Diphenhydramine Toxicity

Continuing Education Activity

Diphenhydramine is most often used for the treatment of nausea, vomiting, allergic rhinitis, mild to severe allergic reactions (e.g., anaphylaxis), and as a mild sleep aid. However, due to easy access to this medication, it is often abused and can lead to acute intoxication. To avoid the potentially serious complications and mortality associated with diphenhydramine toxicity, it must be promptly diagnosed and treated. This activity describes the evaluation and management of diphenhydramine toxicity and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiology of diphenhydramine toxicity.
• Review the appropriate evaluation of diphenhydramine toxicity.
• Outline the management options available for diphenhydramine toxicity.
• Describe interprofessional team strategies for improving care coordination and communication to advance diphenhydramine toxicity management and improve outcomes.

Introduction

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 intoxication with diphenhydramine can have severe, potentially fatal consequences if not managed appropriately in a timely manner.[1]

Etiology

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.[1] 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.[2][3] 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.

Epidemiology

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.[4] Most diphenhydramine intoxication/overdose cases occur in children ages 6 years or younger.[5]

Pathophysiology

Diphenhydramine competes against histamine to bind to H1-receptor sites on effector cells in the respiratory tract, blood vessels, gastrointestinal tract, and 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 by intoxication and overdose.[1][6] 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.[6]

Toxicokinetics

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.[1][6][7] 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.[8] 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).[9] 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.[9][10] 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.[8][9][11] 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.[12]

History and Physical

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.

Evaluation

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.[13] Serum creatinine, urine output, and creatine phosphokinase should be obtained to rule out rhabdomyolysis in the setting of seizure.

Treatment / Management

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.[14][15][16] Other decontamination procedures such as ipecac, cathartics, or gastric lavage have not been proven to be beneficial or routinely used due to a lack of demonstrated efficacy and increased risk of complications.[17][18][19][20][21][22]

There is currently no antidote that specifically works to reverse the effects of diphenhydramine toxicity. The mainstay of therapy for diphenhydramine toxicity is supportive management that addresses the symptomatology of intoxication/overdose. Benzodiazepines (e.g., lorazepam) for seizures or convulsions, sodium bicarbonate for ventricular arrhythmia, and VA-ECMO for hemodynamic support can be used for the management of the clinical manifestations of diphenhydramine toxicity. Physostigmine has been used for acetylcholinesterase inhibition, but it is not currently available. 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.[6][23][24][25][26][15][27][28]

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.[15]

Differential Diagnosis

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.

Prognosis

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. Therefore, 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.

Complications

• Respiratory failure
• Arrhythmias
• Cardiac arrest
• Rhabdomyolysis
• Seizures
• Death

Deterrence and Patient Education

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.

Enhancing Healthcare Team Outcomes

In patients with severe toxicity, a consult with 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.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Eckes L, Tsokos M, Herre S, Gapert R, Hartwig S. Toxicological identification of diphenhydramine (DPH) in suicide. Forensic Sci Med Pathol. 2013 Jun;9(2):145-53. [PubMed: 23065653]

2.

Gardner DM, Kutcher S. Dimenhydrinate abuse among adolescents. Can J Psychiatry. 1993 Mar;38(2):113-6. [PubMed: 8467436]

3.

Rowe C, Verjee Z, Koren G. Adolescent dimenhydrinate abuse: resurgence of an old problem. J Adolesc Health. 1997 Jul;21(1):47-9. [PubMed: 9215510]

4.

Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016. Natl Vital Stat Rep. 2018 Dec;67(9):1-14. [PubMed: 30707673]

5.

Mowry JB, Spyker DA, Cantilena LR, McMillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014 Dec;52(10):1032-283. [PMC free article: PMC4782684] [PubMed: 25559822]

6.

Nishino T, Wakai S, Aoki H, Inokuchi S. Cardiac arrest caused by diphenhydramine overdose. Acute Med Surg. 2018 Oct;5(4):380-383. [PMC free article: PMC6167400] [PubMed: 30338086]

7.

Taglialatela M, Timmerman H, Annunziato L. Cardiotoxic potential and CNS effects of first-generation antihistamines. Trends Pharmacol Sci. 2000 Feb;21(2):52-6. [PubMed: 10664607]

8.

Varma A, Ford L, Patel N, Vale JA. Elimination half-life of diphenhydramine in overdose. Clin Toxicol (Phila). 2017 Jul;55(6):615-616. [PubMed: 28349707]

9.

