Diphenhydramine is significantly more potent in treatment of allergies than a newer generation of antihistamines. As a consequence, it is frequently used when an allergic reaction requires fast, effective reversal of a massive histamine release. Diphenhydramine is available as an over-the-counter drug (OTC) or prescription-only solution for injection. Injectable diphenhydramine can be used for life-threatening reactions (anaphylaxis) to allergens such as bee stings, peanuts, or latex, as an adjunct to epinephrine.
Because of these sedative properties, diphenhydramine is widely used in nonprescription sleep aids for insomnia. The maximum recommended dose is 50 mg (as the hydrochloride salt), as mandated by the U.S. FDA. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such as acetaminophen (paracetamol). An example of the latter is Tylenol PM. Examples of products having diphenhydramine as the only active ingredient include Unisom, Tylenol Simply Sleep, Nytol, ZzzQuil, and Sominex (the version sold in the US and Canada; that sold in the UK uses promethazine). Tolerance against the sedating effect of diphenhydramine builds very quickly; after three days of use at the common dosage, it is no more effective than a placebo. Contrary to popular belief, Diphenhydramine can cause minor psychological dependence when used improperly. 
Diphenhydramine also has antiemetic properties, which make it useful in treating the nausea that occurs in motion sickness. As it causes marked sedation in many individuals, newer-generation antihistamines, including loratadine, cetirizine, and dimenhydrinate, may be preferred for antiemetic use.
There are also topical formulations of diphenhydramine available, including creams, lotions, gels, and sprays. These are used to relieve itching, and have the advantage of causing much less systemic effect (i.e., drowsiness) than oral forms. Diphenhydramine also has local anesthetic properties, and has been used as such in patients allergic to common local anesthetics like lidocaine.
Diphenhydramine is a potent anticholinergic agent. This activity is responsible for the side-effects of dry mouth and throat, increased heart rate, pupil dilation, urinary retention, constipation, and, at high doses, hallucinations or delirium. Other side-effects include motor impairment (ataxia), flushed skin, blurred vision at nearpoint owing to lack of accommodation (cycloplegia), abnormal sensitivity to bright light (photophobia), sedation, difficulty concentrating, short-term memory loss, visual disturbances, irregular breathing, dizziness, irritability, itchy skin, confusion, increased body temperature (in general, in the hands and/or feet), temporary erectile dysfunction, excitability, and, although it can be used to treat nausea, higher doses may cause vomiting. Some side-effects, such as twitching, may be delayed until the drowsiness begins to cease and the person is in more of an awakening mode.
Torsades de pointes can occur as a side-effect of diphenhydramine
Acute poisoning can be fatal, leading to cardiovascular collapse and death in 2–18 hours, and in general is treated using a symptomatic and supportive approach. Diagnosis of toxicity is based on history and clinical presentation, and in general specific levels are not useful. There are several levels of evidence strongly indicating diphenhydramine (similar to chlorpheniramine) can block the delayed rectifierpotassium channel and, as a consequence, prolong the QT interval, leading to cardiac arrhythmias such as torsades de pointes.
Some patients 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. As diphenhydramine is extensively metabolized by the liver, caution should be exercised when giving the drug to individuals with hepatic impairment.
Diphenhydramine is not recommended for patients older than 60 or children under the age of six, unless a physician is consulted. These populations should be treated with second-generation antihistamines such as loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine, and azelastine. Due to its strong anticholinergic effects, diphenhydramine is on the "Beers list" of drugs to avoid in the elderly.
Topical diphenhydramine is sometimes used especially on patients in hospice. This use is without indication and topical diphenhydramine should not be used as treatment for nausea because research does not indicate that this therapy is more effective than alternatives.
Measurement in body fluids
Diphenhydramine can be quantitated 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 patients having ingested diphenhydramine. Quantitation can be to used monitor therapy, confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a death investigation.
Diphenhydramine has been shown to be a potentiator of analgesia induced by morphine in rats. Opioid users, report that Diphenhydramine potentiates any opioid drug, and not just Morphine. The mechanism behind this action is poorly understood. However, many hypotheses exist. Diphenhydramine, could potentially, have interaction with either the Kappa (κ),Delta (δ) or Mu (μ)opiate receptors. This is highly unlikely, but a possibility none-the-less. More likely hypotheses are based around diphenhydramine's antimuscarinic action, and it's possible indirect antiglutaminergic and antiadrenergic effects.
Diphenhydramine is sometimes used as a recreational drug, often by those without access to illegal drugs. These people use it for the sedative properties, as well as the delirium-induced hallucinations at higher doses. Diphenhydramine abuse may cause:
Diphenhydramine is sometimes used recreationally as a deliriant, or as a potentiator of alcohol, opiates,DXM and other depressants. Diphenhydramine is deemed to have limited abuse potential in the United States due 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 the prohibited and controlled substances in the Republic of Zambia. Travelers are advised not to bring this 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.
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