidyl can increase susceptibility to heat stroke, especially during hot weather 2
Management
- Discontinuation of trihexyphenidyl if fever develops 2, 3
- Supportive care with cooling measures 2
- Physostigmine may be considered for severe anticholinergic toxicity 6
- Patients should be cautioned about increased susceptibility to heat stroke while taking trihexyphenidyl 2
Differential Diagnosis of Drug-Induced Fever
Key Considerations
- Drug-induced fever is a diagnosis of exclusion after ruling out infectious causes 6
- The diagnosis is usually established by temporal relationship between starting the drug and onset of fever 6
- Fever persists as long as the drug is continued and typically resolves within 1-3 days after discontinuation 6, 4
Other Drug-Related Fever Syndromes
- Serotonin syndrome: characterized by mental status changes, neuromuscular hyperactivity, and autonomic hyperactivity 6
- Malignant hyperthermia: genetically determined response with intense muscle contraction generating fever 6
- Drug withdrawal fever: can occur with withdrawal from alcohol, opiates, barbiturates, or benzodiazepines 6
Clinical Approach to Suspected Drug-Induced Fever
- Evaluate temporal relationship between drug initiation and fever onset 6
- Look for other symptoms of NMS (muscle rigidity, altered mental status) or anticholinergic syndrome (dry skin/mucous membranes, mydriasis) 6, 1
- Consider discontinuation of the suspected medication if clinically appropriate 6, 7
- Monitor for resolution of fever after drug discontinuation 6
- Avoid rechallenging patients who experienced severe reactions 6
Important Caveats
- Neuroleptic malignant syndrome is a medical emergency requiring immediate intervention 1
- Patients with underlying neurological conditions may be at higher risk for developing drug-induced fever 8
- Elderly patients may be more sensitive to the anticholinergic effects of trihexyphenidyl 2
- Concurrent use of multiple medications with similar adverse effect profiles may increase the risk of fever 5
- Drug-induced fever can be easily overlooked, especially in patients with other potential causes of fever such as infections 3