Stabilization of remission in patients with opioid depen dence: pharmacological and pharmacogenetic aspects

Modern narcology demonstrates a problem of insufficient effectiveness of pharmacotherapy for stabilization of remission in patients with opioid dependence. Effectiveness of the existing pharmacological approaches to solving this problem varies from patient to patient. In Russia, naltrexone is a medication mainly used for stabilization of remission in patients with opioid dependence. The main course of inefficient effectiveness of naltrexone in treatment of opioid dependence could be explained by poor compliance. The effectiveness can be improved by three ways: 1) using extendedrelease formulations of naltrexone; 2) using naltrexone combined with other medications to reduce symptoms resulting in relapse; 3) conducting a pharmacogenetic analysis to provide patients’ stratification by the effectiveness of pharmacotherapy. The main objective of this review is to analyze opportunities for improving pharmacological treatment methods in stabilization of remission in patients with opioid dependence using the combined pharmacotherapy and pharmacogenetic analysis in order to develop individualized pharmacological treatment approach.

1. Анохина И. П. Основные биологические механизмы зависимости от психоактивных веществ // Вопросы наркол. – 2013. – № 6. – С. 40–59.

2. Кибитов А. О. Фармакогенетика болезней зависимости от психоактивных веществ // Наркология. – 2015. – № 11. – С. 61–74.

3. Кибитов А. О., Анохина И. П. Генетические основы этиологии и патогенеза болезней зависимости от психоактивных веществ // Наркология. – 2016. – № 6. – С. 84–104.

4. Крупицкий Е. М., Блохина Е. А. Применение пролонгированных форм налтрексона для лечения зависимости от опиатов // Вопросы наркол. – 2010. – № 4. – С. 32–43.

5. Крупицкий Е. М. и др. Двойное слепое рандомизированное плацебо-контролируемое исследование эффективности комбинированной терапии налтрексоном и гуанфацином для стабилизации ремиссии при опийной наркомании // Журн. неврол. и психиатрии им. С. С. Корсакова. – 2015. – № 10. – С. 39–46.

6. Крупицкий Е. М. и др. Двойное слепое рандомизированное плацебо-контролируемое исследование эффективности применения имлантируемой формы налтрексона пролонгированного действия (продетоксона) для профилактики рецидива опийной наркомании // Вопросы наркол. – 2012. – № 6. – С. 3–27.

7. Крупицкий Е. М. и др. Стабилизация ремиссий у больных опийной наркоманией имплантом налтрексона: фармакогенетический аспект // Журн. неврол. и психиатрии им. C. C. Корсакова. – 2015. – Т. 115. – № 4–2. – С. 14–23.

8. Кукес В. Г. и др. Проблемы клинической фармакогенетики на современном этапе // Клин.мед. – 2007. – Т. 85. – № 2. – С. 58–63.

9. Сиволап Ю. П., Савченков В. А. Злоупотребление опиоидами и опиоидная зависимость. – М.: Медицина, 2005. – Т. 301. – № 2.

10. Batman A. M. et al. The selective dopamine uptake inhibitor, D-84, suppresses cocaine self-dministration, but does not occasion cocaine-like levels of generalization // Eur. Journ. of pharmacology. – 2010. – Vol. 648. – № 1. – P. 127–132.

11. Bauer I. E. et al.The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review // Am. Journ. on Addictions. – 2015. – Vol. 24. – № 1. – P. 15–23.

12. Bond C. et al. Singlenucleotide polymorphism in the human mu opioid receptor gene alters вendorphin binding and activity: possible implications for opiate addiction // Proceedings of the National Academy of Sciences. – 1998. – Vol. 95. – № 16. – P. 9608–9613.

13. Buhler K. M. et al.Common single nucleotide variants underlying drug addiction: more than a decade of research // Addiction biology. – 2015. – Vol. 20. –№ 5. – P. 845–871.

14. Falzone T. L. et al. Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear // Eur. J. of Neuroscience. – 2002. – Vol. 15. – № 1. – P. 158–164.

15. Gerfen C. R. et al.D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons // Science. – 1990. – Vol. 250. –№ 4986. – P. 1429–1432.

16. Gish E. C. et al. Lofexidine, anб2-receptor agonist for opioid detoxification // Annals of Pharmacotherapy. – 2010. – Vol. 44. – № 2. – P. 343–351.

17. Heshmati M., Russo S. J. Anhedonia and the brain reward circuitry in depression // Current Behavioral Neuroscience Reports. – 2015. – Vol. 2. – № 3. – P. 146–153.

