FDA expands Boxed Warning to improve safe use of benzodiazepine drug (original) (raw)

We reviewed postmarketing databases and the published literature on the use of benzodiazepines and associated abuse, misuse, addiction, and physical dependence. In 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S outpatient pharmacies, with alprazolam (38%) being the most common followed by clonazepam (24%) and lorazepam (20%). In 2018, an estimated 50% of patients who were dispensed oral benzodiazepines received them for a duration of two months or longer.2

Postmarketing data suggest that benzodiazepine abuse and misuse are common and that associated harms are substantial but occur primarily when people use benzodiazepines in combination with other drugs. In 2018, an estimated 5.4 million U.S. individuals 12 years and older abused or misused benzodiazepines in the previous year.3 In 2016, the nationally estimated number of emergency department (ED) visits due to nonmedical use of benzodiazepines (n=167,845) was higher than the corresponding estimate for prescription opioids (n=129,863). A relatively smaller proportion involved benzodiazepines alone – 14% (n=23,335) compared to 31% (n=40,499) of visits due to prescription opioid nonmedical use.4 Similarly, among the 8,761 U.S. poison control center calls involving benzodiazepine misuse or abuse in 2017, 63% involved multiple substances – most commonly prescription opioids, alcohol or stimulants – and medical outcomes in these cases were more severe than in cases involving benzodiazepines alone.5 Benzodiazepine-involved overdose deaths increased from 1,298 in 2010 to 11,537 in 2017.6 The proportion of these reported deaths documenting involvement of only benzodiazepines alone was small and decreased over this period, from 3.7% in 2010 to 2.7% in 2017. From 2013-2017, 55% of benzodiazepine-involved overdose deaths also documented involvement of prescription opioids.6

The exact risk of addiction associated with benzodiazepine use is uncertain; however, population data clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur. In one published analysis of National Survey on Drug Use and Health data from 2015 to 2016, a half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.7 In 2017, approximately 1% (n=10,316) of admissions to publicly-funded substance use disorder treatment programs indicated that benzodiazepines were the primary drug of abuse; however, an additional 7% and 10% of admissions indicated benzodiazepines were the secondary and tertiary drug of abuse, respectively.8 For context, the primary drug of abuse was prescription opioids in approximately 3.6% of admissions, and the majority of admissions listed the primary drug of abuse as a non-pharmaeutical substance such as alcohol (33%), heroin (31%), marijuana/hashish (12%), and methamphetamine/speed (6.3%).

Epidemiologic data on benzodiazepine dependence and withdrawal are scarce. A small number of published longitudinal studies identified female sex, older age, mental health conditions and concomitant use of certain medications (e.g., antidepressants) as possible risk factors for long-term or high-dose benzodiazepine use or dependence.9-11

We evaluated 104 cases from the FDA Adverse Event Reporting System (FAERS) database of abuse, dependence, or withdrawal involving a benzodiazepine as a single drug substance reported by patients or health care professionals directly to FDA from January 1, 1968, through June 30, 2019. While this is a small subset of FAERS cases received for benzodiazepines as a whole, we selected a focused case series to identify the most descriptive reports of dependence or withdrawal. Most patients reported that dependence and subsequent withdrawal symptoms developed even when the benzodiazepine (clonazepam, alprazolam, lorazepam, diazepam, triazolam, or oxazepam) was prescribed for therapeutic use. However, patients or others using these medications are unlikely to report directly to FDA about abuse or illicit uses. Approximately 80% of the FAERS cases described benzodiazepine withdrawal, including CNS effects (e.g., insomnia, increased anxiety or panic attacks, memory impairment, depression), cardiovascular effects (e.g., heart rate or rhythm fluctuations), and gastrointestinal effects (e.g., abdominal pain, nausea, diarrhea). These cases reported a wide range of time to dependence, with some describing the onset as early as days to weeks after the start of a benzodiazepine. Similarly, there were variations in the duration of the withdrawal symptoms that lasted from weeks to years. Most of the FAERS cases reported use of the benzodiazepine for months to years. In some cases, the patient reported that the prescriber abruptly discontinued the benzodiazepine rather than prescribing a taper to mitigate withdrawal symptoms. An important limitation in the assessment of these cases was the difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.