Diphenhydramine
Classic antihistamine as sleep aid and for allergies
Diphenhydramine is one of the oldest antihistamines ever developed, dating from the 1940s. In Germany the substance is available over the counter in capsules and tablets as a sleep aid (Vivinox, Betadorm, Hoggar Night, Emesan), as well as in combination products against the common cold and motion sickness. It belongs to the class of ethanolamines and is chemically closely related to clemastine.
Although diphenhydramine is available without prescription, pharmacologically it is a substance with a substantial side effect profile. The sedative component is pronounced, with concomitant anticholinergic, antiemetic and partly local anaesthetic actions. In many countries diphenhydramine is on the list of potentially inappropriate medications for older patients because the risk of confusion, falls and delirium is high. With correct indication and time limited use, however, the substance can be useful.
Mechanism of Action
Diphenhydramine competitively blocks H1 histamine receptors and prevents the action of histamine on vessels, on smooth muscle and on peripheral nerve fibres. The peripheral action explains the antiallergic component: vasodilation, capillary permeability, itching and wheal formation decrease. At the same time, diphenhydramine crosses the blood brain barrier and blocks central H1 receptors. This produces the pronounced sedation that makes the substance usable as a sleep aid.
In addition, diphenhydramine acts as an antagonist at muscarinic acetylcholine receptors, which accounts for dry mouth, constipation, urinary retention and accommodation disturbances. The antiemetic component at the vomiting centre makes the substance useful for motion sickness and for mild nausea. At higher doses, diphenhydramine has local anaesthetic properties and partially acts at sodium channels.
Oral bioavailability is about 40 to 60 percent because of a pronounced first pass metabolism. The half life is 4 to 12 hours, and considerably longer in older patients. Onset occurs after 15 to 30 minutes and the sedative effect lasts 4 to 8 hours. Metabolism is hepatic via CYP2D6 and CYP3A4, with renal elimination of metabolites predominating.
Indications
- Short term treatment of sleep onset and maintenance disorders in adults, mostly over the counter
- Motion sickness (kinetosis) in combination products or as monotherapy
- Allergic reactions such as urticaria, allergic rhinitis, pruritus
- Nausea and vomiting in pregnancy, chemotherapy or post operatively (mostly in combination)
- Extrapyramidal side effects under neuroleptics as emergency therapy (parenteral), less common in Germany
- Allergic reactions in children following medical prescription
Dosage and Administration
Sleep aid in adults: 25 to 50 mg at night, maximum 100 mg per day. Take 30 to 60 minutes before going to bed with a glass of water. Motion sickness: 25 to 50 mg 30 minutes before the start of travel, on long journeys repeated every 4 to 6 hours, maximum 300 mg per day. Allergic reactions: 25 to 50 mg every 6 to 8 hours.
Older patients over 65: use only in exceptional cases when alternatives are unavailable or not tolerated. Low starting dose of 12.5 to 25 mg, close monitoring. Children from 2 years: weight adapted 1 to 2 mg per kg, only after medical consultation. Use is not recommended below the age of 2 because of increased risk of central and cardiac side effects.
Renal impairment: no formal dose adjustment in mild to moderate impairment; cautious dosing in severe impairment. Hepatic impairment: dose reduction in moderate to severe impairment. Duration: self medication should not exceed 2 weeks; if sleep disorders persist, medical workup should be initiated.
Side Effects
Very common and common: sedation, next day fatigue, dry mouth, constipation, blurred vision, urinary complaints, reduced responsiveness, headache, orthostatic hypotension.
Uncommon to rare: paradoxical reactions (restlessness, insomnia, aggression, hallucinations) especially in children and older patients, tachycardia, seizures in overdose, rash, photosensitisation, blood count changes.
Important: in overdose diphenhydramine can cause severe anticholinergic symptoms (central confusion, hallucinations, seizures, tachycardia, hyperthermia) and cardiotoxic effects (QRS widening, torsade de pointes). Diphenhydramine is one of the substances frequently used in suicide attempts; the danger of an overdose is often underestimated. Suspected overdose requires immediate emergency medical care.
