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The Safety Risk Associated with Z-Medications to Treat Insomnia in Substance Use Disorder Patients

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The Safety Risk Associated with Z-Medications to Treat Insomnia in Substance Use Disorder Patients 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 Benzodiazepine receptor agonist is divided in two categories: with Z-Medications to Treat a) Benzodiazepine hypnotics and Insomnia in Substance Use b) Non-benzodiazepine hypnotics. The prescription of Z-medications which is non-benzodiazepine Disorder Patients hypnotic 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 substance use disorder population the prescription of Z-medications 1 Division of Substance Abuse, 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 Sleep 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 alcohol/drugs, be mindful of risk associated with hypnotics particularly with BZRA (Benzodiazepines 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 allosteric modulator. In clinical practice, the risk Zaleplon 1 5-20 profile for both medications is not any different, particularly in Zolpidem 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 Eszopiclone 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 sleep onset. 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 neurotransmitter 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. • Page 2 of 4 • benzodiazepines, decrease seep latency, and increase total sleep time. 1.4g [13]. Rarely did Zolpidem cause coma, respiratory depression, There is no clear change in sleep architecture/sleep staging. depression, cardiovascular toxicity or death. The reports of agitation, hallucinations, psychosis 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, anxiolytics 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, antidepressants, benzodiazepines and Z-medications (Zaleplon, Zolpidem, Zopiclone) [1]. The fatal opioids [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 metabolism 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 psychiatric medication 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 sedative-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, liver, 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
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