Simons KJ, Watson WT, Martin TJ, Chen XY, Simons FE. Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. J Clin Pharmacol. 1990 Jul;30(7):665-71. [PubMed: 2391399]

10.

Blyden GT, Greenblatt DJ, Scavone JM, Shader RI. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. J Clin Pharmacol. 1986 Sep-Oct;26(7):529-33. [PubMed: 3760245]

11.

Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, Chiba K. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8. [PubMed: 17020955]

12.

Radovanovic D, Meier PJ, Guirguis M, Lorent JP, Kupferschmidt H. Dose-dependent toxicity of diphenhydramine overdose. Hum Exp Toxicol. 2000 Sep;19(9):489-95. [PubMed: 11204550]

13.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jan 16, 2017. Diphenhydramine. [PMC free article: PMC547852] [PubMed: 31643789]

14.

Chyka PA, Seger D, Krenzelok EP, Vale JA., American Academy of Clinical Toxicology. European Association of Poisons Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87. [PubMed: 15822758]

15.

Scharman EJ, Erdman AR, Wax PM, Chyka PA, Caravati EM, Nelson LS, Manoguerra AS, Christianson G, Olson KR, Woolf AD, Keyes DC, Booze LL, Troutman WG. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(3):205-23. [PubMed: 16749537]

16.

Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999;37(6):731-51. [PubMed: 10584586]

17.

Position paper: cathartics. J Toxicol Clin Toxicol. 2004;42(3):243-53. [PubMed: 15362590]

18.

Position paper: Ipecac syrup. J Toxicol Clin Toxicol. 2004;42(2):133-43. [PubMed: 15214617]

19.

Position paper: whole bowel irrigation. J Toxicol Clin Toxicol. 2004;42(6):843-54. [PubMed: 15533024]

20.

Höjer J, Troutman WG, Hoppu K, Erdman A, Benson BE, Mégarbane B, Thanacoody R, Bedry R, Caravati EM., American Academy of Clinical Toxicology. European Association of Poison Centres and Clinical Toxicologists. Position paper update: ipecac syrup for gastrointestinal decontamination. Clin Toxicol (Phila). 2013 Mar;51(3):134-9. [PubMed: 23406298]

21.

Benson BE, Hoppu K, Troutman WG, Bedry R, Erdman A, Höjer J, Mégarbane B, Thanacoody R, Caravati EM., American Academy of Clinical Toxicology. European Association of Poisons Centres and Clinical Toxicologists. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol (Phila). 2013 Mar;51(3):140-6. [PubMed: 23418938]

22.

Vale JA, Kulig K., American Academy of Clinical Toxicology. European Association of Poisons Centres and Clinical Toxicologists. Position paper: gastric lavage. J Toxicol Clin Toxicol. 2004;42(7):933-43. [PubMed: 15641639]

23.

Jang DH, Manini AF, Trueger NS, Duque D, Nestor NB, Nelson LS, Hoffman RS. Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. Clin Toxicol (Phila). 2010 Nov;48(9):945-8. [PMC free article: PMC4091778] [PubMed: 21171853]

24.

Kamijo Y, Soma K, Sato C, Kurihara K. Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support. Clin Toxicol (Phila). 2008 Nov;46(9):864-8. [PubMed: 18608279]

25.

Sharma AN, Hexdall AH, Chang EK, Nelson LS, Hoffman RS. Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. Am J Emerg Med. 2003 May;21(3):212-5. [PubMed: 12811715]

26.

Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000 Apr;35(4):374-81. [PubMed: 10736125]

27.

Abdi A, Rose E, Levine M. Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic sodium bicarbonate and i.v. lipid emulsion. West J Emerg Med. 2014 Nov;15(7):855-8. [PMC free article: PMC4251236] [PubMed: 25493135]

28.

Yu JH, Chen DY, Chen HY, Lee KH. Intravenous lipid-emulsion therapy in a patient with cardiac arrest after overdose of diphenhydramine. J Formos Med Assoc. 2016 Nov;115(11):1017-1018. [PubMed: 27421174]

Disclosure: David Huynh declares no relevant financial relationships with ineligible companies.

Disclosure: Malak Abbas declares no relevant financial relationships with ineligible companies.

Disclosure: Ali Dabaja declares no relevant financial relationships with ineligible companies.