Continuing Education Activity

This activity provides healthcare professionals with an in-depth review of diphenhydramine, a first-generation antihistamine commonly prescribed to manage allergic disorders, insomnia, pruritus, urticaria, vertigo, motion sickness, and dystonias. Clinical applications, mechanism of action, adverse effects, contraindications, and off-label uses receive focused attention, ensuring healthcare professionals understand the broad range of conditions where diphenhydramine may play a role. Pharmacokinetics, administration strategies, and clinically significant drug interactions are reviewed to support safe and effective prescribing practices.

This activity also addresses diphenhydramine’s toxicity profile, highlighting risks associated with inappropriate dosing, drug interactions, and patient-specific factors. Evidence-based strategies for optimizing therapeutic benefits while minimizing adverse outcomes are discussed in detail. Healthcare professionals gain essential information to adjust dosing regimens, recognize contraindications, and make informed treatment decisions. By enhancing understanding of diphenhydramine’s clinical utility and safety considerations, this activity supports improved patient care and safer prescribing practices across various care settings.

Objectives:

• Evaluate the mechanisms of action of diphenhydramine.
• Identify the FDA-approved indications and off-label uses of diphenhydramine.
• Assess the possible adverse events associated with diphenhydramine administration.
• Implement effective collaboration and communication among interprofessional team members to improve the efficacy of diphenhydramine pharmacotherapy and the outcomes for patients who might benefit from it.

Indications

FDA-Approved Indications

The intravenous formulation of diphenhydramine is FDA-approved for preventing transfusion reactions, as an adjunct to epinephrine in anaphylaxis after acute symptoms are controlled, and for allergic conditions when oral therapy is not feasible or contraindicated. Diphenhydramine is also approved for motion sickness. The prophylactic use of antihistamines appears to diminish the risk of developing motion sickness compared to a placebo. The antihistamines evaluated in these studies are first-generation antihistamines; these results should not be generalized to second- or third-generation antihistamines. Furthermore, antihistamines are not recommended for the treatment of existing motion sickness.[1] Additionally, diphenhydramine is infrequently used to manage parkinsonism. Although the American Academy of Allergy, Asthma & Immunology advises against administering antihistamines and glucocorticoids to prevent biphasic anaphylaxis, these may be considered for secondary treatment. Antihistamines can alleviate urticaria and itching to improve comfort during anaphylaxis, but antihistamines should not delay the first-line treatment.[2][3]

Off-Label Uses

Diphenhydramine is an over-the-counter first-generation antihistamine used to treat and prevent dystonias, insomnia, pruritis, urticaria, vertigo, and motion sickness.[4] Diphenhydramine also possesses local anesthetic properties for patients with allergies to other, more commonly used local anesthetics; however, this is an off-label use. Additionally, diphenhydramine may be administered to treat oral mucositis.[5] According to the American Academy of Allergy, Asthma & Immunology guidelines, first-generation antihistamines like diphenhydramine can be used for urticaria. However, second-generation antihistamine is the preferred choice.[6] According to the American Academy of Allergy, Asthma & Immunology guidelines, patients with non-allergic rhinitis (NAR), allergic rhinitis (AR), and vasomotor rhinitis (VMR) experience symptoms such as nasal congestion, postnasal drainage, and rhinorrhea, although the underlying mechanisms differ. Postnasal drainage in patients with NAR and VMR is often poorly controlled. Clinicians may consider using first-generation antihistamines as an additional therapy for persistent postnasal drainage. This strategy remains controversial and should be prescribed at the lowest effective dose with careful monitoring for adverse effects.[7] 

Glucocorticoids and antihistamines may also be considered to prevent anaphylaxis or infusion-related reactions when indicated for specific chemotherapy agents.[2] According to the National Comprehensive Cancer Network (NCCN) guidelines, anaphylactic symptoms in mastocytosis should be treated with epinephrine as first-line therapy. Antihistamines (H1 and H2 blockers) and steroids can be added as needed. Systemic hives without organ involvement can be managed with antihistamines.[8] 

