Common side effects include sleepiness, poor coordination, and an upset stomach.[13] There is no clear risk of harm when used duringpregnancy; however, use duringbreastfeeding is not recommended.[15]
It was developed byGeorge Rieveschl and put into commercial use in 1946.[16][17] It is available as ageneric medication.[13] In 2023, it was the 294th most commonly prescribed medication in the United States, with more than 700,000 prescriptions.[18][19]
Diphenhydramine is effective in the treatment of allergies.[24] As of 2007[update], it was the most commonly used antihistamine for acute allergic reactions in the emergency department.[25]
By injection, it is often used in addition toepinephrine foranaphylaxis,[26] although as of 2007[update] its use for this purpose had not been properly studied.[27] Its use is only recommended once acute symptoms have improved.[24]
A bottle of topical "Itch-Stopping Gel" diphenhydramine
Topical formulations of diphenhydramine are available, including creams, lotions, gels, sprays, and eye drops. These are used to relieve itching and have the advantage of causing fewer systemic effects (e.g.,, drowsiness) than oral forms.[28]
Because of itssedative properties, diphenhydramine is widely used in nonprescription sleep aids forinsomnia. The drug is an ingredient in several products sold as sleep aids, either alone or in combination with other ingredients such asparacetamol (acetaminophen) in Tylenol PM andibuprofen in Advil PM. Diphenhydramine can cause minorpsychological dependence.[30] Diphenhydramine has also been used as ananxiolytic.[31]
Diphenhydramine has also been usedoff-label by parents in an attempt to make their children sleep and to sedate them on long-distance flights.[32] This has been met with criticism, both by doctors and by members of the airline industry, because sedating passengers may put them at risk if they cannot react efficiently to emergencies,[33] and because the drug's side effects, especially the chance of aparadoxical reaction, may make some users hyperactive. Addressing such use, theSeattle Children's Hospital argued, in a 2009 article, "Using a medication for your convenience is never an indication for medication in a child."[34]
Diphenhydramine also hasantiemetic properties, which make it useful in treating the nausea that occurs invertigo and motion sickness. However, when taken above the recommended doses, it can cause nausea (especially above 200 mg).[37]
Diphenhydramine is not typically used to treatanxiety because its long-term use may cause adverse effects, such as memory loss, especially in the elderly.[38] Diphenhydramine is not approved by the USFood and Drug Administration (FDA) for treating anxiety.[38] On the other hand,hydroxyzine, a first-generation antihistamine that lacks significant anticholinergic effects, may be used to treat anxiety, although benzodiazepines and antidepressants are considered more effective by most clinicians.[39] The mild anxiolytic effects of hydroxyzine are mostly due to its weak but significant activity as an antagonist of the5-HT2A receptor, a common target of most antidepressant drugs (as well as certain other antihistamines likecyproheptadine andpromethazine). Diphenhydramine is not known to bind to the 5-HT2A receptor, though it is a weak antagonist of the related5-HT2C receptor, which is another target of antidepressant drugs and has a significant role in mood and anxiety.[40][41]
Diphenhydramine is contraindicated in premature infants and neonates, as well as people who are breastfeeding. It is a pregnancy Category B drug. Diphenhydramine has additive effects withalcohol and otherdepressants.Monoamine oxidase inhibitors (MAOIs) prolong and intensify the anticholinergic effect of antihistamines.[42]
The most prominent side effects are dizziness and sleepiness.[43]
Diphenhydramine is a potentanticholinergic agent and a potentialdeliriant in higher doses. This activity is responsible for theside effects of dry mouth and throat,increased heart rate,pupil dilation,urinary retention, constipation, and, at high doses, hallucinations ordelirium. 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 or feet), temporaryerectile dysfunction, and excitability, and although it can be used to treat nausea, higher doses may cause vomiting.[43] Diphenhydramine in overdose may occasionally result inQT prolongation.[44]
Conditions such asrestlessness orakathisia can worsen from increased levels of diphenhydramine, especially with recreational dosages.[47] Normal doses of diphenhydramine, like otherfirst-generation antihistamines, can also make symptoms ofrestless legs syndrome worse.[48]As diphenhydramine is extensively metabolized by theliver, 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.[49] Drowsiness, memory loss, confusion, dry mouth or constipation may also occur in elderly people.[38]
Diphenhydramine is secreted in breast milk.[50] It is expected that low doses of diphenhydramine taken occasionally will cause no adverse effects in breastfed infants. Large doses and long-term use may affect the baby or reduce breast milk supply, especially when combined withsympathomimetic drugs, such as pseudoephedrine, or before the establishment of lactation. A single bedtime dose after the last feeding of the day may minimize the harmful effects of the medication on the baby and the milk supply. Still, non-sedating antihistamines are preferred.[51]
Paradoxical reactions to diphenhydramine have been documented, particularly in children, and it may cause excitation instead of sedation.[47]