18. Hyman S. M. et al. A stresscoping profile of opioid dependent individuals entering naltrexone treatment: a comparison with healthy controls // Psychology of Addictive Behaviors. – 2009. – Vol. 23. – № 4. – P. 613.

19. Kiive E. et al. Effect of б 2Aadrenoceptor C1291G genotype and maltreatment on hyperactivity and inattention in adolescents // Progress in Neuro Psychopharmacology and Biological Psychiatry. – 2010. – Vol. 34. – № 1. – P. 219– 224.

20. Krupitsky E. M. et al.Effects of citalopram treatment of protracted withdrawal (syndrome of anhedonia) in patients with heroin addiction // Addictive Disorders & Their Treatment. – 2002. – Vol. 1. – № 1. – P. 29–33.

21. Krupitsky E. et al. Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant // The Am. J. of Drug and Alcohol Abuse. – 2016. – Vol. 42. – № 5. – P. 614–620.

22. Krupitsky E. et al. Injectable extended release naltrexone for opioid dependence: a double blind, placebocontrolled, multicentre randomised trial // The Lancet. – 2011. – Vol. 377. – № 9776. – P. 1506–1513.

23. Krupitsky E. M. et al. Naltrexone with or without fluoxetine for preventing relapse to heroin addiction in St. Petersburg, Russia // Journal of Substance Abuse Treatment. – 2006. – Vol. 31. – № 4. – P. 319–328.

24. Lachowicz J. E., Sibley D. R. Molecular characteristics of mammalian dopamine receptors // Pharmacology & toxicology. – 1997. – Vol. 81. –№ 3. – P. 105–113.

25. MartinSoelch C. Is depression associated with dysfunction of the central reward system? // Biochemical Society Transactions. – 2009. – Vol. 37. – P. 313–317.

26. Mattay V. S. et al. Catechol Omethyltransferase val158met genotype and individual variation in the brain response to amphetamine // Proceedings of the National Academy of Sciences. – 2003. – Vol. 100. – № 10. – P. 6186–6191.

27. Nestby P. et al. Bremazocine reduces unrestricted free choice ethanol selfadministration in rats without affecting sucrose preference // Psychopharmacology. – 1999. – Vol. 142. – № 3. – P. 309–317.

28. Nestler E. J. Molecular mechanisms of drug addiction // J. Neurosci. – 1992. – Vol. 12. –№ 7. – P. 2439–2450.

29. Parsian A., Zhang Z. H. Human dopamine transporter gene polymorphism (VNTR) and alcoholism // Am. J. of Medical Genetics. – 1997. – Vol. 74. –№ 5. – P. 480–482.

30. Patriquin M. A. et al.Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system // Psychiatric Genetics. – 2015. – Vol. 25. –№ 5. – P. 181–193.

31. Proulx C. D. et al.Reward processing by the lateral habenula in normal and depressive behaviors // Nature Neuroscience. – 2014. – Vol. 17. – P. 1146–1152.

32. Schank J. R. et al. Dopamine вhydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine // Neuropsychopharmacology. – 2006. – Vol. 31. – № 10. – P. 2221–2230.

33. Sinha R. et al.Effects of lofexidine on stress-induced and cueinduced opioid craving and opioid abstinence rates: preliminary findings // Psychopharmacology. – 2007. – Vol. 190. – № 4. – P. 569–574.

34. Spanagel R. Convergent functional genomics in addiction research a translational approach to study candidate genes and gene networks / R. Spanagel// In silico pharmacology. – 2013. – Vol. 1. – № 1. – P. 1.

35. Stein D. J. Depression, anhedonia, and psychomotor symptoms: the role of dopaminergic neurocircuitry // CNSSpectrums. – 2008. – Vol. 13. – №7. – P. 561–565.

36. Valdman A. V. Zvartau E. E. Systems of reinforcement and drug dependence // Drug and Alcohol Dependence. – 1982. – Vol. 10. –№ 4. – P. 295–301.

37. Valenta J. P. et al.мOpioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in LongEvans rats: a delayed effect of ethanol // Psychopharmacology. – 2013. – Vol. 228. – № 3. – P. 389–400.

38. Vereczkei A. et al. Multivariate Analysis of Dopaminergic Gene Variants as Risk Factors of Heroin Dependence // PLoS ONE. – 2013. – Vol. 8. –№6. – Р. e66592.

39. Whitton A. E. et al.Reward processing dysfunction in major depression, bipolar disorder and schizophrenia // Current Opinion in Psychiatry. – 2015. – Vol. 28. – № 1. – P. 7–12.