JOURNAL OF THE CZECH PHARMACEUTICAL SOCIETY AND THE SLOVAK PHARMACEUTICAL SOCIETY

Čes. slov. farm. 2019, 68(4):139-147 | DOI: 10.36290/csf.2019.016

New approach for detoxification of patients dependent on benzodiazepines and Z-drugs for reduction of psychogenic complications

Kateřina Kubová1, Aleš Franc1,*, Jakub Vysloužil1, Jan Šaloun2, David Vetchý1
1 Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
2 Department of Applied Pharmacy, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Czech Republic

Benzodiazepines (BZDs) and Z-drugs are strongly addictive substances, acting on identical GABA receptors. Detoxification should be long-term and gradual, usually by tapering a long-acting BZD (diazepam) but no suitable commercial pharmaceutic product exists with the necessary low drug content. This review describes the specific pharmacological aspects and comparisons of individual BZDs in relation to their effects and addictiveness. The success of the treatment relates to the patient's comfort during this process. Patients are typically afraid of switching to a more suitable long-acting BZD (diazepam), and become stressed during the tapering and anxious from withdrawal symptoms. These obstacles could be overcome through individualized detoxification according to already published withdrawal schedules based on the administration of very precise diazepam doses in a long-term gradual tapering with possible addition of adjuvant drugs. Dose reduction does not change external appearance of the dosage form, and the patient could be treated until the placebo phase. Individually prepared pharmaceutics with different and precise diazepam contents can be used for comfortable detoxification and also may eliminate psychogenic stress during switching, tapering, and the withdrawal period.

Keywords: benzodiazepines; Z-drugs; addiction; tapering; withdrawal; Detoxification

Received: May 24, 2019; Accepted: June 25, 2019; Published: April 1, 2019  Show citation

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Kubová K, Franc A, Vysloužil J, Šaloun J, Vetchý D. New approach for detoxification of patients dependent on benzodiazepines and Z-drugs for reduction of psychogenic complications. Čes. slov. farm. 2019;68(4):139-147. doi: 10.36290/csf.2019.016.
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    References