Topical diphenhydramine is sometimes used, especially for people inhospice. This use is without indication, and topical diphenhydramine should not be used as treatment for nausea because research has not shown that this therapy is more effective than others.[52]
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.[55] Diagnosis of toxicity is based on history and clinical presentation, and in general, precise plasma levels do not appear to provide useful relevant clinical information.[56] Several levels of evidence strongly indicate diphenhydramine (similar tochlorpheniramine) can block thedelayed rectifierpotassium channel and, as a consequence, prolong theQT interval, leading tocardiac arrhythmias such astorsades de pointes.[57]No specificantidote for diphenhydramine toxicity is known, but the anticholinergic syndrome has been treated withphysostigmine for severe delirium or tachycardia.[56]Benzodiazepines may be administered to decrease the likelihood ofpsychosis,agitation, andseizures in people who are prone to these symptoms.[58]
Oralbioavailability of diphenhydramine is in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration.[5] Diphenhydramine, available in various salt forms,[78] such as citrate,[79][80] hydrochloride,[81] and salicylate,[82] exhibits distinct molecular weights and pharmacokinetic properties. Specifically, diphenhydramine hydrochloride and diphenhydramine citrate possess molecular weights of291.8 g/mol[83] and447.5 g/mol,[84] respectively. These variations in molecular weight influence the dissolution rates and absorption characteristics of each salt form.[85]
Theelimination half-life of diphenhydramine has not been fully elucidated, but appears to range between 2.4 and 9.3 hours in healthy adults.[6] 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.[5] 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.[7] A 1998 study found a half-life of 4.1 ± 0.3 hours in young men, 7.4 ± 3.0 hours in elderly men, 4.4 ± 0.3 hours in young women, and 4.9 ± 0.6 hours in elderly women.[86] In a 2018 study in children and adolescents, the half-life of diphenhydramine was 8 to 9 hours.[87]
Diphenhydramine can be quantified in blood, plasma, or serum.[88]Gas chromatography withmass spectrometry (GC-MS) can be used withelectron ionization on full scan mode as a screening test. GC-MS or GC-NDP can be used for quantification.[88] Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positivemethadone results for people having ingested diphenhydramine.[89] 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.[88]
In 1943, diphenhydramine was discovered by chemistGeorge Rieveschl and one of his students, Fred Huber, while they were conducting research intomuscle relaxants at theUniversity of Cincinnati.[90] Huber first synthesized diphenhydramine. Rieveschl then worked withParke-Davis to test the compound, and the company licensed the patent from him.[91] In 1946, it became the first prescription antihistamine in the United States approved by the FDA.[92]
Diphenhydramine is sold under the brand nameBenadryl byMcNeil Consumer Healthcare in the US, UK, Canada, and South Africa.[96] Trade names in other countries includeDimedrol,Daedalon,Nytol, andVivinox. It is also available as ageneric medication.
Procter & Gamble markets an over-the-counter formulation of diphenhydramine as asleep aid under the brand ZzzQuil.[97]
Prestige Brands markets an over-the-counter formulation of diphenhydramine as a sleep aid in the US under the nameSominex.[98]
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 US FDA has required special labeling warning against the use of multiple products that contain diphenhydramine.[99] 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.[100][101]
Diphenhydramine is among prohibited and controlled substances in theRepublic of Zambia,[102] 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.[103]
Although diphenhydramine is widely used and generally considered to be safe for occasional usage, multiple cases ofabuse andaddiction have been documented.[20] Because the drug is cheap and sold over the counter in most countries, adolescents without access to more sought-after illicit drugs are particularly at risk.[104] People with mental health problems—especially those withschizophrenia—are also prone to abuse the drug, which may beself-administered in large doses to treatextrapyramidal symptoms caused by the use ofantipsychotics.[105]
Recreational users report calming effects, mild euphoria, and hallucinations as the desired effects of the drug.[105][106] Research has shown thatantimuscarinic agents, including diphenhydramine, "may have antidepressant and mood-elevating properties".[107] A study conducted on adult males with a history ofsedative 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.[108]
In 2020, an Internet challenge emerged on the social media platformTikTok involving deliberately overdosing on diphenhydramine; dubbed theBenadryl challenge, the challenge encourages participants to consume dangerous amounts of Benadryl to film the resultant psychoactive effects and has been implicated in several hospitalisations[109] and at least two deaths.[110][111][112] An entity reported to have been seen by people while under the effects of diphenhydramine, known as the "Hat Man", has become anInternet meme and anurban legend.[113][114]
^abAHFS Drug Information. Published by authority of the Board of Directors of the American Society of Hospital Pharmacists. 1990.ISBN978-0-930530-96-9.Archived from the original on 14 January 2023. Retrieved9 October 2017.
