Matthew E. Hirschtritt, MD, MPH Department of Psychiatry and Behavioral Sciences, University of California, San Francisco.
Mark Olfson, MD, MPH
Department of Psychiatry, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York, New York; and Department of Psychiatry, The Zucker Hillside Hospital,
Glen Oaks, New York.
Kurt Kroenke, MD
Department of Medicine, Indiana University School of Medicine, Indianapolis; and Regenstrief Institute Inc, Indianapolis, Indiana.
In September 2020, the US Food and Drug Adminis- tration (FDA) announced an anticipated update to the boxed warning on all benzodiazepines to explicitly “address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions” among this class of medications.1 The current boxed warning for benzo- diazepines (eg, alprazolam, lorazepam, clonazepam, diazepam) highlights only the risks of coadministration of opioids and benzodiazepines. Benzodiazepines are prescribed for multiple indications, most notably gen- eralized anxiety disorder, panic, social phobia, insom- nia, and seizure prophylaxis and rescue.
In addition to the revised boxed warning, the FDA is also modifying the detailed prescribing information. The new prescribing information advises physicians to warn patients of the risks of benzodiazepines; assess pa- tients’ risk of abuse, misuse, and addiction; use caution when coprescribing benzodiazepines with opioids; seek the lowest effective dose for the shortest treatment du- ration possible and taper off benzodiazepines slowly; consider alternate therapies; and follow up with pa- tients who are prescribed benzodiazepines frequently.1
This increased caution regarding benzodiazepine use is warranted; fewer benzodiazepine prescriptions are needed. However, when considered without an appro- priate patient-centered context, this enhanced warning
benzodiazepine prescriptions were filled, and in 2018, nearly half of patients who filled an oral benzodiazepine prescription took the medication for 2 or more months.
The risks of drug overdose deaths involving benzo- diazepines are significantly augmented when benzodi- azepines are combined with other sedating medica- tions and drugs, most notably opioids. For instance, among US women aged 30 to 64 years, the rate of benzodiazepine-related deaths increased from approxi- mately 0.5 per 100 000 population in 1999 to nearly 5 per 100 000 population in 2017; however, these data did not distinguish benzodiazepine monotherapy from coad- ministration with other medications.3 Notably, from 1993 to 2014, the national rate per 100 000 outpatient vis- its including combined use of benzodiazepines and opi- oids increased from 9.8 to 62.5,4 and between Septem- ber 2016 and December 2017 an estimated nearly 2 million adults in the US were coprescribed opioids and benzodiazepines.5 This pattern may in part contribute to the recent increase in benzodiazepine-related deaths.
Prolonged benzodiazepine use may also lead to abuse, dependence, and tolerance, leading to misuse, dose escalations, and withdrawal reactions. In the most recent available Treatment Episode Data Set, in 2017 among 2 005 395 admissions to publicly funded sub- stance abuse treatment programs, 17% identified ben-
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Corresponding Author: Matthew E. Hirschtritt, MD, MPH, Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, 401 Parnassus Ave, PO Box 0984, San Francisco, CA 94143 (matthew. firstname.lastname@example.org).
statement might lead to fewer appropriate prescrip- tions and unintended consequences. This Viewpoint re- views the relative benefits and risks of benzodiazepines, discusses potential consequences of the FDA amend- ments, and describes a potential approach for the ratio- nal prescribing of benzodiazepines.
Risks and Benefits of Benzodiazepines
Based on an analysis of nationally representative survey data from 86 186 adults in 2015 and 2016, an estimated 30.6 million reported past-year use of benzodiazepines, 17% of whom reported benzodiazepine misuse, defined as use “without a prescription, in greater amounts or more often than prescribed, longer than prescribed, or any other use other than as prescribed.”2 Rates of benzodi- azepine misuse were highest among younger respon- dents; 51% of respondents aged 18 to 25 years reported misuse compared with 4% of those aged 65 years or older.2 As summarized in the FDA’s Drug Safety Communication,1 in 2019 alone, an estimated 92 million
patients prescribed antidepressants may be at higher risk of using benzodiazepines at higher doses for longer pe- riods. In Danish cohorts of 113 incident and 992 preva- lent users of benzodiazepines for at least 6 months, there was no significant increase in benzodiazepine dose in either group at 2-year follow-up.6
The risks of benzodiazepine misuse among adoles- cents are of particular concern. According to a 2018 survey that included approximately 29 600 high school students, an estimated 3.9% of US 10th- and 12th-grade students reported nonmedical benzodiaz- epine use.7 Adolescents are at risk of developing sub- stance use disorders that may persist through early and late adulthood; use of benzodiazepines in this vulner- able population deserves special attention.
