By Marta Sokolowska, PhD, Associate Director for Controlled Substances in FDA’s Center for Drug Evaluation and Research
FDA continues to focus on the safe use of benzodiazepines. One critical element of increasing our understanding of their benefits and risks is through collaborations and stakeholder outreach. One of the agency’s initiatives on this important topic was to host a workshop earlier this year with Duke-Margolis Center for Health Policy.
Benzodiazepines are a class of drugs that work to produce drowsiness or a calming effect and are widely used to treat many conditions, including anxiety, insomnia, seizures, social phobia, and panic disorder. Benzodiazepines are also used as premedication before some medical procedures. However, it is important for prescribers to consider the risks of benzodiazepine misuse, abuse, addiction, and physical dependence, and monitor patients on therapy, even when patients take the medication as prescribed.
While benzodiazepine prescribing has been trending down since 2016, treatment with benzodiazepines is still widespread; in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient retail and mail-order pharmacies, according to a September 2020 FDA Drug Safety Communication (DSC). Further, this DSC noted that patients are often treated for a long time; in 2018, around half of patients who were dispensed oral benzodiazepines received them for two months or longer. This long time period is noteworthy because patients can experience withdrawal symptoms after discontinuation or dose reduction even when the benzodiazepine was prescribed for therapeutic use. Additionally, every year, almost 5 million people report using benzodiazepines in a manner other than as directed by a physician, with alprazolam being the benzodiazepine most frequently misused.
FDA’s Actions to Help Ensure Safe Use of Benzodiazepines
FDA is aware of the risks of benzodiazepine misuse, abuse, addiction, physical dependence, and withdrawal, and has taken a multifaceted approach to ensure people use these medications safely. For one, the agency has been monitoring safety concerns related to benzodiazepines through analysis of postmarketing safety data, adverse event reports, and the published literature. Our analyses found that abuse and misuse of benzodiazepines are commonly combined with the use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Our findings also supported the known risk of serious withdrawal reactions after people suddenly stop the medication or reduce their dosage too quickly, in some cases lasting for many months. Review of FDA Adverse Event Reporting System reports revealed that some health care providers and patients explicitly requested stronger warnings and better education about the risk of benzodiazepine dependence and withdrawal, even at typical therapeutic doses and with short periods of use.
We have also taken regulatory action. In the September 2020 DSC, FDA announced it would require an update to the Boxed Warning, which includes information on a prescription drug’s label designed to call attention to serious or life-threatening risks, for all benzodiazepines to address the serious risks of misuse, abuse, addiction, physical dependence, and withdrawal reactions, along with the need for a gradual taper when discontinuing or reducing the dose.
Outside of monitoring and regulatory activities, FDA works to raise awareness of risks associated with benzodiazepines through scientific meetings, public-private partnerships, and funded research, as well as engaging with clinicians, patients, and other stakeholders to gather on-the-ground perspectives on medication use. As an example, we’ve spoken with prescribers to better understand prescribing practices and real-world use. Through these conversations, we heard their experiences prescribing, tapering, and discontinuing benzodiazepines, and we learned that some clinicians were either unaware or had limited recall of FDA’s most recent benzodiazepine safety labeling change.
Information Sharing Through Scientific Meetings
To continue to explore benzodiazepine safety, FDA and Duke-Margolis hosted a two-day virtual workshop this past summer that brought together regulators, academic researchers, clinicians, patient advocates, and other stakeholders to share data underlying our benzodiazepine activities and to gather further input related to safe use, including current prescribing and tapering approaches. We also wanted to identify any gaps that may exist in clinician and patient education.
FDA shared information at the workshop from our safety reviews of benzodiazepines, including our most recent review of the abuse potential of alprazolam. Epidemiological data suggest that alprazolam has the highest prescription dispensing rates and the highest frequencies of abuse and related harms; however, few meaningful pharmacological differences were found across the benzodiazepine class.
Other speakers discussed the need for evidence-based tapering schedules and highlighted their perspectives on how and when to use benzodiazepines safely, including:
- Prescribing at the lowest effective dose and shortest time period and not co-prescribing with opioids, unless other treatment options are not available;
- Prescribing cautiously for patients with opioid or other substance use disorders or prior misuse of prescription medications, and for older adults with cognitive impairment or heightened risk for falls;
- Obtaining informed consent from patients after educating them about side effects, safety issues, risk of dependence, and the importance of not sharing benzodiazepines;
- Conducting regular follow up with patients to assess benzodiazepine benefits and risks and offering patient-centered tapering/discontinuation options, especially if the benzodiazepines are not effective or the risks outweigh the benefits; and
- Identifying and using safer treatments that are available for chronic anxiety and insomnia.
Opportunities to Further Promote Safe Use of Benzodiazepines
Another FDA program that participants discussed at the workshop is the Safe Use Initiative. The Safe Use Initiative works to reduce preventable harm from drugs by soliciting and funding projects that develop innovative methods to create, facilitate, and encourage research in the area of safe medication use. Proposals that pertain to benzodiazepines may be eligible for funding.
We also continue to conduct research on publicly available online and social media discussions to explore the contexts in which substances are being used and to gain insight about behaviors related to their use. Through this research, we have found conversations that enhanced our understanding of individuals’ perceptions of and experiences with unapproved benzodiazepines – drugs that have not been subject to FDA review – in online discussions of opioids.
While benzodiazepines can benefit some patients, the workshop participants underscored the need for clinicians to carefully consider the benefits and risks of benzodiazepine use on an individual basis.
These actions and workshop are part of FDA’s ongoing effort to better understand the safe medical use of benzodiazepines and minimize risks associated with their misuse and abuse. The feedback we received through this workshop, along with continued stakeholder engagement and research activities, will help us refine our knowledge and make a positive impact on substance use and associated harms.