Doxylamine is also a potentanticholinergic, meaning that itcauses delirium at high doses (i.e., at much higher doses than recommended).[8] Specifically, it is anantagonist of themuscarinic acetylcholine receptorsM1 throughM5. These sedative and deliriant effects have in some cases led to the drug being used recreationally. Doxylamine was first described in 1948 or 1949.[9]
The first-generation sedating antihistaminesdiphenhydramine,doxepin, doxylamine, andpyrilamine are the most widely used medications in the world for preventing and treating insomnia.[6] As of 2004, doxylamine and diphenhydramine, which are both over-the-counter medications, were the agents most commonly used to treat short-term insomnia.[11] As of 2008 and 2017, over-the-counter antihistamines were not recommended by theAmerican Academy of Sleep Medicine for treatment of chronic insomnia "due to the relative lack of efficacy and safety data".[12][13] Neither version of their guidelines explicitly included or mentioned doxylamine, although diphenhydramine was discussed.[12][13] A 2015 systematic review of over-the-counter sleep aids including doxylamine found little evidence to inform the use of doxylamine for treatment of insomnia.[4]
A majorsystematic review andnetwork meta-analysis of medications for the treatment of insomnia published in 2022 found that doxylamine had aneffect size (standardized mean difference (SMD)) againstplacebo for treatment of insomnia at 4weeks of 0.47 (95%CITooltip confidence interval 0.06 to 0.89).[14] Thecertainty of evidence was rated as moderate.[14] No data were available for doxylamine in terms of longer-term treatment (3months).[14] For comparison, the other sedating medicines assessed,doxepin andtrimipramine (both of which are tricyclic antidepressants) had effect sizes (SMD) at 4weeks of 0.30 (95% CI –0.05 to 0.64) (very low certainty evidence) and 0.55 (95% CI –0.11 to 1.21) (very low certainty evidence), respectively.[14]
Doses of doxylamine that have been used for sleep range from 5 to 50mg, with 25mg being the typical dose.[15][16][17][18]
Doxylamine is used medically as doxylamine succinate, thesuccinatesalt of doxylamine, and is available both alone (brand names Decapryn, Doxy-Sleep-Aid, Unisom) and in combination withpyridoxine (a form ofvitamin B6) (brand names Bendectin, Bonjesta, Diclegis).[22] Doxylamine is available alone asimmediate-releaseoraltablets containing 25mg doxylamine succinate.[22] Oral tablets containing 12.5mg doxylamine succinate as well as oralcapsules containing 25mg doxylamine succinate were also previously available but were discontinued.[22] Thecombination of doxylamine and pyridoxine is available in the form ofextended- anddelayed-release oral tablets containing 10 to 20mg doxylamine succinate and 10 to 20mg pyridoxine hydrochloride.[22] Doxylamine alone is availableover-the-counter, whereas doxylamine in combination with pyridoxine is aprescription-only medication.[22] Doxylamine is also available in over-the-counter nighttimecold medicine products such as NyQuil Cold & Flu (containsacetaminophen, doxylamine succinate 6.25 to 12.5mg, anddextromethorphan hydrobromide), where it serves as the sedating component.[23][24]
Studies of doxylamine'scarcinogenicity in mice and rats have produced positive results for bothliver andthyroid cancer, especially in the mouse.[29] The carcinogenicity of the drug in humans is not well-studied, and theInternational Agency for Research on Cancer lists the drug as "not classifiable as to its carcinogenicity to humans".[30]
Continuous and/or cumulative use ofanticholinergic medications, including first-generation antihistamines, is associated with a higher risk of cognitive decline and dementia in older people.[31][32]
Doxylamine concentrations after a single 25 mg oral dose of doxylamine in healthy volunteers. X-axis represents the time in hours after initial dose.[3]
Doxylamine is a first-generationantihistamine and was discovered by Nathan Sperber and colleagues and was first reported in 1948 or 1949.[43][9][44] It has been the antihistamine component ofNyQuil since 1966.[43]
Bendectin, a combination of doxylamine, pyridoxine (vitamin B6), anddicyclomine (ananticholinergicantispasmodic agent), was marketed for treatment of morning sickness in 1956.[45] This product was reformulated in 1976 to remove dicyclomine.[45] The reformulated product was voluntarily discontinued by the manufacturer in the United States in 1983 due to concerns about an alleged association withcongenital limb defects.[45] However, these concerns have not been supported by studies.[19][20] In 2013, doxylamine/pyridoxine was reintroduced in the United States under the brand name Diclegis.[19][20] The combination was not removed from the market in Canada, where it had been marketed since 1979.[19][20]
InCommonwealth countries, such as Australia, Canada, South Africa, and the United Kingdom, doxylamine is available prepared withparacetamol (acetaminophen) andcodeine under the brand name Dolased, Propain Plus, Syndol, or Mersyndol, as treatment fortension headache and other types ofpain.
Doxylamine succinate is used in generalover-the-counter sleep-aids branded as Somnil (South Africa), Dozile, Donormyl, Lidène (France, Russian Federation), Dormidina (Spain, Portugal), Restavit, Unisom-2, Sominar (Thailand), Sleep Aid (generic, Australia) and Dorminox (Poland).
In the United States:
Doxylamine succinate is the active ingredient in many over-the-counter sleep aids branded under various names.
Doxylamine succinate and pyridoxine (Vitamin B6) are the ingredients of Diclegis, approved by the FDA in April 2013 becoming the only drug approved for morning sickness[46] with a class Asafety rating for pregnancy (no evidence of risk).
Doxylamine preparations are available typically in combination with pyridoxine which may also contain folic acid. Doxylamine usage is thus restricted for pregnant women.
^abcPelser A, Müller DG, du Plessis J, du Preez JL, Goosen C (September 2002). "Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats".Biopharmaceutics & Drug Disposition.23 (6):239–244.doi:10.1002/bdd.314.PMID12214324.S2CID32126626.
^Leybishkis B, Fasseas P, Ryan KF (July 2001). "Doxylamine overdose as a potential cause of rhabdomyolysis".The American Journal of the Medical Sciences.322 (1):48–49.doi:10.1097/00000441-200107000-00009.PMID11465247.
^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. Retrieved14 August 2017.
^abcdefghijklmnopqrstKrystal 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):263–272.doi:10.1016/j.smrv.2012.08.001.PMID23357028.
^abcdVande Griend JP, Anderson SL (2012). "Histamine-1 receptor antagonism for treatment of insomnia".Journal of the American Pharmacists Association.52 (6):e210 –e219.doi:10.1331/JAPhA.2012.12051.PMID23229983.
^Krystal 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 Medicine Reviews.13 (4):265–274.doi:10.1016/j.smrv.2008.08.001.PMID19153052.
^Kalpaklioglu F, Baccioglu A (2012). "Efficacy and safety of H1-antihistamines: an update".Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry.11 (3):230–237.doi:10.2174/1871523011202030230.PMID23173575.