The use of intravenous diphenhydramine may be considered as an adjunct to other treatment modalities.[9] The Society for Immunotherapy of Cancer's statement on immunotherapy for multiple myeloma treatment considers standard premedications up to 60 minutes before infusion to minimize infusion-related reactions (IRRs). A standard premedication regimen may include steroids, intravenous diphenhydramine, ranitidine, and acetaminophen.[10] Diphenhydramine can be used as premedication before ocrelizumab infusions to reduce infusion-related reactions. Although cetirizine is preferred, diphenhydramine is still a viable option, though it may cause increased drowsiness.[11] 

Scombroid poisoning accounts for 5% of all food poisoning cases in the U.S. and 40% of fish-related poisonings, although the actual incidence is likely higher due to underreporting. This condition occurs from consuming improperly preserved fish such as tuna, mackerel, and sardines, where gram-negative bacteria like Morganella morganii and Escherichia coli convert histidine into histamine. This process triggers symptoms such as rashes, urticaria, hypotension, bronchoconstriction, and respiratory distress. Treatment includes antihistamines like diphenhydramine for mild cases and, for severe cases, intravenous antihistamines, corticosteroids, and epinephrine as required.[12][13][14]

Mechanism of Action

Diphenhydramine primarily works by antagonizing the H1 (histamine-1) receptor, although it also has other mechanisms of action.[15] The H1 receptor is located on respiratory smooth muscles, vascular endothelial cells, cardiac tissue, the gastrointestinal tract (GIT), the uterus, immune cells, and the central nervous system (CNS) neurons. When the H1 receptor is stimulated in these tissues, it produces a wide variety of actions, including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and GIT, and eosinophilic chemotaxis promoting the allergic immune response. Diphenhydramine acts as an inverse agonist at the H1 receptor, reversing histamine's effects on capillaries and reducing allergic reaction symptoms. Since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness and suppressing the medullary cough center.[16] The H1 receptor is similar to muscarinic receptors. Therefore, diphenhydramine also acts as an antimuscarinic, a competitive antagonist of the muscarinic acetylcholine receptor, resulting in its use as an antiparkinson medication. Lastly, diphenhydramine acts as an intracellular sodium channel blocker, producing local anesthetic properties.

Pharmacokinetics 

Absorption: Diphenhydramine has an oral bioavailability of 72% (±8%), with peak plasma concentration (Cmax) occurring around 1.5 hours after administration.

Distribution: The volume of distribution is 17 L/kg, and it binds extensively to plasma proteins (approximately 98%).

Metabolism: Diphenhydramine undergoes substantial first-pass metabolism in the liver by the CYP450 system, predominantly by CYP2D6.[17] 

Elimination: Diphenhydramine is primarily excreted in the urine. Only about 2% of diphenhydramine is excreted unchanged in urine. The terminal half-life is roughly 9 hours in adults but shorter in children, with a reported half-life of 5.4 hours.[18]

Administration

Available Dosage Forms and Strengths

The injectable solution is provided at a concentration of 50 mg/mL. Oral dosage forms include tablets with strengths of 25 mg and 50 mg, as well as capsules available in 25 mg and 50 mg strengths. Chewable tablets are formulated with 12.5 mg of diphenhydramine, while dispersible tablets contain 25 mg. Liquid formulations consist of oral solutions containing 12.5 mg/5 mL and 50 mg/30 mL, with elixirs available at 12.5 mg/5 mL and syrups at 12.5 mg/5 mL. These different formulations offer flexible dosing options for both pediatric and adult populations. The topical formulation contains diphenhydramine hydrochloride at 2% and zinc acetate at 0.1%. The following are recommended dosages for allergy symptoms.

