The Unexpected Link: Antihistamines and Fever
Antihistamines are a staple for managing allergy symptoms like sneezing, itching, and runny nose [1.2.1]. Generally considered safe, most users don't expect to develop a fever. However, under specific circumstances, a febrile response—an elevation in body temperature—can occur. Fever is not a typical side effect at prescribed doses but is documented in several contexts, including drug allergy, overdose, and as a less common side effect for certain types like fexofenadine and levocetirizine [1.2.4, 1.2.7]. It's crucial to understand when a fever might signal a more serious issue.
Drug-Induced Fever: A Broader Pharmacological Issue
A drug-induced fever is a febrile response to a medication that resolves after discontinuing the offending drug [1.5.5]. This type of fever is a diagnosis of exclusion, meaning other causes must be ruled out first [1.5.2, 1.5.5]. The mechanisms behind drug fever are diverse [1.5.3, 1.5.4]:
- Hypersensitivity Reactions: This is the most common cause of drug fever [1.5.3, 1.5.6]. The body's immune system mistakenly identifies the drug as a harmful substance, triggering an immune response that can release chemicals causing fever [1.2.3]. This reaction typically occurs 7 to 10 days after starting a new medication [1.5.1].
- Altered Thermoregulation: Certain drugs can interfere with the body's ability to regulate its own temperature [1.5.3]. Antihistamines, particularly first-generation ones with strong anticholinergic properties, can impair the sweating mechanism, which is a primary way the body cools itself [1.5.3, 1.4.6]. This leads to an increase in core body temperature.
- Pharmacologic Effects: Some drugs cause fever as a direct result of their intended action. For example, the destruction of microorganisms by antibiotics can release pyrogens (fever-inducing substances), leading to a temporary fever [1.5.3].
- Idiosyncratic Reactions: These are unpredictable reactions that occur in a small subset of genetically predisposed individuals. Malignant hyperthermia and neuroleptic malignant syndrome are severe examples [1.5.3].
Anticholinergic Toxidrome: The Overdose Risk
A more direct way antihistamines can cause fever is through an overdose, leading to a condition known as anticholinergic toxicity [1.8.1, 1.8.3]. This is especially a risk with older, first-generation antihistamines like diphenhydramine (Benadryl) and chlorpheniramine, which have strong anticholinergic effects [1.2.1, 1.6.4]. The classic symptoms are often remembered by the mnemonic: "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter" [1.8.1, 1.8.6].
Fever in this context arises from two main issues: impaired sweating, which prevents heat loss, and increased heat production from agitation and muscle activity [1.8.2, 1.8.4]. Other signs of antihistamine overdose include flushing, dilated pupils, fast heart rate, urinary retention, and altered mental status like confusion or hallucinations [1.4.1, 1.8.1]. This is a medical emergency requiring immediate attention.
First-Generation vs. Second-Generation Antihistamines
The risk of side effects, including the potential for fever, differs significantly between the two main classes of antihistamines [1.6.1].
| Feature | First-Generation Antihistamines | Second-Generation Antihistamines |
|---|---|---|
| Examples | Diphenhydramine (Benadryl), Chlorpheniramine, Doxylamine [1.2.1] | Cetirizine (Zyrtec), Loratadine (Claritin), Fexofenadine (Allegra) [1.2.1] |
| Sedation | High (readily cross blood-brain barrier) [1.6.2, 1.6.4] | Low/Non-sedating (do not easily cross blood-brain barrier) [1.6.2, 1.6.5] |
| Anticholinergic Effects | Strong (dry mouth, blurred vision, urinary retention) [1.6.4] | Minimal [1.6.1] |
| Risk of Fever | Higher, primarily through anticholinergic effects in overdose [1.5.3, 1.4.1] | Lower, but can occur as a rare side effect or in hypersensitivity reactions [1.2.4, 1.2.7] |
| Safety Profile | More side effects and higher overdose risk [1.6.2] | Generally safer with fewer drug interactions [1.6.2, 1.6.5] |
When to Be Concerned
If you develop a fever while taking an antihistamine, it's important to assess the situation. A fever accompanied by other symptoms like a rash, joint pain, or general swelling could indicate a drug allergy or serum sickness [1.2.3]. If the fever is high and occurs with confusion, rapid heart rate, and very dry skin, it could be a sign of anticholinergic toxicity, especially if a higher-than-recommended dose was taken [1.4.1, 1.8.1].
It is also possible for the underlying condition for which you are taking the antihistamine, such as a viral infection like the common cold, to be the actual cause of the fever [1.4.4]. If your condition lasts for more than a week, worsens, or occurs with a persistent headache and fever, you should consult a doctor [1.2.5].
Conclusion
So, can antihistamines cause fever? Yes, though it is not a common event at standard therapeutic doses. The risk is highest in cases of overdose with first-generation antihistamines, which can lead to life-threatening anticholinergic toxicity. Fever can also manifest as part of a hypersensitivity reaction or, rarely, as a direct side effect of newer-generation drugs. It is essential to use antihistamines as directed and to seek medical attention if a fever is accompanied by other concerning symptoms. Always consult a healthcare professional to distinguish between a benign side effect and a more serious medical issue.