^abSimons KJ, Watson WT, Martin TJ, Chen XY, Simons FE (July 1990). "Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children".Journal of Clinical Pharmacology.30 (7):665–71.doi:10.1002/j.1552-4604.1990.tb01871.x.PMID2391399.S2CID25452263.
^abKrystal AD (August 2009). "A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: the empirical basis for U.S. clinical practice".Sleep Med Rev.13 (4):265–74.doi:10.1016/j.smrv.2008.08.001.PMID19153052.
^Rickels K (1992). "Diphenhydramine-induced paradoxical excitation".Journal of Clinical Psychopharmacology.12 (3):222–223.doi:10.1097/00004714-199206000-00013.
^abcdef"Diphenhydramine Hydrochloride".Drugs.com. American Society of Health-System Pharmacists. 6 September 2016.Archived from the original on 15 September 2016. Retrieved28 September 2016.
^abThomas A, Nallur DG, Jones N, Deslandes PN (January 2009). "Diphenhydramine abuse and detoxification: a brief review and case report".Journal of Psychopharmacology.23 (1):101–5.doi:10.1177/0269881107083809.PMID18308811.S2CID45490366.
^Banerji A, Long AA, Camargo CA (2007). "Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: a literature review".Allergy and Asthma Proceedings.28 (4):418–26.doi:10.2500/aap.2007.28.3015.PMID17883909.S2CID7596980.
^Young WF (2011). "Chapter 11: Shock". In Humphries RL, Stone CK (eds.).CURRENT Diagnosis and Treatment Emergency Medicine. LANGE CURRENT Series (Seventh ed.). McGraw–Hill Professional.ISBN978-0-07-170107-5.
^Aminoff MJ (2012). "Chapter 28. Pharmacologic Management of Parkinsonism & Other Movement Disorders". In Katzung B, Masters S, Trevor A (eds.).Basic & Clinical Pharmacology (12th ed.). The McGraw-Hill Companies, Inc. pp. 483–500.ISBN978-0-07-176401-8.
^Monson K, Schoenstadt A (8 September 2013)."Benadryl Addiction". eMedTV. Archived from the original on 4 January 2014.
^Dinndorf PA, McCabe MA, Friedrich S (August 1998). "Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses".The Journal of Pediatrics.133 (2):293–5.doi:10.1016/S0022-3476(98)70240-9.PMID9709726.
^Sicari V, Zabbo CP (2021). "Diphenhydramine".StatPearls. Treasure Island (FL): StatPearls Publishing.PMID30252266.Archived from the original on 28 May 2022. Retrieved27 December 2021.
^Coskey RJ (February 1983). "Contact dermatitis caused by diphenhydramine hydrochloride".Journal of the American Academy of Dermatology.8 (2):204–206.doi:10.1016/S0190-9622(83)70024-1.PMID6219138.
^abde Leon J, Nikoloff DM (February 2008). "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports".CNS Spectrums.13 (2):133–5.doi:10.1017/s109285290001628x.PMID18227744.S2CID10856872.
Weschules DJ (December 2005). "Tolerability of the compound ABHR in hospice patients".Journal of Palliative Medicine.8 (6):1135–43.doi:10.1089/jpm.2005.8.1135.PMID16351526.
^Huynh DA, Abbas M, Dabaja A (2021).Diphenhydramine Toxicity.PMID32491510.
^abBrunton L, Chabner B, Knollmann B (2011). "Chapter 32. Histamine, Bradykinin, and Their Antagonists". In Brunton L (ed.).Goodman & Gilman's The Pharmacological Basis of Therapeutics (12e ed.). McGraw Hill. pp. 242–245.ISBN978-0-07-162442-8.
^Khalifa M, Drolet B, Daleau P, Lefez C, Gilbert M, Plante S, et al. (February 1999). "Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine".The Journal of Pharmacology and Experimental Therapeutics.288 (2):858–65.doi:10.1016/S0022-3565(24)38031-0.PMID9918600.
^Cole JB, Stellpflug SJ, Gross EA, Smith SW (December 2011). "Wide complex tachycardia in a pediatric diphenhydramine overdose treated with sodium bicarbonate".Pediatric Emergency Care.27 (12):1175–7.doi:10.1097/PEC.0b013e31823b0e47.PMID22158278.S2CID5602304.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.Archived from the original on 20 April 2019. Retrieved14 August 2017.
^abcTatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters".European Journal of Pharmacology.340 (2–3):249–58.doi:10.1016/s0014-2999(97)01393-9.PMID9537821.