Dosage

Mild Symptoms

• Adult

  • 25 to 50 mg every 4 to 6 hours as needed (PO/IM/IV)
  • Max: 300 mg daily (PO); 100 mg/dose, up to 400 mg daily (IM/IV)
• Pediatric

  • 2 to 5 years: 6.25 mg every 4 to 6 hours as needed; max 37.5 mg daily (PO/IM/IV)
  • 6 to 11 years: 12.5 to 25 mg every 4 to 6 hours as needed; max 150 mg/day (PO/IM/IV)
  • 12 years and older: use adult dosing

More Severe Symptoms

• Adult

  • 25 to 50 mg every 2 to 4 hours as needed (PO/IM/IV)
  • Max: 300 mg daily (PO); 100 mg/dose, up to 400 mg daily (IM/IV)
• Pediatric

  • 2 to 11 years: 1 to 2 mg/kg every 2 to 4 hours as needed (PO/IM/IV); max: 300 mg daily (PO); 100 mg/dose, up to 400 mg daily (IM/IV)
  • 12 yo and older: use adult dosing

Extrapyramidal Symptoms

• 25 to 50 mg every 6 to 8 hours as needed (PO/IM/IV)
• Max 300 mg daily (PO); 100 mg/dose, up to 400 mg/day (IM/IV)
• Pediatric

  • 2 to 11 years: 1 to 2 mg/kg every 6 to 6 hours as needed (PO/IM/IV); max 50 mg/dose, up to 300 mg daily (IM/IV)
  • 12 years and older: use adult dosing

Insomnia (Short Treatment)

• 25 to 50 mg, 30 min before bedtime as needed (PO). However, the American Academy of Sleep Medicine suggests that clinicians should not use diphenhydramine for sleep onset or sleep maintenance insomnia.[19]
• Pediatric - 12 yo and older: 25 to 50 mg, 30 min at bedtime as needed (PO).

Motion Sickness Prevention

• 25 to 50 mg, every 4 to 6 hours as needed (PO/IM/IV)
• Start 30 min before event; max 300 mg daily (PO); 100 mg/dose, up to 400 mg daily (IM/IV)
• Pediatric dose:

  • 2 to 5 years: 6.25 mg, every 4 to 6 hours as needed (PO/IM/IV); start 30 min before the event; max 37.5 mg daily
  • 6 to 11 years: 12.5 to 25 mg, every 4 to 6 hours as needed (PO/IM/IV); start 30 min before the event; max 150 mg daily
  • 12 years and older: use adult dosing

Pruritis/Urticaria

• 25 to 50 mg, every 4 to 6 hours as needed (PO/IM/IV); max 300 mg daily (PO); 100 mg/dose up to 400 mg daily (IM/IV)
• Pediatric

  • 2 to 5 years: 6.25 mg, every 4 to 6 hours as needed (PO/IM/IV); max 37.5 mg daily
  • 6 to 11 years: 12.5 to 25 mg, every 4 to 6 hours as needed (PO/IM/IV); max 150 mg daily
  • 12 years and older: use adult dosing
• Topical Treatment

  • Apply as needed; max 4 times daily [20]
  • For local anesthesia:

    • Prepare a 1% solution of diphenhydramine (10 mg/mL)
    • Draw up all the contents of a vial containing 50 mg/mL diphenhydramine into a 10 mL syringe. Measure the volume of the syringe at 1 mL. 
    • Dilute the contents of the syringe with 4 mL of 0.9% sodium chloride to yield a final volume of 5 mL. This is now diphenhydramine 1% (10 mg/mL).[21][22]
    • This use is off-label. Watch for tissue necrosis.

Sedation

• 25 to 50 mg, every 4 to 6 hours as needed (PO/IM/IV); max 300 mg daily (PO); 100 mg/dose up to 400 mg daily (IM/IV)

Specific Patient Populations

Hepatic impairment: The product labeling does not provide information about using diphenhydramine for hepatic impairment. The lowest effective dose should be administered.

