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Home , Eszopiclone, Zaleplon, Zolpidem

Riaz U, et al., J Addict Addictv Disord 2020, 7: 054 DOI: 10.24966/AAD-7276/100054 HSOA Journal of Addiction & Addictive Disorders Review Article

Introduction The Safety Risk Associated receptor is divided in two categories: with Z-Medications to Treat a) Benzodiazepine and in Substance Use b) Non-benzodiazepine hypnotics. The prescription of Z-medications which is non-benzodiazepine Disorder Patients is common in daily clinical practice, particularly among primary medical providers to treat patients with insomnia. This trend Usman Riaz, MD1* and Syed Ali Riaz, MD2 is less observed among psychiatrist, but does exist. While treating population the prescription of Z-medications 1 Division of , Department of Psychiatry, Montefiore Medical should be strongly discouraged secondary to well documented Center/Albert Einstein College of Medicine, Bronx NY, USA safety risks. There is sufficient data available suggesting against the 2Department of Pulmonology/Critical Care and Medicine, Virtua Health, prescription of Z-medications to treat insomnia in substance abuse New Jersey, USA patients. Though treating insomnia is essential in substance use disorder patients to prevent relapse on /drugs, be mindful of risk associated with hypnotics particularly with BZRA ( Abstract and Non benzodiazepines hypnotics).

Z-medications are commonly prescribed in clinical practices Classification of Z-medications despite the safety concerns. Although these medications are Name of medication Half-life (hr) Adult dose (mg). considered safer than benzodiazepines, both act on GABA-A receptors as an . In clinical practice, the risk 1 5-20 profile for both medications is not any different, particularly in 1.5-4.5 5-10 substance use disorder population. The safety risk is more alarming Zolpidem CR 1.5-4.5 6.25-12.5 due to possible abuse, dependence and tolerance related issues 5-8 1-3 in this population. Physicians should be careful while prescribing these medications and if indicated, its use should be limited over Eszopiclone is the only agent FDA approved to treat insomnia >30 brief period of time and close patient monitoring is recommended. day use in general population. Keywords: Benzodiazepine receptor agonist; Substance use disorder; Z-medications Insomnia symptoms indications Zaleplon treats . Abbreviations Zolpidem IR treats sleep onset, Zolpidem Er treats sleep onset and maintenance, Eszopicolone treats sleep onset and maintenance. BZRA: Benzodiazepine receptor agonist; BZRA-Non benzodiazepines are DEA IV schedule and pregnancy GABA: Gamma amino butyric acid; category C. Z-medications: Zaleplon, Zolpidem, Eszopiclone; BZ: Benzodiazepine; Mechanism of action BZ a1/BZ a2/BZ a3: Benzodiazepine alpha subunits. Sleep promoting is GABA; Gamma amino *Corresponding author: Usman Riaz, Division of Substance Abuse, Department butyric acid is a predominately inhibitory neurotransmitter in of Psychiatry, Montefiore Medical Center/Albert Einstein College of Medicine, brain receptor (ventrolateral preoptic nucleus). GABA Receptors: Bronx NY, USA, Tel: +1 7188293440; Fax: +1 7188284899; E-mail: usriaz@ GABA-A, GABA-B, GABA-C. GABA-A receptor complex: montefiore.org Pantameric transmembrane structure, modulates chloride ion Citation: Riaz U, Riaz SA (2020) The Safety Risk Associated with Z-Medica- channel, and hyperpolarizes neurons. BZRA cause allosteric tions to Treat Insomnia in Substance Use Disorder Patients. J Addict Addictv modification of the GABA-A receptor to potentiate GABA effect. Disord 7: 54. (BZRA) Benzodiazepines hypnotics (Non selective) bind with Bz α1, Received: September 22, 2020; Accepted: September 28, 2020; Published: Bz α2 and Bz α3 subunits of GABA-A receptors. Bz α1: hypnotic October 07, 2020 and amnestic Bz α2 and Bz α3: antiseizure, and muscle relaxing. (BZRA) Non-benzodiazepines hypnotics (Selective) bind mainly Copyright: © 2020 Riaz U, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestrict- with Bzα1subunits of GABA-A receptor. Bz α1: hypnotic and ed use, distribution, and reproduction in any medium, provided the original author amnestic Z-medications modify GABA-A receptor increase affinity/ and source are credited. effectiveness of GABA (Chloride channel), has similar efficacy to Citation: Riaz U, Riaz SA (2020) The Safety Risk Associated with Z-Medications to Treat Insomnia in Substance Use Disorder Patients. J Addict Addictv Disord 7: 54.