    1. Lavania S., Ram D., Praharaj S. K., Khan A. H. Pattojoshi A. Deliberate self-harm in nondepressed substance-dependent patients. J. Addict. Med. 2012; 6(4), 247-252. Go to original source... Go to PubMed...
    2. Soumerai S. B., Simoni-Wastila L., Singer C., Mah C., Gao X. M., Salzman C., Ross-Degnan D. Lack of relationship between long-term use of benzodiazepines and escalation to high dosages. Psychiatr. Serv. 2003; 54(7), 1006-1011. Go to original source... Go to PubMed...
    3. Janhsen K., Patrik R., Hoffmann K. The problems of long-term treatment with benzodiazepines and related substances. Dtsch. Arztebl. Int. 2015; 112(1-2), 1-7. Go to original source... Go to PubMed...
    4. Linnet K., Gudmundsson L. S., Birgisdottir F. G., Sigurdsson E. L., Johannsson M., Tomasdottir M. O., Sigurdsson J. A. Multimorbidity and use of hypnotic and anxiolytic drugs: cross-sectional and follow-up study in primary healthcare in Iceland. BMC Fam. Pract. 2016; 17(1), 69. Go to original source... Go to PubMed...
    5. Olfson M., King M., Schoenbaum M. Benzodiazepine use in the United States. JAMA Psychiatry 2015; 72(22), 136-142. Go to original source... Go to PubMed...
    6. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr. Opin. Psych. 2005; 18(3), 249-255. Go to original source... Go to PubMed...
    7. Lader M. History of benzodiazepine dependence. J. Subst. Abuse Treat. 1991; 8(1-2), 53-59. Go to original source... Go to PubMed...
    8. Argyropulous S. V., Nutt D. J. The use of benzodiazepines in anxiety and other disorders. Eur. Neuropsychopharmacol. 1999; (9), S407-S412. Go to original source... Go to PubMed...
    9. Atack J. R. The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics. Expert. Opin. Investig. Drugs 2005; 14(5), 601-618. Go to original source... Go to PubMed...
    10. Gould R. A., Ott M. W., Pollack M. H. A meta-analysis of treatment outcome for panic disorder. Clin. Psychol. Rev. 1995; 15(8), 819-844. Go to original source...
    11. Silber M. H. Chronic insomnia. N. Engl. J. Med. 2005; 353(8), 803-810. Go to original source... Go to PubMed...
    12. Riss J., Cloyd J., Gates J., Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol. Scand. 2008; 118(2), 69-86. Go to original source... Go to PubMed...
    13. Mayo-Smith M. F., Beecher L. H., Fischer T. L., Gorelick D. A., Guillaume J. L., Hill A., Melbourne J. Management of alcohol withdrawal delirium: an evidence-based practice guideline. Arch. Intern. Med. 2004; 164(13), 1405-1412. Go to original source... Go to PubMed...
    14. Dell'osso B., Lader M. Do benzodiazepines still deserve a major role in the treatment of psychiatric disorders? A critical reappraisal. Eur. Psychiatry 2013; 28(1), 7-20. Go to original source... Go to PubMed...
    15. Salzman C. 1990. Benzodiazepine dependence, toxicity, and abuse: a task force report of the American psychiatric association. Washington D.C.: American Psychiatric Pub. 1990. Go to original source...
    16. Lader M., Tylee A., Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23(1), 19-34. Go to original source... Go to PubMed...
    17. Lader M. Benzodiazepines revisited - will we ever learn? Addiction 2011; 106(12), 2086-2109. Go to original source... Go to PubMed...
    18. Licata S. C., Rowlett J. K. Abuse and dependence liability of benzodiazepine-type drugs: GABA a receptor modulation and beyond. Pharmacol. Biochem. Behav. 2008; 90(1), 74-89. Go to original source... Go to PubMed...
    19. Tanimoto Y., Onishi Y., Sato Y., Kizaki H. Benzodiazepine receptor agonists modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential. Jpn. J. Pharmacol. 1999; 79(2), 177-183. Go to original source... Go to PubMed...
    20. Šonka K. Hypnotika. Remedia 2003; 13(6), 434-441. Go to original source...
    21. Greenblatt D. J., Shader R. I., Divoll M., Harmatz J. S. Benzodiazepines: a summary of pharmacokinetic properties. Br. J. Clin. Pharmacol. 1981; 11(S1), 11-16. Go to original source... Go to PubMed...
