Tools
Diphenhydramine Toxicity
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
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
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](A1)
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](B2)
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](B3)
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.
References
Eckes L, Tsokos M, Herre S, Gapert R, Hartwig S. Toxicological identification of diphenhydramine (DPH) in suicide. Forensic science, medicine, and pathology. 2013 Jun:9(2):145-53. doi: 10.1007/s12024-012-9383-5. Epub 2012 Oct 12 [PubMed PMID: 23065653]
Level 3 (low-level) evidenceGardner DM, Kutcher S. Dimenhydrinate abuse among adolescents. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 1993 Mar:38(2):113-6 [PubMed PMID: 8467436]
Level 3 (low-level) evidenceRowe C, Verjee Z, Koren G. Adolescent dimenhydrinate abuse: resurgence of an old problem. The Journal of adolescent health : official publication of the Society for Adolescent Medicine. 1997 Jul:21(1):47-9 [PubMed PMID: 9215510]
Level 3 (low-level) evidenceHedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2011-2016. National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System. 2018 Dec:67(9):1-14 [PubMed PMID: 30707673]
Mowry JB, Spyker DA, Cantilena LR Jr, McMillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clinical toxicology (Philadelphia, Pa.). 2014 Dec:52(10):1032-283. doi: 10.3109/15563650.2014.987397. Epub [PubMed PMID: 25559822]
Nishino T, Wakai S, Aoki H, Inokuchi S. Cardiac arrest caused by diphenhydramine overdose. Acute medicine & surgery. 2018 Oct:5(4):380-383. doi: 10.1002/ams2.351. Epub 2018 Jun 25 [PubMed PMID: 30338086]
Taglialatela M, Timmerman H, Annunziato L. Cardiotoxic potential and CNS effects of first-generation antihistamines. Trends in pharmacological sciences. 2000 Feb:21(2):52-6 [PubMed PMID: 10664607]
Level 3 (low-level) evidenceVarma A, Ford L, Patel N, Vale JA. Elimination half-life of diphenhydramine in overdose. Clinical toxicology (Philadelphia, Pa.). 2017 Jul:55(6):615-616. doi: 10.1080/15563650.2017.1296153. Epub 2017 Mar 28 [PubMed PMID: 28349707]
Simons KJ, Watson WT, Martin TJ, Chen XY, Simons FE. Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. Journal of clinical pharmacology. 1990 Jul:30(7):665-71 [PubMed PMID: 2391399]
Blyden GT, Greenblatt DJ, Scavone JM, Shader RI. Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration. Journal of clinical pharmacology. 1986 Sep-Oct:26(7):529-33 [PubMed PMID: 3760245]
Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, Chiba K. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug metabolism and disposition: the biological fate of chemicals. 2007 Jan:35(1):72-8 [PubMed PMID: 17020955]
Radovanovic D, Meier PJ, Guirguis M, Lorent JP, Kupferschmidt H. Dose-dependent toxicity of diphenhydramine overdose. Human & experimental toxicology. 2000 Sep:19(9):489-95 [PubMed PMID: 11204550]
Level 2 (mid-level) evidence. Diphenhydramine. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:(): [PubMed PMID: 31643789]
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. Clinical toxicology (Philadelphia, Pa.). 2005:43(2):61-87 [PubMed PMID: 15822758]
Level 3 (low-level) evidenceScharman 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. Clinical toxicology (Philadelphia, Pa.). 2006:44(3):205-23 [PubMed PMID: 16749537]
Level 3 (low-level) evidence. 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. Journal of toxicology. Clinical toxicology. 1999:37(6):731-51 [PubMed PMID: 10584586]
Level 3 (low-level) evidence. Position paper: cathartics. Journal of toxicology. Clinical toxicology. 2004:42(3):243-53 [PubMed PMID: 15362590]
Level 3 (low-level) evidence. Position paper: Ipecac syrup. Journal of toxicology. Clinical toxicology. 2004:42(2):133-43 [PubMed PMID: 15214617]
Level 3 (low-level) evidencePosition paper: whole bowel irrigation. Journal of toxicology. Clinical toxicology. 2004; [PubMed PMID: 15533024]
Level 3 (low-level) evidenceHöjer 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. Clinical toxicology (Philadelphia, Pa.). 2013 Mar:51(3):134-9. doi: 10.3109/15563650.2013.770153. Epub 2013 Feb 13 [PubMed PMID: 23406298]
Level 1 (high-level) evidenceBenson 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. Clinical toxicology (Philadelphia, Pa.). 2013 Mar:51(3):140-6. doi: 10.3109/15563650.2013.770154. Epub 2013 Feb 18 [PubMed PMID: 23418938]
Level 1 (high-level) evidenceVale JA, Kulig K, American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position paper: gastric lavage. Journal of toxicology. Clinical toxicology. 2004:42(7):933-43 [PubMed PMID: 15641639]
Level 3 (low-level) evidenceJang DH,Manini AF,Trueger NS,Duque D,Nestor NB,Nelson LS,Hoffman RS, Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. Clinical toxicology (Philadelphia, Pa.). 2010 Nov [PubMed PMID: 21171853]
Level 3 (low-level) evidenceKamijo Y, Soma K, Sato C, Kurihara K. Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support. Clinical toxicology (Philadelphia, Pa.). 2008 Nov:46(9):864-8. doi: 10.1080/15563650802116151. Epub [PubMed PMID: 18608279]
Level 3 (low-level) evidenceSharma AN, Hexdall AH, Chang EK, Nelson LS, Hoffman RS. Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. The American journal of emergency medicine. 2003 May:21(3):212-5 [PubMed PMID: 12811715]
Level 3 (low-level) evidenceBurns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Annals of emergency medicine. 2000 Apr:35(4):374-81 [PubMed PMID: 10736125]
Level 2 (mid-level) evidenceAbdi A, Rose E, Levine M. Diphenhydramine overdose with intraventricular conduction delay treated with hypertonic sodium bicarbonate and i.v. lipid emulsion. The western journal of emergency medicine. 2014 Nov:15(7):855-8. doi: 10.5811/westjem.2014.8.23407. Epub 2014 Sep 19 [PubMed PMID: 25493135]
Level 3 (low-level) evidenceYu JH, Chen DY, Chen HY, Lee KH. Intravenous lipid-emulsion therapy in a patient with cardiac arrest after overdose of diphenhydramine. Journal of the Formosan Medical Association = Taiwan yi zhi. 2016 Nov:115(11):1017-1018. doi: 10.1016/j.jfma.2016.06.005. Epub 2016 Jul 12 [PubMed PMID: 27421174]