Diphenhydramine was first made by George Rieveschl and came into commercial use in 1946. It is available as a generic medication. The wholesale price in the developing world as of 2014[update] is about US$0.01 per dose. In the United States, it costs less than US$25 for a typical month’s supply. It is sold under the trade name Benadryl, among others. In 2016 it was the 210th most prescribed medication in the United States with more than 2 million prescriptions.
Diphenhydramine is effective in treatment of allergies. As of 2007[update], it was the most commonly used antihistamine for acute allergic reactions in the emergency department.
By injection it is often used in addition to epinephrine for anaphylaxis. Its use for this purpose had not been properly studied as of 2007[update]. Its use is only recommended once acute symptoms have improved.
Topical formulations of diphenhydramine are available, including creams, lotions, gels, and sprays. These are used to relieve itching and have the advantage of causing fewer systemic effects (e.g., drowsiness) than oral forms.
Because of its sedative properties, diphenhydramine is widely used in nonprescription sleep aids for insomnia. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol) in Tylenol PM or ibuprofen in Advil PM. Diphenhydramine can cause minor psychological dependence. Diphenhydramine can cause sedation and has also been used as an anxiolytic.
Diphenhydramine also has antiemetic properties, which make it useful in treating the nausea that occurs in vertigo and motion sickness.
Topical diphenhydramine is sometimes used especially for people in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.
The most prominent side effect is sedation. A typical dose creates driving impairment equivalent to a blood-alcohol level of 0.10, which is higher than the 0.08 limit of most drunk-driving laws.
Some people have an allergic reaction to diphenhydramine in the form of hives. However, restlessness or akathisia can also be a side effect made worse by increased levels of diphenhydramine, especially with recreational dosages. Normal doses of diphenhydramine, like other first generation antihistamines, can make symptoms of restless legs syndrome worse. As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.
Anticholinergic use later in life is associated with an increased risk for cognitive decline and dementia among older people.
Diphenhydramine overdose symptoms may include:
Oral bioavailability of diphenhydramine is in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration. The primary route of metabolism is two successive demethylations of the tertiary amine. The resulting primary amine is further oxidized to the carboxylic acid. The elimination half-life of diphenhydramine has not been fully elucidated, but appears to range between 2.4 and 9.3 hours in healthy adults. A 1985 review of antihistamine pharmacokinetics found that the elimination half-life of diphenhydramine ranged between 3.4 and 9.3 hours across five studies, with a median elimination half-life of 4.3 hours. A subsequent 1990 study found that the elimination half-life of diphenhydramine was 5.4 hours in children, 9.2 hours in young adults, and 13.5 hours in the elderly.
Diphenhydramine can be quantified in blood, plasma, or serum.Gas chromatography with mass spectrometry (GC-MS) can be used with electron ionization on full scan mode as a screening test. GC-MS or GC-NDP can be used for quantification. Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for people having ingested diphenhydramine. Quantification can be used to monitor therapy, confirm a diagnosis of poisoning in people who are hospitalized, provide evidence in an impaired driving arrest, or assist in a death investigation.
Diphenhydramine is deemed to have limited abuse potential in the United States owing to its potentially serious side-effect profile and limited euphoric effects, and is not a controlled substance. Since 2002, the U.S. FDA has required special labeling warning against use of multiple products that contain diphenhydramine. In some jurisdictions, diphenhydramine is often present in postmortem specimens collected during investigation of sudden infant deaths; the drug may play a role in these events.
Diphenhydramine is among prohibited and controlled substances in the Republic of Zambia, and travelers are advised not to bring the drug into the country. Several Americans have been detained by the Zambian Drug Enforcement Commission for possession of Benadryl and other over-the-counter medications containing diphenhydramine.
Although diphenhydramine is widely used and generally considered to be safe, multiple cases of abuse and addiction have been documented. Because the drug is cheap and sold over the counter in most countries, adolescents without access to stronger, illicit drugs are particularly at risk. People with mental health problems—especially those with schizophrenia—are also prone to abuse the drug, which is self-administered in large doses to treat extrapyramidal symptoms caused by the use of antipsychotics.
Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug. Research has shown that antimuscarinic agents, such as diphenhydramine, "may have antidepressant and mood-elevating properties". A study conducted on adult males with a history of sedative abuse found that subjects who were administered a high dose (400 mg) of diphenhydramine reported a desire to take the drug again, despite also reporting negative effects, such as difficulty concentrating, confusion, tremors, and blurred vision.
Diphenhydramine is marketed under the trade name Benadryl by McNeil Consumer Healthcare in the U.S., Canada, and South Africa. Trade names in other countries include Dimedrol, Daedalon, and Nytol. It is also available as a generic medication.
Procter & Gamble markets an over-the-counter formulation of diphenhydramine as a sleep aid under the brand ZzzQuil. In 2014 this product had annual sales of over $120 million and had a 29.3% share of the $411 million sleep-aid market category.
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