    22. Hibell B., Guttormsson U., Ahlström S., Balakireva O., Bjarnason T., Kokkevi A., Kraus L. The 2011 ESPAD report: substance use among students in 36 European countries. Stockholm: Swedish Council for Information on Alcohol and other Drugs 2012; 123-124.
    23. Radcliff S., Yue J., Rocco G., Aiello S. E., Ickowicz E., Hurd Z., Beers M. H. Updated Beers criteria for potentially inappropriate medication use in older adults. J. Am. Geriatr. Soc. 2015; 63(22), 2227-2246. Go to original source... Go to PubMed...
    24. Ballóková A. Rational use of benzodiazepines in elderly. Farmi. News 2012; 9, 12-13.
    25. Echizenya, M. Mishima, K. Satoh, K. Enhanced heat loss and age-related hypersensitivity to diazepam. J. Clin. Psychopharmacol. 2004; 24(6), 639-646. Go to original source... Go to PubMed...
    26. Gérardin M., Victorri-Vigneau C., Guerlais M., Guillou-Landreat M., Grall-Bronnec M., Jolliet P. Benzodiazepines consumption: does dependence vary with age? Subst. use Misuse 2014; 49(11), 1417-1425. Go to original source... Go to PubMed...
    27. Preskorn S. H. A way of conceptualizing benzodiazepines to guide clinical use. J. Psychiatr. Pract. 2015; 21(6), 436-441. Go to original source... Go to PubMed...
    28. Fialová D., Topinková E. Appropriate choce of drugs and drug dosing in geriatric patients. Klin. Farmakol. Farm. 2013; 27, 18-22.
    29. Hajak G., Müller W. E. Wittchen H. U., Pittrow D., Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003; 98(10), 1371-1378. Go to original source... Go to PubMed...
    30. Casati A., Sedefov R., Pfeiffer-Gerschel T. Misuse of medicines in the European Union: a systematic review of the literature. Eur. Addict. Res. 2012; 18(5), 228-245. Go to original source... Go to PubMed...
    31. Lessenger J. E., Feinberg S. D. Misuse of prescription and over-the-counter medicines in South London nightclubs. J. Subst. Use 2016; 21(5), 495-500. Go to original source...
    32. Lugoboni F., Mirijello A., Faccini M., Casari R., Cossari A., Musi G., Addolorato G. Quality of life in a cohort of high-dose benzodiazepine dependent patients. Drug Alcohol Depend. 2014; 142, 105-109. Go to original source... Go to PubMed...
    33. Lozano Ó. M., Rojas A. J., Fernandez C. F. Psychiatric comorbidity and severity of dependence on substance users: how it impacts on their health-related quality of life? J. Ment. Health 2017; 26(2), 119-126. Go to original source... Go to PubMed...
    34. Mant A., Walsh R. A. Reducing benzodiazepine use. Drug Alcohol Rev. 1997; 16(1), 77-84. Go to original source... Go to PubMed...
    35. Smith D. E., Wesson D. R. The benzodiazepines: current standards for medical practice. Springer Science & Business Media 2012.
    36. Ashton H. Benzodiazepines: how they work & how to withdraw: medical research information from a benzodiazepine withdrawal clinic. University of Newcastle 2001.
    37. Sellers E. M. Alcohol, barbiturate and benzodiazepine withdrawal syndromes: clinical management. Can. Med. Assoc. J. 1988; 139(2), 113.
    38. Abernethy D. R., Greenblatt D. J., Shader R. I. Treatment of diazepam withdrawal syndrome with propranolol. Ann. Intern. Med. 1981; 94(3), 354-345. Go to original source... Go to PubMed...
    39. da Silva P. S. L., Reis M. E., Fonseca T. S. M., Fonseca M. C. M. Opioid and benzodiazepine withdrawal syndrome in PICU patients: which risk factors matter? J. Addict. 2016; 10(2), 110-116. Go to original source... Go to PubMed...
    40. Vorma H., Naukkarineh H. Symptom severity and quality of life after benzodiazepine withdrawal treatment in participants with complicated dependence. Addict. Behav. 2004; 29(6), 1059-1065. Go to original source... Go to PubMed...
    41. Frare F., Perugi G. Managing benzodiazepine withdrawal. Heroin Add. & Rel. Clin. Probl. 2000; 2, 1-18.
