Diphenhydramine is a first-generation antihistamine with anticholinergic and sedative properties. It is most commonly used for the treatment of nausea, vomiting, allergic rhinitis, mild to severe allergic reactions (e.g., anaphylaxis), and as a mild sleep aid. While used for a wide array of medical indications, diphenhydramine is also one of the most commonly abused medications in the United States (U.S.). Acute intoxications of diphenhydramine can have severe, potentially fatal consequences if not managed appropriately in a timely manner.
Diphenhydramine toxicity can occur via oral, topical, or intravenous administration. However, it is likely that toxic diphenhydramine exposures are a result of oral ingestion, given the accessibility of oral diphenhydramine compared to other diphenhydramine formulations. Diphenhydramine overdose or intoxication can be either accidental or intentional. While intentional diphenhydramine overdose/intoxication can be observed in individuals attempting self-harm/suicide, there is documentation of individuals utilizing diphenhydramine to produce pleasant and euphoric effects. It is important to note that diphenhydramine can also be found in certain over-the-counter combination medications, such as those used for the treatment of coughs and colds.
In 2016, a study demonstrated that diphenhydramine overdoses made up 3.2% of drug overdose deaths in the U.S. In the same study, diphenhydramine ranked among the top 15 drugs most frequently involved in drug overdose deaths in the U.S. Most diphenhydramine intoxication/overdose cases occur in children ages 6 years or younger.
Diphenhydramine competes against histamine to bind to H1-receptor sites on effector cells in the respiratory tract, blood vessels, gastrointestinal tract, and in the CNS. Within the CNS, diphenhydramine can occupy, even at therapeutic doses, H1-receptors in the frontal cortex, temporal cortex, hippocampus, and pons. This can lead to significant sedation and can produce moderate to severe neurological and respiratory signs/symptoms characterized in intoxication and overdose. Due to its effects on muscarinic receptors, diphenhydramine can produce anticholinergic effects, such as blurred vision, dry mouth, urinary retention, impotence, tachycardia, and gastrointestinal effects, such as nausea and constipation.
Diphenhydramine can also have negative cardiovascular consequences in the setting of toxicity. ECG changes can be observed, which include the widening of the QRS-complex and tachycardia, possibly caused by the anticholinergic effects of diphenhydramine. More specifically, diphenhydramine can affect the delayed rectifier potassium ion channels of the heart as it can act as a blocker of potassium channels. These channels are responsible for the rapid component of the cardiac repolarizing current. This leads to the prolongation of the QT-interval and a flattening of the T-wave. As a result, individuals are at increased risk of developing potentially fatal arrhythmias, such as torsade de pointes.
Diphenhydramine pharmacokinetics do not appear to change in the event of intoxication/overdose. Peak serum levels of diphenhydramine are reached approximately 2 to 3 hours after oral administration. The elimination half-life of diphenhydramine can vary between age groups. For pediatric patients, the elimination half-life is approximately 5 hours (range: 4 to 7 hours). For adult patients, the elimination half-life is approximately 9 hours (range: 7 to 12 hours), and approximately 13.5 hours (range: 9 to 18 hours) for elderly patients (range: 9 to 18 hours). Diphenhydramine is lipophilic and has a relatively large volume of distribution (Vd).
Vd can also vary between age groups. For pediatric patients, the Vd is approximately 22 L/kg (range: 15 to 28 L/kg). For adult patients, the Vd is approximately 17 L/kg (range: 13 to 20 L/kg), and approximately 14 L/kg (range: 7 to 20 L/kg) for elderly patients. It is extensively metabolized by the liver via cytochrome P450 enzymes. Most of the diphenhydramine that is hepatically metabolized undergoes N-demethylation via CYP2D6, with minor demethylation occurring via CYP1A2, CYP2C9, AND CYP2C19. The drug undergoes metabolism to much smaller degrees in the pulmonary and renal system and is thus, minimally removed by hemodialysis. Studies have shown that diphenhydramine toxicity is dose-dependent. One retrospective study observed that moderate symptoms, characterized as agitation, confusion, hallucinations, and ECG disturbances, occurred at doses of 0.3 grams. Furthermore, severe symptoms, characterized as delirium/psychosis, seizures, coma, and death, manifested at doses of 1 gram or more.