Renal impairment: Diphenhydramine is often used by patients with end-stage kidney disease (ESKD) for allergies and itching. However, limited data on its safety and dosing in ESKD are available. High protein binding may hinder its removal during dialysis, raising concerns about adverse effects and overdose. Clinicians should exercise caution in prescribing diphenhydramine in this population.[23]

Pregnancy considerations: Diphenhydramine crosses the placenta.[24] Antihistamines like diphenhydramine and doxylamine are often used in early pregnancy to treat nausea and vomiting by reducing stimulation of the vomiting center through their effects on the vestibular system.[25] The American College of Obstetricians and Gynecologists (ACOG) recommends a combination of doxylamine and pyridoxine as the preferred treatment option. Common adverse reactions include sedation, constipation, and drowsiness.[26]

Breastfeeding considerations: Higher doses or prolonged use may lead to sedation, irritability, or a reduced milk supply, especially when combined with medications like pseudoephedrine or before lactation is fully established. Non-sedating antihistamines are preferred alternatives. Furthermore, high doses can decrease prolactin levels, which may impact lactation in postpartum women. Therefore, the use of diphenylamine during lactation should be avoided.[27]

Pediatric patients: Pediatric exposures to diphenhydramine are primarily due to accidental, unsupervised ingestions, especially in children aged 2 to 4 years. Adverse events commonly included tachycardia, somnolence, hallucinations, mydriasis, agitation, and, less frequently, seizures. Fatalities, although rare, were often associated with child abuse or homicide.[28] A physiologically based pharmacokinetic (PBPK) model can predict diphenhydramine pharmacokinetics in pediatrics. The model can aid healthcare providers in personalizing dosing regimens to optimize therapeutic efficacy and minimize adverse effects in children.[29]

Older patients: According to the American Geriatric Society guidelines, diphenhydramine possesses strong anticholinergic properties and should be generally avoided; however, for acute allergic reactions, it may be used under strict monitoring.[30]

Adverse Effects

The following adverse effects have been observed in patients receiving diphenhydramine therapy.

Common adverse effects associated with diphenhydramine administration include:

• Drowsiness
• Dizziness
• Impaired coordination
• Headache
• Epigastric discomfort
• Thickened bronchial secretions
• Dry mucous membranes
• Constipation
• Euphoria
• Ataxia
• Dysuria
• Urinary retention
• Hypotension
• Blurred vision
• Diplopia
• Palpitations
• Tachycardia
• Photosensitivity
• Diaphoresis
• Erectile dysfunction
• Early menses
• Anorexia
• CNS stimulation, paradoxical [31]

Severe adverse effects associated with diphenhydramine administration include:

• Anaphylaxis/anaphylactoid reaction
• QT prolongation
• Anemia, hemolytic
• Thrombocytopenia
• Agranulocytosis
• Leukopenia
• Pancytopenia
• Arrhythmias
• Toxic psychosis
• Labyrinthitis, acute
• Heatstroke [32]
• Seizures [33]

Drug-Drug Interactions

Diphenhydramine has additive effects with alcohol and other CNS depressants, including hypnotics, sedatives, and tranquilizers. Monoamine oxidase A inhibitors prolong and intensify the anticholinergic effects of antihistamines. Diphenhydramine should not be combined with medications that have potent anticholinergic properties, such as tricyclic antidepressants, chlorpromazine, olanzapine, benztropine, trihexyphenidyl, hydroxyzine, loperamide, oxybutynin, due to the increased risk of additive anticholinergic effects.[34]

Contraindications

Diphenhydramine is contraindicated for patients with documented hypersensitivity, premature infants, and neonates. Diphenhydramine should also not be administered to breastfeeding mothers. The parenteral formulation can cause tissue necrosis when used as a local anesthetic.

Warning and Precautions 

• Diphenhydramine may cause postrenal obstruction, leading to urinary retention and, thus, decreased glomerular filtration rate. If acute kidney injury develops, discontinue diphenhydramine and begin supportive care for acute kidney injury if needed.[35]
• Diphenhydramine may cause CNS depression, which can impair driving or operating heavy machinery.
• Diphenhydramine is considered a high-risk medication for older patients because of increased fall risk from dizziness, sedation, and hypotension.
• Use with caution in patients with asthma, hyperthyroidism, cardiovascular disease, hypertension, or increased ocular pressure.
• Inhibition of fast sodium channels and repolarizing potassium channels (Ikr) can prolong the action potential and the QT interval, leading to QTc prolongation.[36][37][38]
• In pediatric patients, paradoxical stimulation (characterized by confusion and agitation) is typically the initial sign of an adverse effect, which may be succeeded by sedation and coma.[31]