    42. Ashton H. Benzodiazepine withdrawal: an unfinished story. BMJ 1984; 288(6424), 1135. Go to original source... Go to PubMed...
    43. Voshaar R., Gorgels W., Mol A., van Balkom A., Mulder J., van de Lisdonk E. Long-term outcome of two forms of randomised benzodiazepine discontinuation. Br. J. Psychiatry 2006; 188, 188-189. Go to original source... Go to PubMed...
    44. Ashton H. How to wean patients off benzodiazepines. Pulse 2004; 64, 50-53.
    45. Busto U., Sellers E. M., Naranjo C. A., Cappell H., Sanchez-Craig M., Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N. Engl. J. Med. 1986; 315(14), 854-859. Go to original source... Go to PubMed...
    46. Rosebush P. I., Mazurek M. F. Catatonia after benzodiazepine withdrawal. J. Clin. Psychopharmacol. 1996; 16(4), 315-319. Go to original source... Go to PubMed...
    47. Lin S. K. Rapid detoxification of benzodiazepine or Z-drugs dependence using acetylcholinesterase inhibitors. Med. Hypotheses 2014; 83(1), 108-110. Go to original source... Go to PubMed...
    48. Lader M. Benzodiazepine harm: how can it be reduced? Br. J. Clin. Pharmacol. 2014; 77(2), 295-301. Go to original source... Go to PubMed...
    49. Kawasaki S. S., Jacapraro J. S., Rastegar D. A. Safety and effectiveness of a fixed-dose phenobarbital protocol for inpatient benzodiazepine detoxification. J. Subst. Abuse Treat. 2012; 43(3), 331-334. Go to original source... Go to PubMed...
    50. Nešpor K. Substance abuse preventinon and approaches to managing of cure dependence. Prakt. Lék. 2010; 90, 93-96.
    51. Authier N., Balayssac D., Sautereau M., Zangarelli A., Courty P., Somogyi A. A. Eschalier A. Benzodiazepine dependence: focus on withdrawal syndrome. Ann. Pharm. Fr. 2009; 67(6), 408-413. Go to original source... Go to PubMed...
    52. Lader M., Kyriacou A. Withdrawing benzodiazepines in patients with anxiety disorders. Curr. Psychiatry Rep. 2016; 18(1), 8. Go to original source... Go to PubMed...
    53. Ries R. K. Use of anticonvulsants in benzodiazepine withdrawal. Am. J. Addic. 1998; 7(3), 198-204. Go to original source...
    54. McElroy S. L., Keck P. E., Mawrence J. M. Treatment of panic disorder and benzodiazepine withdrawal with valproate. J. Neuropsychiatry Clin. Neurosci. 1991; 3, 232-233. Go to original source... Go to PubMed...
    55. Zitman F. G., Couvee J. E. Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper off. Br. J. Psychiatry 2001; 178(4), 317-324. Go to original source... Go to PubMed...
    56. Lader M., Olajide D. A. Comparison of buspirone and placebo in relieving benzodiazepine withdrawal symptoms. J. Clin. Psych. 1987; 7(1), 11-15. Go to original source...
    57. Chiae R. P., Pancheri P., Casacchia M., Stratta P., Kotzalidis G. D., Zibellini M. Assessment of the efficacy of buspirone in patients affected by generalized anxiety disorder, shifting to buspirone from prior treatment with lorazepam: a placebo-controlled double-blind study. J. Clin. Psych. 1995; 15(1), 12-19. Go to original source... Go to PubMed...
    58. Nakao M., Takeuchi T., Nomura K., Teramoto T., Yano E. Clinical application of paroxetine for tapering benzodiazepine use in non-major-depressive outpatients visiting an internal medicine clinic. Psychiatry Clin. Neurosci. 2006; 60(5), 605-610. Go to original source... Go to PubMed...
    59. Chandrasekaran P. K. Employing mirtazapine to aid benzodiazepine withdrawal. Singapore Med. J. 2008; 49(6), 166-167.
    60. Ansseau M., de Roeck J. Trazodone in benzodiazepine dependence. J. Clin. Psych. 1993; 54(5), 189-191.
    61. Müller H., Seifert F., Maler J. M., Kornhuber J., Sperling W. Agomelatine reduces craving in benzodiazepine addicts: a follow-up examination of three patients. Singapore Med. J. 2012; 53(11), e228-e230.
