Insomnia in general practice: the role of doxylamine
https://doi.org/10.21518/2079-701X-2020-2-45-53
Abstract
The general practitioner encounters all three forms of insomnia: idiopathic, chronic and acute. Idiopathic and chronic patients should receive specialized care by neurologist, psychiatrist or sleep disorders specialists because they require deep differential diagnosis and complex treatment. Acute insomnia patients need quick help to prevent the negative health impact and chronisation of sleep disruption. In theRussian Federation, the GP has access to three kinds of sleep drugs: benzodiazepines, melatonin receptor agonists, antihistamines. However, modern benzodiazepines are unavailable inRussiaand older benzodiazepines can lead to dependence. Melatonin receptor agonists are not effective enough for acute insomnia. Among available antihistamines, doxylamine is the most convenient option in clinical practice. Doxylamine has a good profile of safety and efficacy, it is included in the local clinical guidelines for insomnia. Also, doxylamine is the only sleep drug available for pregnant women. This paper presents a portrait of doxylamine and comments on its clinical niches and contraindications. We also discuss the pharmacology of doxylamine, drug interactions, and prescription modes. There are also three clinical case studies, presenting the typical acute insomnia patients and logic for their evaluation, underlining key clinical features of this disorder.
About the Authors
D. I. BurchakovRussian Federation
Denis I. Burchakov, Cand. of Sci. (Med), Associate Professor, Chair for Endocrinology
3A/2, Malaya Semenovskaya St., Moscow, 107023, Russia
M. V. Tardov
Russian Federation
Mikhail V. Tardov, Dr. of Sci. (Med.), Physician of Superior Merit, Leading Researcher, Department of Audiology and Inner Ear Pathology
18A/2, Zagorodnoe Sh., Moscow, 117152, Russia
References
1. Melnikov A.Yu. Acute Insomnia: Natural Course and Correction Modalities. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2019;119(4):28–35. (In Russ.) doi: 10.17116/jnevro201911904228.
2. Polouektov M.G., Buzunov R.V., Averbukh V.M., Verbitskiy E.V., Zakharov A.V., Kel’manson I.A. et al. Project of clinical recommendations on diagnosis and treatment of chronic insomnia in adults. Consilium Medicum. Nevrologiya i revmatologiya = Consilium Medicum. Neurology and Rheumatology. 2016;(2):41–51. (In Russ.) Available at: https://con-med.ru/magazines/neurology/neurology-02-2016/proekt_klinicheskikh_rekomendatsiy_po_diagnostike_i_lecheniyu_khronicheskoy_insomnii_u_vzroslykh/https://con-med.ru/magazines/neurology/neurology-02-2016/proekt_klinicheskikh_rekomendatsiy_po_diagnostike_i_lecheniyu_ khronicheskoy_insomnii_u_vzroslykh/
3. Kovalzon V.M. The role of histaminergic system of the brain in the regulation of sleepwakefulness cycle. Phiziologiya cheloveka = Human physiology. 2013;39(6):13–23. (In Russ.) doi: 10.7868/s0131164613060088.
4. Bakker R.A., Nicholas M.W., Smith T.T., Burstein E.S., Hacksell U., Timmerman H. et al. In vitro pharmacology of clinically used central nervous system-active drugs as inverse H(1) receptor agonists. J Pharmacol Exp Ther. 2007;322(1):172– 179. doi: 10.1124/jpet.106.118869.
5. Simons F.E.R. Advances in H1-antihistamines. N Engl J Med. 2004;351:2203–2217. doi: 10.1056/NEJMra033121.
6. Martínez-Gómez M.A., Carril-Avilés M.M., Sagrado S., Villanueva-Camañas R.M., MedinaHernández M.J. Characterization of antihistamine-human serum protein interactions by capillary electrophoresis. J Chromatogr A. 2007;1147(2):261–269. doi: 10.1016/j.chroma.2007.02.054.
7. Friedman H., Greenblatt D.J., Scavone J.M., Burstein E.S., Ochs H.R., Harmatz J.S., Shader R.I. Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women. Clin Pharmacokinet. 1989;16:312–316. doi: 10.2165/00003088-198916050-00003.
8. Strygin K.N. The Role of Central Histamine Receptor Blockers in the Treatment of Insomnia. Zhurnal nevrologii i psikhiatrii imeniS.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2018;118(4):73–82. doi: 10.17116/jnevro20181184273.
9. Smith G.M., Smith P.H. Effects of doxylamine and acetaminophen on postoperative sleep. Clin Pharmacol Ther. 1985;37(5):549–557. doi: 10.1038/clpt.1985.87.
10. Hausser Hauw C., Fleury B., Scheck F., Pello J.Y., Lebeau B. Effect on sleep architecture and residual effect of a dose of 15 mg of doxylamine in healthy volunteers. Sem Hop. 1995;71(23–24):742–750.
11. Schadeck B., Chelly M., Amsellem D., Cohen A., Peraudeau P., Scheck F. Comparative efficacy of doxylamine (15 mg) and zolpidem (10 mg) for the treatment of common insomnia. A placebo-controlled study. Sem Hop Inf. 1996;72(13–14):428–439.
12. Videla S., Lahjou M., Guibord P., Xu Z., Tolrà C., Encina G. Food effects on the pharmacokinetics of doxylamine hydrogen succinate 25 mg film-coated tablets: a single-dose, randomized, two-period crossover study in healthy volunteers. Drugs in R&D. 2012;12:217–225. doi: 10.2165/11641640-000000000-00000.