Patients with diphenhydramine toxicity present with an extension of adverse effects and generally include CNS depression and anticholinergic symptoms. Patients that present with mild to moderate poisoning exhibit more anticholinergic symptoms, which include dry mucous membranes, disorientation, tachycardia, mydriasis, urinary retention, hyperthermia, and decreased bowel sounds. Patients with more severe toxicity may also have severe delirium, seizures, psychosis, hypotension, dystonic reactions, hallucinations, and cardiac arrhythmias (i.e., QT prolongation and QRS prolongation). In rare cases, there are reports of rhabdomyolysis and renal failure in patients with prolonged agitation, coma, or seizures.
An assessment utilizing the ABCDE (airway, breathing, circulation, disability, exposure) approach should be performed upon initial presentation to assess the severity of intoxication/overdose quickly. Vital signs, including blood pressure, heart rate, respiratory rate, temperature, and oxygen saturation, should be obtained to aid in this initial assessment. An EKG should be obtained and assessed for any changes that may indicate the presence of any arrhythmias (e.g., torsades de pointes). An acetaminophen level should also be obtained to either confirm or rule out acetaminophen as a coingestant.
Diphenhydramine plasma levels do not provide any relevant clinical information and are also not readily available. Furthermore, despite undergoing extensive hepatic metabolism, diphenhydramine is not expected to cause any abnormal elevations in liver function tests or be linked to liver injury. Serum creatinine, urine output, and creatine phosphokinase should be obtained to rule out rhabdomyolysis in the setting of seizure.
If the patient presents within 1 hour of ingestion of diphenhydramine, decontamination techniques may be considered. Single-dose activated charcoal may benefit, especially as anticholinergic effects may result in decreased gastrointestinal motility leading to delayed absorption of diphenhydramine. However, the use of charcoal is avoided in patients with altered mental status unless the airway is protected. Other decontamination procedures such as ipecac, cathartics, or gastric lavage have not been proven to be beneficial or routinely used due to lack of demonstrated efficacy and increased risk of complications.
There is currently no antidote that specifically works to reverse the effects of diphenhydramine toxicity. The mainstay of therapy of diphenhydramine toxicity is supportive management that addresses the symptomatology of intoxication/overdose. Benzodiazepines (e.g., lorazepam) for seizures or convulsions, physostigmine for acetylcholinesterase inhibition, sodium bicarbonate for ventricular arrhythmia, and VA-ECMO for hemodynamic support can be used for management of the clinical manifestations of diphenhydramine toxicity. There is growing support for the utilization of intravenous lipid emulsion therapy; however, its efficacy in this setting remains controversial. Diphenhydramine is minimally dialyzable, and thus, there is little support for hemodialysis in the management of diphenhydramine toxicity.
In pediatric cases, ingested diphenhydramine dose less than 7.5 mg/kg is safe for home observation. However, patients demonstrating any behavioral changes other than mild drowsiness or mild stimulation should be referred to an emergency department. Pediatric ingestions of diphenhydramine more than 7.5 mg/kg require referral to a healthcare facility.
The differential diagnosis should include any substance or condition that may alter mentation, result in tachycardia, urinary retention, seizures, or other anticholinergic effects. Other organic processes should also be included, such as meningitis or sepsis. To help with ruling out causes, the time of onset of delirium is important. Toxin-induced delirium occurs more rapidly and abruptly than organic causes. In patients with altered mental status, hyperthermia, and agitation, salicylate toxicity should also be ruled out.
Given early identification and management in a timely manner, the prognosis for diphenhydramine toxicity or overdose is good. Recovery is likely; however, complications may occur from prolonged hospital stays such as pneumonia. Patients may be considered for discharge if they remain asymptomatic beyond four hours of diphenhydramine oral exposure or eight hours if dermal exposure. However, a patient may be admitted if they display moderate to severe signs of anticholinergic toxicity.
Education to both the patients and the parents of pediatric patients about the proper use of medication is important. Parents should be educated not to use diphenhydramine in children younger than 12 years of age without the direction of a physician. Patients should also be educated about over the counter products containing diphenhydramine and other anticholinergic medications.
In patients with severe toxicity, a consult to a medical toxicologist or poison control center may be beneficial. If intoxication or overdose occurred accidentally, patient or caregiver education is key to decrease repeated episodes. Proper storage techniques and the utilization of children-proof containers should be emphasized to keep medications out of the reach of children, given most incidences are pediatric. Collaboration with emergency medicine pharmacists might be beneficial as they can recommend appropriate supportive therapy and identify any drug-drug interactions as well. Concomitant administration of diphenhydramine with other medications that can also cause sedation or respiratory depression should be avoided.
If intoxication or overdose occurred with the intention of self-harm, psychiatric services should be consulted as part of inpatient care. Referral to outpatient behavioral health resources prior to discharge would also be warranted to mitigate the risk of repeated intoxication or overdose.
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