There is uncertainty regarding the association of benzodiazepine use and subsequent risk of dementia. A recent cohort study among 235 465 Danish adults with an affective disorder (including depressive and bipolar disorders) revealed no association between
The challenge for physicians
is simultaneously considering the risks of benzodiazepines while selectively and cautiously using benzodiazepines when clinically appropriate.
zodiazepines as secondary or tertiary drugs of abuse, whereas only 1% identi- fied benzodiazepines as their primary drug of abuse.1 In contrast, few pub- lished reports have addressed benzodi- azepine withdrawal and dependence, al- though the few studies that do exist suggest that women, older patients, pa- tients with mental health conditions, and
(Reprinted) JAMA Published online January 8, 2021 E1 © 2021 American Medical Association. All rights reserved.
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benzodiazepine use and later development of dementia.8 Con- versely, in a nested case-control analysis of this same cohort, lower benzodiazepine use was associated with risk of dementia but higher use was not, suggesting the possibility of a potential protec- tive relationship with benzodiazepine use.8
Furthermore, benzodiazepines are effective for treating vari- ous forms of anxiety. A meta-analysis of 58 trials (sample size range, 9-229; mean, 72.5; median, 60) that compared benzodiazepines with placebo for anxiety disorders demonstrated that benzodiaz- epines were more effective than placebo in trials of patients with higher baseline anxiety severity scores and among studies with shorter treatment durations.9 To date, no published meta- analyses have compared benzodiazepines with selective serotonin reuptake inhibitors for anxiety.
Potential Unintended Consequences
of an Enhanced Boxed Warning
In the context of this revised warning, physicians may restrict their use of benzodiazepines, in some cases without appropriate regard for patient-specific needs and risks factors that could predispose spe- cific patients to adverse effects of benzodiazepines. Absent this con- textual information, physicians might inappropriately withhold ben- zodiazepine therapy, thereby leading to poorly treated anxiety disorders and insomnia, as well as precipitation of withdrawal among patients already using benzodiazepines. There are currently no US guidelines that specifically address use of benzodiazepines; how- ever, the practice guideline from the American Psychiatric Associa- tion includes benzodiazepines among first-line pharmacologic treat- ment strategies for panic disorder.10
Many patients with anxiety disorders may benefit from antide- pressants or various forms of psychotherapy (most notably cogni- tive behavior therapy); however, a significant number of patients will derive inadequate symptom relief from these modalities or may have limited access to psychotherapeutic treatments. Likewise, pa- tients with residual and impairing anxiety or insomnia may use al-
cohol, cannabinoids, or illicit substances that not only have little to no evidence of efficacy for anxiety and insomnia but also may worsen these symptoms with long-term use. The risks of developing sub- stance use disorders with these nonprescribed substances is likely higher than with use of benzodiazepines, especially given that use of these substances is not medically regulated.
Toward the Rational Use of Benzodiazepines
The challenge for physicians is simultaneously considering the risks of benzodiazepines while selectively and cautiously using benzodi- azepines when clinically appropriate. Ideally, physicians will seek a balance between overprescribing of benzodiazepines to patients at risk and underuse of these effective medications when indicated.
As the FDA recommends, patients should be carefully screened for risk factors before initiating benzodiazepines, including sub- stance use disorders, a history of misuse of prescribed medications, cognitive impairment, older age and risk of falls, and concomitant use of opioids. Physicians should consider alternate pharmacological and behavioral strategies before using benzodiazepines whenever pos- sible and appropriately engage patients in a discussion regarding the risks and benefits of benzodiazepines. Among patients already pre- scribed a benzodiazepine, physicians should regularly reevaluate their use of benzodiazepines, aiming for the lowest effective dose. Follow- ing the behavioral change model of advise, assess, and address, pa- tients should be informed of the risks of benzodiazepines, assessed for their willingness and perceived ability to decrease their use, and offered a tailored plan to gradually taper their dose while monitoring for recurrent symptoms and withdrawal.
Like all medications, benzodiazepines have the potential for both harm and benefit. Physicians should help patients weigh these fac- tors and develop a treatment plan that is safe and effective as well as flexible and responsive to changing circumstances. The newly en- hanced boxed warning appropriately highlights the real risks posed by benzodiazepines; it is up to physicians to judiciously act on but not overreact to this information.
Published Online: January 8, 2021. doi:10.1001/jama.2020.22106
Conflict of Interest Disclosures: Dr Hirschtritt reported being supported in part by a contract from the California Mental Health Services Oversight and Accountability Commission (outside of the current work) and being employed by the Permanente Medical Group Inc. No other disclosures were reported.
Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the Permanente Medical Group Inc.
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E2 JAMA Published online January 8, 2021 (Reprinted)
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