13. Videla S., Cebrecos J., Lahjou M., Wagner F., Guibord P., Xu Z. Pharmacokinetic Dose Proportionality Between Two Strengths (12.5 mg and 25 mg) of Doxylamine Hydrogen Succinate Film-Coated Tablets in Fasting State: A Single-Dose, Randomized, Two-Period Crossover Study in Healthy Volunteers. Drugs in R&D. 2013;13:129–135. doi: 10.1007/s40268-013-0015-7.
14. Wein A.M. Report on Donormil’s study in patients with insomnia. Moscow: Center for somnological research; 1997. (In Russ.) Available at: https://www.dropbox.com/s/is2qquy2lzdm91v/Wein%20report%201997.docx?dl=0.
15. Levin Ya.I., Strygin K.N. Donormil in therapy of insomnia. Lechenie nervnykh boleznei = Treatment of nervous diseases. 2005;6(2):23–26. (In Russ.) Available at: https://www.rmj.ru/articles/obshchiestati/Doksilamin_Donormil_v_lechenii_insomnii.
16. Smulevich A.B., Zheleznova M.V., Pavlova L.K. The use of the drug “Donormil” in the treatment of sleep disorders of medium and mild severity in the practice of a psychiatrist. Psikhiatriya i psik¬ hofarmakoterapiya = Psychiatry and Psychopharmacotherapy. 2006;(1):12–17. (In Russ.) Available at: https://con-med.ru/magazines/psikhiatriya_i_psikhofarmakoterapiya_im_p_b_ganushkina/psikhiatriya_i_psikhofarmakoterapiya_im_p_b_ganushkina-01-2006/primenenie_preparata_quot_donormil_quot_pri_lechenii_narusheniy_sna_sredney_i_legkoy_stepeni_vyrazhe/
17. Gustov A.V., Smirnov A.A., Zheltova O.Yu. Efficacy of donormyl in the treatment of insomnia in patients with dyscirculatory encephalopathy. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2006;106(3):56–67. (In Russ.) Available at: http://www.fesmu.ru/elib/Article.aspx?id=143391.
18. Melnikov A.S., Lavrik S.Yu., Bikbulatova L.F., Raginene I.G., Ivanova Ya.A., Zakharov A.V. Effectiveness of reslip (doxylamine) in shortterm insomnia: multicenter comparative randomized study. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2017;117(4):56–59. (In Russ.) doi: 10.17116/jnev-ro20171174256-59.
19. Allison M., Hale C. A Phase I Study of the Pharmacokinetics and Pharmacodynamics of Intranasal Doxylamine in Subjects with Chronic Intermittent Sleep Impairment. Drugs in R&D. 2018;18:129–136. doi: 10.1007/s40268-0180232-1.
20. Pelser A., Müller D.G., du Plessis J., du Preez J.L., Goosen C. Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats. Biopharm Drug Dispos. 2002;23(6):239–244. doi: 10.1002/bdd.314.
21. Friedman H., Greenblatt D.J. The pharmacokinetics of doxylamine: use of automated gas chromatography with nitrogen-phosphorus detection. J Clin Pharmacol. 1985;25(6):448– 451. doi: 10.1002/j.1552-4604.1985.tb02875.x.
22. Hamelin B., Bouayad A., Méthot J., Jobin J., Desgagnés P., Poirier P. et al. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clinical Pharmacology & Therapeutics. 2000;67(5):466–477. doi: 10.1067/mcp.2000.106464.
23. Lessard E., Yessine M.-A., Hamelin B.A., Gauvin C., Labbé L., O’Hara G. et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol. 2001;21(2):175–184. doi: 10.1097/00004714-200104000-00009.
24. Bartra J., Valero A.L., Del Cuvillo A., Dávila I., Jáuregui I., Montoro J. et al. Interactions of the H1 antihistamines. J Investig Allergol Clin Immunol. 2006;16(Suppl. 1):29–36. Available at: http://www. jiaci.org/issues/vol16s1/5.pdf.
25. Seto A., Einarson T., Koren G. Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis. Am J Perinatol. 1997;14(3):119–124. doi: 10.1055/s-2007-994110.
26. Popescu F.D. H1 antihistamines and driving. J Med Life. 2008;1(3):262–268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20108503.
27. Cho H., Myung J., Suh H.S., Kang H.-Y. Antihistamine use and the risk of injurious falls or fracture in elderly patients: a systematic review and meta-analysis. Osteoporos Int. 2018;29:2163–2170. doi: 10.1007/s00198-0184564-z.
28. Gray S.L., Anderson M.L., Dublin S., Hanlon J.T., Hubbard R., Walker R. et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401–407. doi: 10.1001/jamainternmed.2014.7663.
29. Poluzzi E., Raschi E., Godman B., Koci A., Moretti U., Kalaba M. Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe. PLoS One. 2015;10(3):e0119551. doi: 10.1371/journal. pone.0119551.
30. Zaman Huri H., Hui Xin C., Sulaiman C.Z. Drugrelated problems in patients with benign prostatic hyperplasia: a cross sectional retrospective study. PLoS One. 2014;9(1):e86215. doi: 10.1371/journal.pone.0086215.
Review
For citations:
Burchakov DI, Tardov MV. Insomnia in general practice: the role of doxylamine. Meditsinskiy sovet = Medical Council. 2020;(2):45-53. (In Russ.) https://doi.org/10.21518/2079-701X-2020-2-45-53