^abcdefghijklmnoKrystal AD, Richelson E, Roth T (August 2013). "Review of the histamine system and the clinical effects of H1 antagonists: basis for a new model for understanding the effects of insomnia medications".Sleep Medicine Reviews.17 (4):263–72.doi:10.1016/j.smrv.2012.08.001.PMID23357028.
^Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG (October 2006). "Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes".Bioorganic & Medicinal Chemistry.14 (19):6640–58.doi:10.1016/j.bmc.2006.05.077.PMID16782354.
^Lovenberg TW, Roland BL, Wilson SJ, Jiang X, Pyati J, Huvar A, et al. (June 1999). "Cloning and functional expression of the human histamine H3 receptor".Molecular Pharmacology.55 (6):1101–7.doi:10.1124/mol.55.6.1101.PMID10347254.S2CID25542667.
^abLiu C, Ma X, Jiang X, Wilson SJ, Hofstra CL, Blevitt J, et al. (March 2001). "Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow".Molecular Pharmacology.59 (3):420–6.doi:10.1124/mol.59.3.420.PMID11179434.S2CID123619.
^abcdeBolden C, Cusack B, Richelson E (February 1992). "Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells".The Journal of Pharmacology and Experimental Therapeutics.260 (2):576–80.doi:10.1016/S0022-3565(25)11335-9.PMID1346637.
^abcDomino EF (1999). "History of modern psychopharmacology: a personal view with an emphasis on antidepressants".Psychosomatic Medicine.61 (5):591–8.doi:10.1097/00006842-199909000-00002.PMID10511010.
^Taylor KM, Snyder SH (May 1972). "Histamine methyltransferase: inhibition and potentiation by antihistamines".Molecular Pharmacology.8 (3):300–10.doi:10.1016/S0026-895X(25)12747-8.PMID4402747.
^Wang C, Paul S, Wang K, Hu S, Sun CC (2017). "Relationships among Crystal Structures, Mechanical Properties, and Tableting Performance Probed Using Four Salts of Diphenhydramine".Crystal Growth & Design.17 (11):6030–6040.Bibcode:2017CrGrD..17.6030W.doi:10.1021/acs.cgd.7b01153.
^Rao DD, Venkat Rao P, Sait SS, Mukkanti K, Chakole D (2009). "Simultaneous Determination of Ibuprofen and Diphenhydramine Citrate in Tablets by Validated LC".Chromatographia.69 (9–10):1133–1136.doi:10.1365/s10337-009-0977-3.S2CID97766056.
^Rao DD, Sait SS, Mukkanti K (April 2011). "Development and validation of an UPLC method for rapid determination of ibuprofen and diphenhydramine citrate in the presence of impurities in combined dosage form".Journal of Chromatographic Science.49 (4):281–286.doi:10.1093/chrsci/49.4.281.PMID21439118.
^Kamijo Y, Soma K, Sato C, Kurihara K (November 2008). "Fatal diphenhydramine poisoning with increased vascular permeability including late pulmonary congestion refractory to percutaneous cardiovascular support".Clinical Toxicology.46 (9):864–868.doi:10.1080/15563650802116151.PMID18608279.S2CID43642257.
^Scavone JM, Greenblatt DJ, Harmatz JS, Engelhardt N, Shader RI (July 1998). "Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers".J Clin Pharmacol.38 (7):603–9.doi:10.1002/j.1552-4604.1998.tb04466.x.PMID9702844.S2CID24989721.
^abcPragst F (2007). "Chapter 13: High performance liquid chromatography in forensic toxicological analysis". In Smith RK, Bogusz MJ (eds.).Forensic Science (Handbook of Analytical Separations). Vol. 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".Pediatric Emergency Care.26 (9):665–6.doi:10.1097/PEC.0b013e3181f05443.PMID20838187.S2CID31581678.
^Ritchie J (24 September 2007)."UC prof, Benadryl inventor dies". Business Courier of Cincinnati.Archived from the original on 24 December 2008. Retrieved14 October 2008.
^"Zambia".Country Information > Zambia. Bureau of Consular Affairs, U.S. Department of State.Archived from the original on 21 July 2015. Retrieved17 July 2015.
^Forest E (27 July 2008)."Atypical Drugs of Abuse".Articles & Interviews. Student Doctor Network.Archived from the original on 27 May 2013.
Björnsdóttir I, Einarson TR, Gudmundsson LS, Einarsdóttir RA (December 2007). "Efficacy of diphenhydramine against cough in humans: a review".Pharmacy World & Science.29 (6):577–83.doi:10.1007/s11096-007-9122-2.PMID17486423.S2CID8168920.
Cox D, Ahmed Z, McBride AJ (March 2001). "Diphenhydramine dependence".Addiction.96 (3):516–7.PMID11310441.
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