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benzodiazepines, decrease seep latency, and increase total sleep time. 1.4g [13]. Rarely did Zolpidem cause , respiratory , There is no clear change in sleep architecture/sleep staging. depression, cardiovascular toxicity or death. The reports of agitation, , and coma from Z-medications overdose Data suggesting safety risk profile while prescribing have been published [14]. Over the last few year’s increasingly flags Z-medications from forensics cases, drug facilated crimes and motor vehicles crash In a large cohort of patients attending United Kingdom prime statistics indicate that mortality from Z-medications may be similar care, and hypnotics drugs were associated with significant to benzodiazepines. Bizarre behaviors, falls, accidents, and other mortality over seven years period, after adjusting for a arrange of injuries may lead to death. The majority of cases in which Zolpidem potential confounders. The dose response association with mortality was thought to contribute to death were overdoses with most common found for all the three classes of study drugs. (Benzodiazepines, co-ingestants being alcohol, , benzodiazepines and Z-medications (Zaleplon, Zolpidem, ) [1]. The fatal [15]. A significant association between using Zolpidem toxicity of Zopiclone was not significantly different from that of and suicide or suicidal attempt in people with or without comorbid Benzodiazepines as a group when adjusted for usage [2]. psychiatric issues [16]. While prescribing Zolpidem it’s recommended lower doses for Z-medications are potential risk of complex sleep related behavior women due to slower and possible excessive blood levels such as sleep eating and sleep driving. However, risks of complex the following morning. It can cause impairment in driving skills, sleep-related behaviors and next-morning impairment have been memory, and coordination. They have profound effect on nocturnal increasingly recognized, and non-benzodiazepines should not be and next day psychomotor body balance, reaction times and ability considered any safer than other hypnotics per se. One study found to multitask. There is an overwhelming degree of evidence, both that Zolpidem accounted for 12 percent of all emergency department experimental and epidemiological, implicating benzodiazepines in visits for adverse drug events related to in particular, but Z-medications as well, with fatal and non-fatal motor the United States over the period of 2009 to 2011, and 21 percent vehicle accidents. Though some limitations and discrepancies persist, of all such visits involving adult’s ≥65 years of age [17]. Perhaps both streams of evidence (experimental and epidemiological), when surprisingly, Zolpidem was implicated in more Adult Emergency considered together, support a strong causal argument for exposure room visits than any other psychiatric medication and caused a of these drugs resulting in motor vehicle accidents. It seems more markedly high number of Adult Emergency room visits relative to the research is necessary to elucidate with certainty which medications, at number of outpatient visits at which it was prescribed, particularly what doses, and in which patients increases risk beyond an acceptable compared with antidepressants and benzodiazepines [18]. degree so as to enable effective targeted interventions to reduce The use of -hypnotics in patients either with or without motor vehicle harm [3]. Z-medications induced neuropsychiatric insomnia was associated with subsequent cancer development in the effects such as hallucinations and psychosis have been described Taiwanese population. Increased risks of oral, , and breast cancer for over 15 years particularly with Zolpidem. The mechanism doesn’t appear to be entirely dose related or due to elevated plasma were found in the patients with the use of sedative-hypnotics. The use concentration of Zolpidem [4]. Drug interaction between Zolpidem of sedative-hypnotics should be discouraged for treating patients with and various serotonergic and nor adrenergic agents include SSRI’s or without insomnia in Taiwan [19]. venlafaxine, and tricyclic antidepressants have been reported to Improvements in sleep with sedative use are statistically induce hallucinations [5]. significant, but the magnitude of effect is small. The increased risk Tolerance, dependence, withdrawals are all reported with of adverse events is statistically significant and potentially clinically Z-medications though this appear to be less severe and with lower relevant in older people at risk of falls and cognitive impairment. incidence than for traditional benzodiazepines in the treatment of In people over 60, the benefits of these drugs may not justify the insomnia [6]. Withdrawals symptomology resembles that from increased risk, particularly if the patient has additional risk factors for benzodiazepines, including insomnia, , craving, anxiety, cognitive or psychomotor adverse events [20]. There is improved risk , palpitations and rarely seizures and psychosis [7]. Rebound profile includes: the effects of Zaleplon on psychomotor and cognitive insomnia, upon immediate cessation of the hypnotic drug has been performance; tolerance, withdrawal and rebound; respiratory reported with higher dose of Zolpidem [8]. This phenomenon has depression; sleep architecture; and other treatment-emergent not been reported with therapeutic doses of Zopicolone and Zaleplon adverse effects [9]. In terms of evidence regarding any association [9]. The potential for Zolpidem abuse and dependence in insomniacs of Z-medications specifically to dementia, the evidence is primarily is being increasingly recognized with warning on product labels restricted to a few sub-analyses in benzodiazepine studies previously appearing since 2004 [10]. Though the abuse potential exists for alluded to, which suggest a similar risk of dementia as was seen with all Z-medications it is more commonly reported for Zolpidem and benzodiazepines. A single Taiwanese case-control study reported an Zopicolone [8,11]. increased risk of dementia with Zolpidem compared with for non- users, but other than this there appears to be a lack of studies solely on Overdose, chronic abuse, poising and death have been reported Z-medications and dementia with benzodiazepines excluded [21,22]. from all Z-medications. In an American poison control center study, Zolpidem overdose was more likely to lead to intensive care It is also concluded in literature that anxiolytics, , and admission when co ingested with over the counter cold and flu hypnotics are associated with a limited increase in the risk of fractures. preparations, other psychotropic medication or [12]. Garnier For most drugs a dose-response relationship was present, and drugs et al reported the first large case series of Zolpidem poisoning in 1994, with a half-life >24 h tended to be associated with a higher risk of where toxicity predominately involved sedation with ingestion up to fractures than drugs with a shorter half-life. This point to a dose-

