Can perphenazine (antipsychotic medication) cause fever?

Perphenazine and Fever: Clinical Considerations

Yes, perphenazine can cause fever, particularly as part of neuroleptic malignant syndrome (NMS), a rare but potentially life-threatening adverse effect of antipsychotic medications. 1, 2

Mechanisms of Perphenazine-Induced Fever

Perphenazine, a phenothiazine antipsychotic medication, can cause fever through several mechanisms:

1. Neuroleptic Malignant Syndrome (NMS):

   • Characterized by the tetrad of mental status changes, fever, muscle rigidity, and autonomic dysfunction 1
   • Caused by dopamine D2 receptor antagonism in the hypothalamus, leading to increased set point and loss of heat-dissipating mechanisms 1
   • Potentially lethal with mortality rates of 10-15% if not recognized and treated promptly 1

2. Drug-Induced Hypersensitivity Reaction:

   • The FDA label specifically mentions "hyperpyrexia" as a potential adverse effect 2
   • May occur as part of a systemic lupus erythematosus-like syndrome 2

3. Subcortical Brain Damage Interaction:

   • Perphenazine is contraindicated in patients with suspected or established subcortical brain damage as it may trigger hyperthermic reactions with temperatures exceeding 104°F 2
   • These reactions may occur up to 14-16 hours after drug administration 2

Clinical Presentation and Timing

When perphenazine causes fever:

• NMS typically presents with:

  • High fever (up to 41°C/105.8°F)
  • Altered mental status
  • Muscle rigidity
  • Autonomic instability (tachycardia, blood pressure fluctuations, diaphoresis) 1

• Timing of fever:

  • May not occur immediately after drug administration
  • Can develop days after starting the medication
  • May persist for 1-7 days after discontinuation 1

Risk Factors

Patients at higher risk for perphenazine-induced fever include:

• Those with subcortical brain damage 2
• Patients taking concomitant psychotropic medications 1
• Dehydrated patients 1
• Those with physical exhaustion 1
• Patients with preexisting organic brain disease 1
• Young adults and male patients (2:1 male-to-female ratio for NMS) 1

Management

If perphenazine-induced fever is suspected:

1. For NMS:

   • Immediate discontinuation of perphenazine
   • Intensive supportive care
   • Consider dantrolene or bromocriptine in severe cases 1

2. For hyperthermic reactions in patients with subcortical brain damage:

   • Total body ice-packing is recommended
   • Antipyretics may be useful 2

3. For drug-induced fever:

   • Discontinue perphenazine
   • Monitor until fever resolves (may take up to 7 days) 1

Differential Diagnosis

When evaluating fever in a patient taking perphenazine, consider:

• Infection (most common cause of fever in hospitalized patients)
• Other drug-induced fevers
• Serotonin syndrome (distinct from NMS but can present similarly) 1
• Other causes listed in guidelines, such as acalculous cholecystitis, pancreatitis, pulmonary infarction, etc. 1

Prevention and Monitoring

• Avoid perphenazine in patients with subcortical brain damage 2
• Use with caution in patients with risk factors for NMS
• Monitor vital signs, especially during initiation or dose increases
• Consider serum procalcitonin levels to help discriminate between drug-induced fever and infection 1, 3

Important Caveats

• NMS is rare but potentially fatal if not recognized promptly
• Fever may persist for several days after perphenazine discontinuation
• Rechallenge with perphenazine after a fever reaction should be avoided unless absolutely necessary 1
• The diagnosis of drug-induced fever is usually established by the temporal relationship between fever and starting/stopping the medication 1