    62. Benyamina A., Naassila M., Bourin M. Potential role of cortical 5-HT 2A receptors in the anxiolytic action of cyamemazine in benzodiazepine withdrawal. Psychiatry Res. 2012; 198(2), 307-312. Go to original source... Go to PubMed...
    63. Pecinovská O. Delirium u závislostí na návykových látkách. Neurológia pre prax 2011; 12(5), 210-214.
    64. Sattar S. P., Bhatia S. C., Petty F. Potential benefits of quetiapine in the treatment of substance dependence disorders. J. Psychiatry Neurosci. 2004; 29(6), 452-457.
    65. Cantopher T., Olivieri S., Cleave N., Edwards J. G. Chronic benzodiazepine dependence: a comparative study of abrupt withdrawal under propranolol cover versus gradual withdrawal. Br. J. Psychiatry 1990; 156(3), 406-411. Go to original source... Go to PubMed...
    66. Link B. G., Struening E. L., Rahav M., Phelan J. C., Nuttbrock L. On stigma and its consequences: evidence from a longitudinal study of men with dual diagnoses of mental illness and substance abuse. J. Health. Soc. Behav. 1997; 38, 177-190. Go to original source...
    67. Håkonsen H., Eilertsen M., Borge H., Toverud E. L. Generic substitution: additional challenge for adherence in hypertensive patients? Curr. Med. Res. Opin. 2009; 25(10), 2515-2521. Go to original source... Go to PubMed...
    68. Nuzzarello A. Does cognitive behavior therapy assist slow-taper alprazolam discontinuation in panic disorder? Am. J. Psychiatry 1994; 151(6), 876-881. Go to original source... Go to PubMed...
    69. Otto M. W., Pollack M. H., Sachs G. S., Reiter S. R., Meltzer-Brody S., Rosenbaum J. F. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Am. J. Psychiatry 1993; 150(10), 1485-1490. Go to original source... Go to PubMed...
    70. Franc A., Kubová K., Elbl J., Muselík, J., Vetchý D., Šaloun J., Opatřilová R. Diazepam filled hard capsules intended for detoxification of patients addicted to benzodiazepines and Z-drugs. Eur. J. Hosp. Pharm. 2019; 26(1), 10-15. Go to original source... Go to PubMed...
    71. List of medicinal products: authorised under Article 126a of Directive 2001/83/EC of the of 6 November 2001 on the Community Code relating to medicinal products for human use. Pharmaceuticals - community register, European Parliament and of the Council European Comission - http://ec.europa.eu/health/documents/community-register/html/except_index.htm
    72. Newton D. W., Schulman S. G., Becker C. H. Limitations of compounding diazepam suspensions from tablets. AJHP 1976; 33(5), 450-452. Go to original source...
    73. van Santen E. D., Barends M., Frijlink H. W. Breaking of scored tablets: a review. Eur. J. Pharm. Biopharm. 2002; 53(2), 139-145. Go to original source... Go to PubMed...
    74. Venables H. J., Wells J. I. Powder mixing. Drug Dev. Ind. Pharm. 2001; 27(7), 599-612. Go to original source... Go to PubMed...
    75. Mahapatra A. K., Sameeraja N. H., Murthy P. N. Development of modified-release tablets of zolpidem tartrate by biphasic quick/slow delivery system. AAPS PharmsciTech. 2015; 16(3), 579-588. Go to original source... Go to PubMed...
    76. Franc A., Rabišková M., Goněc R. Impregnation: a progressive method in the production of solid dosage forms with low content of poorly soluble drugs. EJPPS 2011; 16(3); 85-91.
    77. Shanmugam S. Granulation techniques and technologies: recent progresses. Bioimpacts 2015; 5(1); 55-63. Go to original source... Go to PubMed...
    78. Trapani G., Lopedota A., Boghetich G., Latrofa A., Franco M., Sanna E., Liso G. Encapsulation and release of the hypnotic agent zolpidem from biodegradable polymer microparticles containing hydroxypropyl-β-cyclodextrin. Int. J. Pharm. 2003; 268(1-2), 47-57. Go to original source... Go to PubMed...
    79. Lopedota A., Cutrignelli A., Trapani A., Boghetich G., Denora N., La Quintana V., Liso G. Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam. J. Microencapsul. 2007; 24(3), 214-224. Go to original source... Go to PubMed...

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