J Addict Addictv Disord ISSN: 2578-7276, Open Access Journal Volume 7 • Issue 4 • 100054 DOI: 10.24966/AAD-7276/100054 Citation: Riaz U, Riaz SA (2020) The Safety Risk Associated with Z-Medications to Treat Insomnia in Substance Use Disorder Patients. J Addict Addictv Disord 7: 54.

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dependent risk of, for example, falls leading to fractures. However, 5. Elko CJ, Burgess JL, Robertson WO (1998) Zolpidem associated halluci- the increased risk of fractures with past use may suggest an effect of nations and serotonin reuptake inhibition: A possible interaction. J Toxicol the condition for which the drug was prescribed rather than the drug Clin Toxicol 36: 195-203. per se ( by indication) [23]. 6. Dang A, Garg A, Rataboli PV (2011) Role of Zolpidem in the management of insomnia. CNS Neurosci Ther 17: 387-397. The effect of benzodiazepines and Z-medications on respiratory disease states is not yet perfectly clear due to the disparity of results 7. Chein CC, Huanga HT, Lung FW, Lin CH (2011) Zolpidem withdrawal between acute respiratory effects as measured in smaller experimental delirium, seizure and acute psychosis: Case reports and literature review. Journal Substance Abuse 16: 330-338. studies and longer term clinical outcomes in observational studies. Given that population based studies examining outcomes from 8. Greenblatt DJ, Roth T (2012) Zolpidem for insomnia. Expert Opin Phar- exposure to these drugs have been predominantly case-control macother 13: 879-893. and retrospective cohort designs, prospective evidence, or even a 9. Barbera J, Shapiro C (2005) Benefit risk assessment of Zaleplon in the meta-analysis of the available studies would be useful to persuade treatment of insomnia. Drug Saf 28: 301-318. researchers and clinicians of any causal truth behind these associations. 10. Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P (2007) Evidence of Zolp- This is yet another example where findings from one discipline are idem abuse and dependence: Results of the French center for evaluation not clearly in accord with those of another for these drugs and efforts and information on Phramacodepedence (CEIP) network survey. Br J Clin should be made to reconcile this discrepant mistranslation in findings Pharmacol 64: 198-209. between pharmacology and epidemiology [24]. 11. Cimolai N (2007) Zopicolone: Is it a pharmacological agent for abuse? Conclusion Can Fam Physician 53: 2124-2129. 12. Zosel A, Osterberg EC, Mycyk MB (2011) Zolpidem misuse with other BZRA (Non benzodiazepines hypnotics) have a structure that medications or alcohol frequently results in intensive care unit admission. is different from the benzodiazepines and includes more targeted Am J Ther 18: 305-308. action at specific GABA type A receptor. Z-medications, although 13. Garnier R, Guerault E, Muzard D, Azoyan P, Chaumet-Riffaud AE, et al. considered safer in comparison to benzodiazepines, are not free of (1994) Acute Zolpidem poisoning- anyalysis of 344 cases. J Toxicol Clin risks. Z-medications have increased likelihood of abuse, relapse, Toxicol 32: 392-404. dependency, tolerance and potential for overdose when combined with alcohol or other substances. Similar to benzodiazepines there 14. Louis CJ, Fernandez B, Beaumont C, Pinillos MA, Bardom A, et al. (2008) A case of zaleplon