Priscus list: diphenhydramine is listed on the German Priscus list as potentially inappropriate for older patients. The risk of delirium, falls and cognitive impairment is elevated in this age group. Older patients with sleep disorders should preferably receive other options.
Interactions
- Centrally depressant substances (alcohol, benzodiazepines, opioids, barbiturates, other antihistamines, neuroleptics): strongly enhanced sedation and respiratory depression
- Anticholinergics (tricyclic antidepressants, biperiden, scopolamine, tolterodine): additive anticholinergic side effects up to anticholinergic delirium
- MAO inhibitors: enhanced anticholinergic effects; avoid combination
- QT prolonging substances (amiodarone, sotalol, macrolides, quinolones): additive QT prolongation and torsade risk
- Antihypertensives: enhanced hypotension
- CYP2D6 substrates and inhibitors (metoprolol, risperidone, fluoxetine): plasma levels may fluctuate
Special Notes
Contraindications: known hypersensitivity, narrow angle glaucoma, urinary retention with prostatic hypertrophy, acute asthma attack, porphyria, epilepsy (relative contraindication because of lowered seizure threshold), children under 2 years, third trimester of pregnancy.
Pregnancy: possible in the first and second trimesters after careful consideration; in the third trimester cautious because of risk of neonatal withdrawal symptoms. In pregnancy related nausea, diphenhydramine is occasionally used. Breastfeeding: passes into breast milk; sedation of the infant is possible and milk production may be reduced, so breastfeeding during therapy is not recommended.
Driving ability: often impaired the day after intake, particularly in combination with alcohol. Maintain at least 8 hours between intake and driving or operating machinery. In older patients impairment lasts longer than in younger people.
Tolerance: the sedative effect fades within a few days to weeks of regular intake. This often leads to dose escalation, which worsens anticholinergic side effects without improving sleep quality. Long term self medication is therefore not sensible.
Monitoring: clinical assessment of effectiveness after 2 weeks; if sleep disorder persists, medical workup. In older patients document cognitive function and fall risk and consider an alternative.
You might also be interested in
- Clemastine (Tavegil), related ethanolamine antihistamine
- Cetirizine, less sedating antihistamine
- Brotizolam, short acting benzodiazepine
- Prothipendyl (Dominal), low potency neuroleptic
- Dimenhydrinate, diphenhydramine derivative for motion sickness
Frequently Asked Questions
Is diphenhydramine as a sleep aid harmless because it is available without prescription?
No. Over the counter availability does not mean the substance has few side effects. Diphenhydramine has a pronounced anticholinergic profile, can precipitate delirium and falls in older patients and carries severe toxic effects in overdose. Self medication should not exceed 2 weeks; in chronic sleep disorders medical workup is necessary.
Why does the effect wear off over time?
The central histamine system downregulates with regular blockade and tolerance to the sedative effect develops. Continuous intake does not sustainably improve sleep but increases anticholinergic side effects. Cognitive behavioural therapy for insomnia (CBT I) is the long term effective option.
Can I take diphenhydramine in older age?
Caution is warranted. The Priscus list names diphenhydramine as a potentially inappropriate medication for older patients because of the risk of delirium, cognitive impairment and falls. Alternatives such as melatonin, low potency neuroleptics or cognitive behavioural therapy are preferable in this age group.
Does diphenhydramine also work in allergic reactions?
Yes, diphenhydramine is a first generation antihistamine and can relieve allergic symptoms. Because of the strong sedation, however, it is not the first choice for allergic rhinitis or chronic urticaria. Modern non sedating antihistamines such as cetirizine, loratadine or desloratadine are better tolerated and preferable for everyday use.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guidelines on Sleep Disorders and Urticaria
- Gelbe Liste, Diphenhydramine active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
Legal Notice and Disclaimer
The information provided on this page is for general informational purposes only and does not constitute medical advice, diagnosis or treatment recommendation. It does not replace consultation with a licensed physician or pharmacist. Medicines should only be taken on medical prescription or via a pharmacy. All information is based on product information and recognised scientific sources published at the time of creation; the manufacturer's current summary of product characteristics is always authoritative. Sanoliste assumes no liability for the completeness, timeliness or accuracy of the information presented. In a medical emergency, call the emergency number 112 (Europe).