What is Drug-Induced Fever?
Drug-induced fever, or pyrexia, is a febrile response that is temporally associated with the administration of a medication and resolves after the drug is discontinued [1.3.1]. It is considered a diagnosis of exclusion, meaning other potential causes of fever, like infections, must be ruled out first [1.3.2]. The fever can range from a low-grade temperature to a dangerously high one, but most commonly falls between 38.9°C (102°F) and 40°C (104°F) [1.3.1]. While a fever is a common symptom of illness, when it's caused by a medication, the person may otherwise feel surprisingly well [1.4.5]. The onset can be unpredictable, appearing within hours of a dose or not until 7 to 10 days into therapy [1.3.3].
The Mechanisms: How Can a Drug Give You a Fever?
A medication can trigger a fever through several distinct pathophysiological mechanisms. The exact pathway often depends on the drug's class and properties [1.5.3].
Hypersensitivity Reactions
This is the most common cause of drug fever [1.5.5]. In this scenario, the drug or its metabolites act as an antigen, triggering an immune response. This can lead to the formation of antigen-antibody complexes that stimulate the release of pyrogens (fever-inducing substances), resulting in a fever [1.5.5]. This mechanism is often implicated with drugs like penicillins, sulfonamides, and anticonvulsants such as phenytoin [1.5.3, 1.5.4].
Altered Thermoregulation
Some drugs directly interfere with the body's central temperature-regulating mechanisms in the hypothalamus [1.5.5]. They can either increase heat production or decrease heat dissipation. For example, sympathomimetic agents like amphetamines can increase the metabolic rate, while anticholinergic drugs like atropine and some antihistamines can impair sweating, which is a primary cooling mechanism [1.5.5].
Reactions Related to Drug Administration
Fever can be a direct result of the administration process itself. This can happen if a solution is contaminated or if the drug has intrinsic pyrogenic properties, like amphotericin B and bleomycin [1.5.5]. Inflammation at the injection or infusion site (phlebitis) can also cause a localized inflammatory response that leads to a systemic fever [1.5.5].
Pharmacologic Effects of the Drug
The intended action of a drug can sometimes lead to fever. A classic example is the Jarisch-Herxheimer reaction, which occurs when antibiotics cause a massive die-off of microorganisms (like in the treatment of syphilis), leading to a large release of pyrogenic substances from the dead microbes [1.5.5]. Similarly, some chemotherapy agents cause fever by inducing tumor cell death, which in turn releases endogenous pyrogens [1.5.5].
Idiosyncratic Reactions
These are unpredictable reactions that occur in genetically susceptible individuals [1.5.3]. The most well-known examples are Malignant Hyperthermia and Neuroleptic Malignant Syndrome.
- Malignant Hyperthermia (MH) is a rare, life-threatening genetic disorder triggered by certain volatile anesthetics (e.g., halothane) and the muscle relaxant succinylcholine [1.9.2]. It causes a rapid and uncontrolled increase in skeletal muscle metabolism, leading to extreme hyperthermia [1.9.4].
- Neuroleptic Malignant Syndrome (NMS) is an adverse reaction most often caused by antipsychotic (neuroleptic) drugs that block dopamine receptors, leading to high fever and severe muscle rigidity [1.5.2, 1.5.3].
- Serotonin Syndrome results from an excess of serotonin, often from a combination of drugs like SSRI antidepressants and certain pain medications or illicit drugs. High fever is a key and potentially fatal symptom [1.8.1, 1.8.5].
Common Medications That Cause Fever
Virtually any drug can cause a fever, but some classes are more frequently implicated than others.
Antimicrobials
This is the most common group of drugs to cause fever [1.5.1]. Beta-lactams like penicillins and cephalosporins are frequent offenders [1.4.5]. Other examples include sulfonamides, vancomycin, minocycline, and rifampin [1.7.3, 1.4.3].
Anticonvulsants
Medications used to treat seizures are also a well-known cause. This includes phenytoin, carbamazepine, and barbiturates [1.4.3, 1.7.4].
Cardiovascular Drugs
Several drugs used to treat heart conditions can induce pyrexia. Common examples include methyldopa, procainamide, and quinidine [1.7.3]. Less commonly, hydralazine, captopril, and nifedipine have also been implicated [1.4.3].
Central Nervous System (CNS) Agents
This broad category includes antidepressants (tricyclics, MAOIs), which can alter thermoregulation, and antipsychotics (phenothiazines), which can cause NMS [1.5.5, 1.7.1].
Comparison of Fever-Inducing Drug Classes
| Drug Class | Common Examples | Primary Mechanism(s) | Typical Onset |
|---|---|---|---|
| Antimicrobials | Penicillins, Cephalosporins, Sulfonamides | Hypersensitivity, Pharmacologic effect (Jarisch-Herxheimer) [1.5.5] | 7-10 days (Hypersensitivity) or hours (Jarisch-Herxheimer) [1.3.3, 1.5.5] |
| Anticonvulsants | Phenytoin, Carbamazepine | Hypersensitivity [1.4.1] | Variable, often after several weeks |
| Cardiovascular | Methyldopa, Procainamide, Quinidine | Hypersensitivity [1.5.3] | Variable, often days to weeks |
| Anesthetics | Halothane, Succinylcholine | Idiosyncratic (Malignant Hyperthermia) [1.9.2] | Minutes to hours during or after anesthesia [1.9.3] |
| Antipsychotics | Haloperidol, Phenothiazines | Idiosyncratic (NMS), Altered Thermoregulation [1.5.3, 1.5.2] | Days to weeks [1.5.2] |
| Antidepressants | SSRIs, MAOIs, TCAs | Altered Thermoregulation, Idiosyncratic (Serotonin Syndrome) [1.5.5, 1.8.1] | Hours to days, especially with dose changes or combinations [1.8.4] |
Diagnosis and Management
Diagnosing drug-induced fever requires a high index of suspicion [1.4.4]. A key diagnostic clue is a fever that appears without a clear source of infection in a patient who has recently started a new medication [1.2.2]. Associated findings like a skin rash (seen in 18-29% of cases) or eosinophilia (an increase in a type of white blood cell) can support the diagnosis but are not always present [1.2.6, 1.2.3].
The definitive diagnosis and primary treatment are one and the same: withdrawal of the suspected offending drug [1.6.2]. If the fever is drug-induced, it will typically resolve within 48 to 72 hours of stopping the medication [1.4.4]. Re-challenging with the drug is not typically recommended as it can cause a more rapid and severe reaction [1.3.3]. In severe cases like MH or Serotonin Syndrome, emergency medical intervention is required, which may include specific antidotes like dantrolene for MH or supportive care and benzodiazepines for Serotonin Syndrome [1.6.1].
Authoritative Review on Drug Fever
Conclusion
While fever is most often a sign of infection, it is essential to consider medication as a potential cause, especially in patients taking multiple drugs. A wide array of common medications, from antibiotics to heart medications, can trigger a febrile response through various mechanisms. Recognizing the possibility of a drug-induced fever allows for a prompt diagnosis by discontinuing the culprit drug, preventing unnecessary and costly medical tests and ensuring patient safety.