overdose. Clin Toxicol 46: 782. is a significant mortality risk associated with Z-medications, which should discourage the daily use of these medications especially in 15. Darke S, Deady M, Duflou J (2012) Toxicology and characteristics of substance use disorder patients. deaths involving Zolpidem in New South Wales, Australia 2001-2010. Journal Forensic Science 57: 1259-1262. Acknowledgement 16. Sun Y, Lin CC, Lu CJ, Hsu CY, Kao CH (2016) Association between zolp- idem and suicide, a national population based case control study. Mayo None. Clin Proc 91: 308-315. Role of the Funding Source 17. Hampton LM, Daubresse M, Chang HY, Alexander GC, Budnitz DS (2014) Emergency department visits by adults for psychiatric medication Authors states that this study was not financed. adverse events. JAMA Psychiatry 71: 1006-1014. Contributors 18. Bush DM (2013) Emergency department visits for adverse reactions in- volving the insomnia medication zolpidem. In The CBHSQ Report. Sub- Both authors contributed equally to this manuscript stance Abuse and Mental Health Services Administration, Rockville, USA. Conflict of Interest 19. Fang HF, Lee TY, Hui KC, Yim H, Chi MJ, et al. (2019) Association be- tween Sedative-hypnotics and subsequent cancer in patients with and with- Authors have no conflict of interest. out insomnia: A 14-year follow-up study in Taiwan. J Cancer 10: 2288- 2298. References 20. Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE (2005) Sedative hypnotics in older people with insomnia: Meta-analysis of risks and ben- 1. Weich S, Pearce HL, Croft P, Singh S (2014) Effect of and hyp- efits. BMJ 331: 1169. notic drug prescriptions on mortality hazards: Retrospective cohort study. British Medical Journal 348: 1996. 21. Chen PL, Lee WJ, Sun WZ, Oyang YJ, Fuh JL (2012) Risk of dementia in patients with insomnia and long-term use of hypnotics: A population-based 2. Reith Dunedin School of Medicine, University of Otago, 3rd Floor Chil- retrospective cohort study. PLoS One 7: 49113. dren’s Pavilion, Dunedin Hospital, Great King Street, Dunedin, New Zea- land DM, Fountain New Zealand National Poisons Centre, University of 22. Shih HI, Lin CC, Tu YF, Chang CM, Hsu HC, et al. (2015) An increased Otago, Dunedin, New Zealand J, McDowell Population and Environmen- risk of reversible dementia may occur after zolpidem derivative use in the tal Health, Institute of Environmental Science & Research, Wellington, elderly population: A population-based case-control study. Medicine 94: New Zealand R, Tilyard M (2003) Comparison of the fatal toxicity index 809. of zopiclone with benzodiazepines. J Toxicol Clin Toxicol 41: 975-980. 23. Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J (2001) Zolpidem use 3. Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Ineutel I, et al. (2008) and hip fractures in older people. J Am Geriatr Soc 49: 1685-1690. Road traffic accident risk related to prescriptions of the hypnotics zopi- clone, zolpidem, and . Sleep Med 9: 818-822. 24. Brandt J, Leong C (2017) Benzodiazepines and z-drugs: An Updat- ed review of major adverse outcomes reported on in epidemiologic re- 4. Tsai MJ, Huang YB, Wu PC (2003) A novel clinical pattern of visual hallu- search. Drugs R D 17: 493-507. cination after Zolpidem use. J Toxicol Clin Toxicol 41: 869-872.

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