Monitoring

Baseline creatinine levels should be obtained for pediatric patients. All patients should be screened for mental alertness and relief of symptoms. The intravenous infusion rate should be no higher than 25 mg/min. Diphenhydramine should be stored at 15 to 30 °C (room temperature) and protected from freezing and light. Clinicians should monitor patients for adverse anticholinergic effects such as sedation, constipation, and urinary retention.[35]

Toxicity

Signs and Symptoms of Overdose

Diphenhydramine overdose can cause significant toxicity and result in various sequelae, including agitation, cardiac arrhythmias, rhabdomyolysis and the classic anticholinergic toxidrome.[39][40][41][42][41][39] Signs and symptoms of a diphenhydramine overdose are listed below.

• Delirium
• Agitation
• Confusion
• Restlessness
• Hallucinations
• Ataxia
• Tremor
• Seizure
• Dry sweat glands and mucous membranes
• Flushed skin
• Elevated body temperature
• Mydriasis and blurry vision
• Urinary retention
• Tachycardia
• Rhabdomyolysis

Management of Overdose

Treatment of a diphenhydramine overdose may involve the following:

• Activated charcoal: may be attempted if the patient presents within 1 hour of ingesting oral diphenhydramine
• Benzodiazepines: typically administered for agitation and seizures

  • Phenobarbital and propofol may be preferred; avoid phenytoin and fosphenytoin, as they further block sodium channels
• Sodium bicarbonate: prolongs the QRS interval and is typically administered to overcome sodium channel blockade

  • Adult dose: 2 mEq/kg (typically 2 to 3 ampules of bicarbonate) via continuous infusion. Mix 3 ampules of sodium bicarbonate in 1L D5W, and run this infusion at 250 mL/hr.
• Magnesium sulfate: should be administered intravenously for a prolonged QT interval
• Vasopressors: administered to treat hypotension
• Physostigmine: acetylcholinesterase inhibitor that binds reversibly to inhibit acetylcholinesterase in the central and peripheral nervous system, which in turn allows acetylcholine to bind to muscarinic receptors to overcome the anticholinergic block. Physostigmine should be administered while in contact with a medical toxicologist or poison control specialist.

  • Dose: 0.5 to 2 mg over 5 min (IV)
  • The onset of action typically occurs within 20 minutes
  • Atropine should be ready at the bedside, and patients should be monitored for bradycardia

Further studies are needed to investigate the potential treatment of diphenhydramine toxicity using sodium bicarbonate and intravenous lipid emulsion therapy.[43] Severe diphenhydramine toxicity can cause cardiac adverse effects due to sodium channel blockade. Lipid emulsion therapy may serve as an alternative treatment, as the lipids bind to diphenhydramine, potentially reversing its blockage of sodium channels.[44]

Enhancing Healthcare Team Outcomes

Diphenhydramine is now available over the counter, but that does not mean that interprofessional healthcare team members should not pay close attention when patients report self-administering it. Clinicians must educate the patient on the safe use of this agent. While the drug is relatively safe, it should not be combined with alcohol, other sedatives, and hypnotics. The patient should be shown how to read the product labeling and advised not to take more than the recommended dose. Parents should also be educated on the safe storage of this agent to prevent accidental ingestion by children.[31] Immunologists can provide valuable insight into refractory anaphylaxis. Emergency medicine physicians need to be prepared to handle potential overdose or severe reactions. Toxicologists offer expertise in managing toxic exposures and adverse effects related to diphenhydramine. Collaboration among interprofessional teams and exchanging information can enhance patient outcomes and mitigate adverse events related to diphenhydramine therapy.

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Disclosure: Vincent Sicari declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Christopher Zabbo declares no relevant financial relationships with ineligible companies.