Drugs can cause dysregulation of the hypothalamic–pituitary–adrenal axis which can result in a rise in core temperature. This type of hyperthermia is unresponsive to antipyretics and can be complicated by rhabdomyolysis, multi-organ failure and disseminated intravascular coagulation Organic causes of fever such as infection must be ruled out. Syndromes associated with drug-induced fever include neuroleptic malignant syndrome and anticholinergic, sympathomimetic and serotonin toxicity The class of offending drugs, as well as the temporal relationship to starting or stopping them, assists in differentiating between neuroleptic malignant syndrome and serotonin toxicity Immediate inpatient management is needed. The mainstay of management is stopping the drug, and supportive care often in the intensive care unit Keywords: fever, hyperthermia, muscle rigidity, rhabdomyolysis Introduction Drugs that alter the neurotransmitters noradrenaline (norepinephrine), dopamine and serotonin can affect thermoregulation by the hypothalamic–pituitary– adrenal axis.1,2 In drug-induced hyperthermia the core temperature is at least 38.3 °C.3 Hyperthermia can be complicated by peripheral factors such as increased heat production (e.g. with 3,4-methylenedioxymethamphetamine (MDMA/ ecstasy) and other sympathomimetics) and decreased heat loss (e.g. with anticholinergic drugs). Excessive heat production can result in life-threatening complications such as rhabdomyolysis and secondary hyperkalaemia, metabolic acidosis, multi-organ failure and disseminated intravascular coagulation.1 The most commonly used drugs that affect thermoregulation include antipsychotic drugs, serotonergic drugs (especially when taken in combination), sympathomimetic drugs, anaesthetics and drugs with anticholinergic properties (Table 1). Table 1 Drugs commonly known to cause hyperthermia and associated muscle rigidity Drug-induced syndrome Associated drugs Neuroleptic malignant syndrome Antipsychotics (haloperidol, olanzapine), some antiemetics (metoclopramide), withdrawal of antiparkinson drugs Serotonin toxicity Serotonin reuptake inhibitors, monoamine oxidase inhibitors, dextrometorphan, tramadol, tapentadol, linezolid, St John’s wort (toxicity most often occurs when the drugs are used in combination) Anticholinergic toxicity Antispasmodics, anticholinergic drugs, plant alkaloids (such as belladonna, Brugmansia) and mushrooms (e.g. Amanita) Sympathomimetic syndrome Phenthylamines, e.g. amphetamines, methamphetamines (MDMA), cocaine, monoamine oxidase inhibitors Malignant hyperthermia Volatile anaesthetics and depolarising muscle relaxants, e.g. suxamethonium Uncoupling of oxidative phosphorylation Salicylates in overdose, dinitrophenol Open in a separate window Non-drug-induced causes of hyperthermia There are numerous causes of complicated hyperthermia that are not due to drug exposure (Table 2). Non-drug causes should always be considered and excluded. Lethal catatonia (which can develop over weeks), central nervous system lesions or infections, and tetanus can all cause hyperthermia associated with muscle rigidity. The diagnosis is based on the history and clinical picture. Table 2 Non-drug causes of hyperthermia and muscle rigidity Non-drug-induced causes Associated features Severe catatonia Severe rigidity accompanied by psychosis, severe affective disorder, stupor Heat stroke Extreme dehydration, exercise or stress in hot, humid environments particularly in patients taking diuretics Central nervous system infection General malaise, neurological deterioration, meningeal irritation Tetanus Trismus, muscle spasm starting from the neck down, profuse sweating, spasticity intensified by stimuli Thyrotoxicosis Tachycardia, tremor and hypertension Phaeochromocytoma Tachycardia, hypertension and tremor, diaphoresis, agitation Open in a separate window Thyrotoxicosis and phaeochromocytoma should be considered in the differential diagnosis of hyperthermia. However, they are rarely associated with muscle rigidity.