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A Review of Alprazolam Use, Misuse, and Withdrawal Copyright © 2017 American Society of Addiction Medicine

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A Review of Alprazolam Use, Misuse, and Withdrawal Copyright © 2017 American Society of Addiction Medicine REVIEW A Review of Alprazolam Use, Misuse, and Withdrawal Nassima Ait-Daoud, MD, Allan Scott Hamby, MD, Sana Sharma, MD, and Derek Blevins, MD involved in ED visits related to drug misuse (SAMHSA, Alprazolam is one of the most widely prescribed benzodiazepines for 2013). 10/25/2018 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD38k+bDukTnmaPqdvLJ6faZl2ZVgRM9M6DN4fDksE+1oUWFvbrFN5vnw== by https://journals.lww.com/journaladdictionmedicine from Downloaded Downloaded the treatment of generalized anxiety disorder and panic disorder. Its Benzodiazepines are implicated in approximately one- clinical use has been a point of contention as most addiction special- third of intentional overdoses or suicide attempts (Henderson from ists consider it to be highly addictive, given its unique psychody- et al., 1993). A database review of poisoning admissions to a https://journals.lww.com/journaladdictionmedicine namic properties which limit its clinical usefulness, whereas many regional toxicology service revealed that when alprazolam primary care physicians continue to prescribe it for longer periods was involved, the median length of stay (LOS) was 19 hours, than recommended. Clinical research data has not fully shed light on which was 1.27 (95% confidence interval [CI] 1.04, 1.54) its ‘‘abuse liability,’’ yet it is one of the most frequently prescribed times longer compared with other benzodiazepines, and benzodiazepines. ‘‘Abuse liability’’ is the degree to which a psycho- patients were 2.06 (95% CI 1.27, 3.33) times more likely active drug has properties that facilitate people misusing it, or to be admitted to the intensive care unit (ICU) compared with becoming addicted to it, and is commonly used in the literature. other benzodiazepines after multivariate analysis adjusting for We have replaced it in our manuscript with ‘‘misuse liability’’ as it age, dose, sex, time to ingestion, and co-ingested drugs by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD38k+bDukTnmaPqdvLJ6faZl2ZVgRM9M6DN4fDksE+1oUWFvbrFN5vnw== reflects a more updated terminology consistent with the Diagnostic (Isbister et al., 2004). In a longitudinal cohort study between and Statistical Manual of Mental Disorders (DSM-5). In this paper, July 1, 2011, and June 30, 2012, more than half of the patients we have reviewed alprazolam’s indications for use, its effect on who visited hospital and ‘‘community practice-based research pregnant women, misuse liability, withdrawal syndrome, pharmaco- network’’ received benzodiazepine prescriptions at least once dynamic properties, and suggest better clinical prescription practice from their primary care physician (PCP). Those clinicians of alprazolam by presenting an indepth theory of its clinical effects were found to prescribe benzodiazepines disproportionately with use and withdrawal. to patients with at least some known risk factors for benzodi- azepine-related adverse events including increased age, pul- Key Words: alprazolam, benzodiazepines, generalized anxiety monary diseases, and other substance use disorders (Kroll disorder, misuse, panic disorder, withdrawal et al., 2016). There are significant discrepancies between prescribing (J Addict Med 2018;12: 4–10) habits and risk associated with the use of benzodiazepines, including alprazolam, largely due to the lack of important data lprazolam is not only the most commonly prescribed informing clinicians on best clinical practice. While more benzodiazepine, but it is the most commonly prescribed A recent research studies involving benzodiazepines are scant, psychotropic medication in the United States, accounting for the subject of alprazolam misuse continues to be a reality with more than 48 million prescriptions dispensed in 2013 (Grohol, which many providers struggle and should continue to be 2016). This persists despite the fact that many prescribers addressed. We have performed an indepth review of the consider alprazolam to have high misuse liability and it is alprazolam literature, summarizing older and newer publica- shown to result in a more severe withdrawal syndrome than tions, in an attempt to provide a better understanding of how other benzodiazepines, even when tapered according to man- alprazolam’s unique pharmacokinetic and pharmacodynamic ufacturer guidelines (Browne and Hauge, 1986; Kantor, properties affect its misuse liability and offer some prescrip- 1986). Based on national emergency department (ED) visit tion guidelines for its safe and effective use. data, alprazolam is the second most common prescription medication and the most common benzodiazepine to be INDICATIONS