Diphenhydramine was one of the first antihistamines developed in the late 1940s and is the prototype of the ethanolamine class of first-generation antihistamines, which also includes dimenhydrinate, its closest chemical relative, as well as orphenadrine, phenyltoloxamine, doxylamine, and halogenated diphenhydamine derivatives.
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. Diphenhydramine can cause minor psychological dependence when used improperly. It does not alter sleep stages 3-4 or REM sleep
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, such as meclozine, 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 effects (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.
Various derivatives of diphenhydramine including the muscle relaxant orphenadrine (Norflex) and bromodiphenhydramine (Ambrodyl) are used clinically and in research.
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.
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 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 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.
Diphenhydramine is sometimes used as a recreational drug, often by those without access to illegal drugs. It is used for its sedative properties and (at higher doses) delirium-induced hallucinations. In many people it can produce a distinctive weak to moderate euphoria due to a rise in the dopamine:acetylcholine ratio in the CNS. A fourth use, perhaps the most common, and one which is used clinically, is to intensify the effects of opioids and to make supplies last longer by lowering opioid requirements for a given targeted objective. Recreational use of diphenhydramine may cause:
^ abcdSimons KJ, Watson WT, Martin TJ, Chen XY, Simons FE (July 1990). "Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children". J. Clin. Pharmacol.30 (7): 665–71. doi:10.1002/j.1552-4604.1990.tb01871.x. PMID2391399.
^Raphael GD, Angello JT, Wu MM, Druce HM (April 2006). "Efficacy of diphenhydramine vs desloratadine and placebo in patients with moderate-to-severe seasonal allergic rhinitis". Ann. Allergy Asthma Immunol.96 (4): 606–14. doi:10.1016/S1081-1206(10)63557-0. PMID16680933.
^Young WF (2011). "Chapter 11: Shock". In Roger L. Humphries RL, Stone CK. CURRENT Diagnosis and Treatment Emergency Medicine,. LANGE CURRENT Series)\ (Seventh ed.). McGraw-Hill Professional. ISBN0-07-170107-9.
^Aminoff MJ (2012). "Chapter 28. Pharmacologic Management of Parkinsonism & Other Movement Disorders". In Katzung B, Masters S, Trevor A. Basic & Clinical Pharmacology (12th ed.). The McGraw-Hill Companies, Inc. pp. 483–500. ISBN978-0-07-176401-8.
^Morin CM, Koetter U, Bastien C, Ware JC, Wooten V (November 2005). "Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial". Sleep28 (11): 1465–71. PMID16335333.
^ abcBrunton L, Chabner B, Knollmann B (2011). "Chapter 32. Histamine, Bradykinin, and Their Antagonists". In Brunton L. Goodman & Gilman's The Pharmacological Basis of Therapeutics (12e ed.). McGraw Hill. pp. 242–245. ISBN978-0-07-162442-8.
^ abde Leon J, Nikoloff DM (February 2008). "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports". CNS Spectr.13 (2): 133–5. PMID18227744.
^Medical Economics (2000). Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements, 2000 (21st ed.). Montvale, NJ: Medical Economics Company. ISBN1-56363-341-8.
Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G (2012). "ABH Gel is Not Absorbed from the Skin of Normal Volunteers". Journal of Pain and Symptom Management43 (5): 961–966. doi:10.1016/j.jpainsymman.2011.05.017. PMID22560361.
^ abcPragst F (2007). "Chapter 13: High performance liquid chromatography in forensic toxicological analysis". In Smith RK, Bogusz MJ. Forensic Science (Handbook of Analytical Separations)6 (2nd ed.). Amsterdam: Elsevier Science. p. 471. ISBN978-0-444-52214-6.
^Rogers SC, Pruitt CW, Crouch DJ, Caravati EM (September 2010). "Rapid urine drug screens: diphenhydramine and methadone cross-reactivity". Pediatr. Emerg. Care26 (9): 665–6. doi:10.1097/PEC.0b013e3181f05443. PMID20838187.
^Yamashiro K, Kiryu J, Tsujikawa A, Nonaka A, Honjo M, Tanihara H, Nishiwaki H, Honda Y, Ogura Y (July 2001). "Suppressive effects of histamine H1 receptor antagonist diphenhydramine on the leukocyte infiltration during endotoxin-induced uveitis". Exp. Eye Res.73 (1): 69–80. doi:10.1006/exer.2001.1008. PMID11428864.
^Reiner PB, Kamondi A (April 1994). "Mechanisms of antihistamine-induced sedation in the human brain: H1 receptor activation reduces a background leakage potassium current". Neuroscience59 (3): 579–88. doi:10.1016/0306-4522(94)90178-3. PMID8008209.
^Marinetti L, Lehman L, Casto B, Harshbarger K, Kubiczek P, Davis J (October 2005). "Over-the-counter cold medications-postmortem findings in infants and the relationship to cause of death". J. Anal. Toxicol.29 (7): 738–43. doi:10.1093/jat/29.7.738. PMID16419411.
^Baselt RC (2008). Disposition of Toxic Drugs and Chemicals in Man. Biomedical Publications. pp. 489–492. ISBN0-9626523-7-7.
Cox D, Ahmed Z, McBride AJ (March 2001). "Diphenhydramine dependence". Addiction96 (3): 516–7. PMID11310441.
Björnsdóttir I, Einarson TR, Gudmundsson LS, Einarsdóttir RA (December 2007). "Efficacy of diphenhydramine against cough in humans: a review". Pharm. World Sci.29 (6): 577–83. doi:10.1007/s11096-007-9122-2. PMID17486423.