First-generation H1 antihistamine (sedating)
Diphenhydramine is an antihistamine used to relieve allergy symptoms (sneezing, runny nose, itching) and as a sleep aid. It is a first-generation antihistamine: it causes marked drowsiness. You should avoid driving or operating machinery after taking it.
Also known as: Benadryl, difenidramina, diphenhydramine
DailyMed/FDA (NIH/NLM) — OTC Diphenhydramine label (Drug Facts): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f1e83e43-011c-4470-bd55-fb2818a9fc84
OTC DailyMed label (Drug Facts): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f1e83e43-011c-4470-bd55-fb2818a9fc84 — pharmacokinetics: PubMed PMID 3760245 (Pharmacokinetics of diphenhydramine and a demethylated metabolite, 1986); PMID 2391399 (Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly, 1990)
Sedating antihistamine + SSRI: mild additive sedation.
Diphenhydramine is a first-generation antihistamine with central sedative effect, and sertraline can cause drowsiness or fatigue, especially at treatment start. The combination adds up the sedative effect, potentially causing daytime drowsiness, reduced concentration and a higher risk of falls in the elderly. It is not contraindicated, but caution is recommended: prefer less sedating antihistamines if needed, avoid driving and monitor symptoms. In the elderly, consider the anticholinergic burden of diphenhydramine (confusion, urinary retention, dry mouth).
Sedating antihistamine + SSRI: mild additive sedation. Watch for daytime drowsiness.
Both may cause sedation and additive anticholinergic effects.
Symptoms of excessive sedation.
Daytime drowsiness, confusion in the elderly.
Use with caution; watch for daytime drowsiness.
DailyMed (FDA) — approved Diphenhydramine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d8944f3c-acef-4ebe-9633-7d641ae95edf ; approved Sertraline label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=91e24d17-ff0a-449c-9472-b9df74c98456 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sedating antihistamine + tramadol: additive sedation and seizure risk.
Diphenhydramine (first-generation antihistamine) and tramadol (opioid) both depress the central nervous system; the diphenhydramine label warns that antihistamines are most likely to cause dizziness, sedation and hypotension in elderly patients, and the combination adds this effect to that of the opioid, with a risk of excessive sedation, drowsiness, confusion and falls. Avoid the combination whenever possible (especially in the elderly), use the lowest effective doses, monitor sedation and advise the patient not to drive or operate machinery during the combination.
Diphenhydramine + tramadol: additive sedation and CNS depression risk. Avoid in the elderly or monitor closely.
Additive CNS depressant effect; tramadol lowers the seizure threshold.
Level of consciousness and neurological symptoms.
Seizures, excessive drowsiness, confusion.
Avoid in elderly/frail patients; watch for sedation and neurological symptoms.
DailyMed (FDA) — approved Diphenhydramine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d8944f3c-acef-4ebe-9633-7d641ae95edf ; approved Tramadol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f0e33bd-65f8-446a-886f-e7e16a142ce5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Sedating antihistamine + opioid: additive CNS depression.
The diphenhydramine label documents that "diphenhydramine has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc.)" and the morphine label classifies "Benzodiazepines and Other Central Nervous System (CNS) Depressants" as an interaction with risk of "profound sedation, respiratory depression, coma, and death" due to additive pharmacologic effect. Diphenhydramine is an H1 antihistamine with central sedative effect and morphine is an opioid with CNS and respiratory depression — the sum is particularly risky in the elderly, patients with COPD, sleep apnoea or polypharmacy. Avoid whenever possible; if unavoidable (e.g., uraemic pruritus or allergic reaction in a patient on morphine), use the lowest dose, watch for sedation and respiratory rate, and inform the patient not to drive or operate machinery. Consider non-sedative alternatives (second-generation H1 antihistamines, such as cetirizine, for pruritus).
Diphenhydramine + morphine: additive sedation and CNS depression. Risk of somnolence, dizziness and respiratory depression. Avoid or monitor closely.
Both depress the CNS, potentiating sedation and respiratory depression.
Level of consciousness, respiratory rate, oximetry.
Deep drowsiness, bradypnoea, confusion.
Avoid the combination; if unavoidable, use the lowest dose and watch sedation/respiration.
DailyMed (FDA) — approved Diphenhydramine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d8944f3c-acef-4ebe-9633-7d641ae95edf ; approved Morphine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57ee014e-744e-65e1-e063-6394a90a8c93 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Food may reduce gastric irritation.
May take with food if stomach discomfort occurs.
EMC-UK (MHRA) — approved Diphenhydramine SmPC: https://www.medicines.org.uk/emc/product/1476/smpc
Alcohol markedly potentiates diphenhydramine sedation.
Avoid alcohol during treatment.
EMC-UK (MHRA) — approved Diphenhydramine SmPC: https://www.medicines.org.uk/emc/product/1476/smpc
Anticholinergic effects may thicken secretions and impair expectoration.
Use with caution in patients with asthma/COPD.
EMC-UK (MHRA) — approved Diphenhydramine SmPC: https://www.medicines.org.uk/emc/product/1476/smpc
Anticholinergic effects may worsen urinary retention.
Use with caution in men with symptomatic prostatic hyperplasia.
EMC-UK (MHRA) — approved Diphenhydramine SmPC: https://www.medicines.org.uk/emc/product/1476/smpc
Diphenhydramine has anticholinergic effects that may precipitate angle-closure glaucoma.
Contraindicated in untreated angle-closure glaucoma.
EMC-UK (MHRA) — approved Diphenhydramine SmPC: https://www.medicines.org.uk/emc/product/1476/smpc
Occasional use is generally considered safe; avoid high doses near term (theoretical risk of oxytocic/neonatal effects).
Use the lowest possible dose for a short duration.
Low milk levels; occasional use compatible with infant monitoring.
No specific additional contraception.
EMC-UK (MHRA) — approved Diphenhydramine SmPC: https://www.medicines.org.uk/emc/product/1476/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
First-generation H1 antihistamine with marked sedative effect and antimuscarinic, antiemetic and antipruritic properties. Blocks histamine effects on the respiratory mucosa and skin (relief of sneezing, runny nose, itching) and, by central action, produces drowsiness — also used as an occasional hypnotic.
Diphenhydramine competitively antagonises histamine H1 receptors, blocking the vasodilator and capillary permeability effects of histamine. Unlike second-generation antihistamines, it crosses the blood-brain barrier — blockade of central H1 receptors explains the marked sedation.
Diphenhydramine is well absorbed orally, with plasma peaks 1–3 hours after the dose; plasma protein binding is ~80–85% and the volume of distribution is ~4.5 L/kg. Antihistamine effects begin ~30 minutes after intake.
Diphenhydramine undergoes substantial hepatic first-pass metabolism, predominantly by CYP2D6 (with CYP3A4 pathways); the metabolites (including N-desmethyl) are eliminated in the urine. Oral bioavailability is ~72%, reflecting the first-pass effect.
The mean elimination half-life is ~8.4 hours in adults (13.5 hours in the elderly; shorter in children); the clinical duration of effect is 4–6 hours. Half-life is prolonged in hepatic impairment.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