FOR USE AND EFFICACY Alprazolam is a high-potency triazolobenzodiazepine on From the University of Virginia, Department of Psychiatry and Neurobeha- that is US Food and Drug Administration (FDA)-approved for 10/25/2018 vioral Sciences. Charlottesville, VA (NA-D, SS, DB); Sentara RMH the treatment of anxiety and panic disorders. Alprazolam is Medical Center: 2010 Health Campus Drive, Harrisonburg, VA (ASH). biotransformed by hepatic microsomal oxidation, yielding 4 Received for publication March 29, 2017; accepted July 2, 2017. The authors report no conflicts of interest. and a-hydroxyalprazolam as its principal metabolites, and is Send correspondence to Nassima Ait-Daoud, MD, Associate Professor, metabolized by cytochrome P450 (CYP) 3A4 (Greenblatt and University of Virginia, Department of Psychiatry and Neurobehavioral Wright, 1993). Sciences, P.O. Box 800623, Charlottesville, VA 22908. E-mail: nat7b@ The US FDA’s approval for alprazolam came after 2 virginia.edu. large, randomized, clinical trials that demonstrated short-term Copyright ß 2017 American Society of Addiction Medicine ISSN: 1932-0620/17/1201-0004 efficacy and clinically acceptable tolerability versus placebo DOI: 10.1097/ADM.0000000000000350 (Ballenger et al., 1988; Klerman, 1988). A plasma 4 J Addict Med Volume 12, Number 1, January/February 2018 Copyright © 2017 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited. J Addict Med Volume 12, Number 1, January/February 2018 Alprazolam Use, Misuse, and Withdrawal concentration range between 20 and 40 ng/mL has been included in the review were heterogeneous, of poor quality, suggested for targeting symptoms of panic disorder, with and only addressed short-term effects, thus limiting the higher concentrations being associated with more significant significance of the findings. Additionally, it was not clear central nervous system depressant effects. The side effects of if the clinical effect of alprazolam was due to a unique alprazolam tablets are likely to be an extension of its phar- antidepressant effect or rather a nonspecific effect on co- macological activity, and most commonly include drowsiness, occurring anxiety and sleep-related issues. The authors also dizziness, fatigue, dysarthria, headache, memory impairment, questioned the funding sources of the trials and the possibility and depression. of interpretation bias favoring alprazolam, as no other trial In a review of its efficacy as monotherapy for the involving other benzodiazepines has been conducted for this treatment of anxiety, panic disorder, and depression, Jonas indication. and Cohon (1993) reviewed 84 studies of alprazolam versus It is also worth noting that the number of clinical trials active-drug comparators and/or placebo. They found that involving alprazolam significantly decreased circa the advent alprazolam was superior to placebo and as effective or of newer antidepressants, such as selective serotonin reuptake superior to all comparator benzodiazepines, including diaze- inhibitors (SSRIs), and that there are no clinical trials directly pam, lorazepam, and bromazepam; all comparator antidepres- comparing alprazolam or any other benzodiazepines with sants, including amitriptyline, imipramine, and dothiepin (or SSRIs or other newer antidepressants as monotherapy for dosulepin, a tricyclic antidepressant not approved for use in anxiety disorder, panic disorder, or depression. However, the United States); and buspirone for the treatment of anxiety while the available data show that alprazolam monotherapy disorder, as measured by reductions in the Hamilton Rating is as effective as other benzodiazepines for the treatment of Scale for Anxiety (HAM-A). The review found that the onset anxiety and panic disorders, this must be considered along of the anxiolytic effect was significantly more rapid for with its propensity for tolerance, dependence, and rebound alprazolam compared with amitriptyline, and its antipanic anxiety. effect was significantly more rapid compared with proprano- lol and imipramine. However, a 2011 meta-analysis of all ALPRAZOLAM AND PREGNANCY single or double-blind, randomized controlled trials compar- The US FDA has identified alprazolam and other ing alprazolam with other benzodiazepines in the treatment of benzodiazepines as pregnancy category D, which indicates panic disorder found no significant differences on any of the prior evidence of human fetal risk. Twenty-one to 33% of outcomes of clinical efficacy, including mean panic attack pregnant females are estimated to receive psychotropic drugs frequency, improvement in HAM-A score, and proportion of (Levenson, 2011), and often these medications are prescribed patients free of panic attacks at the final evaluation (Moylan to treat psychiatric symptoms that predate the pregnancy. et al., 2011). Alprazolam is relatively more toxic than other Despite the
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