Monday, March 29, 2021

The New Black Box Warnings On Benzodiazepines



The FDA started communicating that there was going to be a new black box warning in the package inserts of benzodiazepines starting last fall.  Black box warnings are defined as applying to potential problems with medications that can lead to serious or life-threatening complications.  These warnings have been around since 1979 and they are included in the package insert or detailed prescribing information included with every medication. They are also available on line by searching “[drug name] FDA package insert”.  The changes in the package insert for benzodiazepines (in this case diazepam and clonazepam) are shown in the graphic at the top of this page. In this case the old package insert is on the left and the new one that I received in the mail on March 18, 2021 is on the right.

Benzodiazepines are controversial medications and have been over most of their 60-year existence.  Current benzodiazepines and z-drugs that are primarily used for sleep and their release dates are listed in the graphic below:

At the time of their original release the primary indication for the medication was anxiety (although current diagnostic nomenclature was not in use at the time) and that continued to be the main indication until the advent of higher potency benzodiazepines like clonazepam, lorazepam, and alprazolam. Higher potency benzodiazepines were used for panic disorder and panic attacks. As clinical use expanded it became clear that these medications also reinforced their own use and that people could develop a substance use disorder with all medications in this class.  They were also noted to be cross tolerant with alcohol and other sedative hypnotics so that the use of benzodiazepines expanded to detoxification applications.

When it became apparent that some people were not able to stop using benzodiazepines, escalated the dose, or began acquitting them from non-medical sources strategies were developed to minimize their use as much as possible.  The following timeline looks at how the treatment guidelines for anxiety and panic changed over the years with the goal of minimizing benzodiazepine exposure.

The graphic illustrates that benzodiazepines have gone from a primary role (and in some case very high dose role) in the treatment of panic disorder to a secondary and time limited role.
  Clinical prescribing typically expands on the original FDA approved indications. In the case of benzodiazepines, it is common to see them prescribed for various types of situational anxiety like public speaking or air travel.  It is also very common to see them prescribed for both transient emotional disorders (from a time limited stressor) and ongoing emotional disorders from chronic stressors.  In society today there is always a performance enhancement aspect. A common example is the person who consumes a lot of caffeine in the daytime to stay energetic and alert at work and in the gym who needs to take a benzodiazepine to treat the expected insomnia.  The main problem in prescribing the medication to a benzodiazepine naïve patient is that it is not possible to predict with certainty how they will respond.  With any medication that reinforces its own intake a substantial number of people will stop taking to due to side effects – typically excessive sedation or cognitive problems. Patients at risk with notice a euphorigenic effects that is very reinforcing.  A large number of people will take it as prescribed. In my experience, fewer people will take benzodiazepines if they receive informed consent that they are a potentially addictive medication.

The move to benzodiazepines by psychiatrists and primary care physicians came after decades of using medications with a much lower therapeutic index – primarily barbiturates but also meprobamate (Miltown) and ethchlorvynol (Placidyl). For the initial decades of use, it was taught that it was nearly impossible to ingest a lethal overdose of benzodiazepines unless they were combined with alcohol.  

Withdrawal effects with benzodiazepines can also be significant.  They depend on the duration of use, dose of medication, and pharmacological properties of the medication. In the most severe case, withdrawal delirium or withdrawal seizures can occur and both are potentially life-threatening situations compounded by the lack of effective treatment facilities.

From an epidemiological standpoint, one question is what is the current level of benzodiazepine use and is it changing over time?  Are there any direct measures of prescriptions rather than proxies like overdose deaths or benzodiazepine-based office visits?  There is a business that does collect prescriptions in retail pharmacies and has done that for the past 60 years. That data is proprietary and tends to be available only in glimpses where it is referenced by the purchaser.  In all of my searches on this subject, I located an FDA presentation on prescription patterns of controlled substances (3).  In the benzodiazepine section of that presentation there are a fairly consistent 20 million prescriptions per year between 2009 and 2015.  The commonest prescribed benzodiazepines were alprazolam (50-60%), lorazepam (25%), and diazepam (10-15%).  Further analysis shows that about 75-80% of all these prescriptions were from non-psychiatric physicians and 15% by psychiatrists and 15% by nurse practitioners and physician assistants.  67% of all benzodiazepine prescriptions were for women.  By age demographics 80% of all prescriptions were to people who were 40-59 (41.4%) and 60+ (38.2%).  This information is interesting because there is a life stage correlation with increased benzodiazepine use and use by the oldest demographic that has been flagged in the geriatric literature as being higher risk because of falls and cognitive impairment.

A global perspective on benzodiazepine use is available from INCB (International Narcotics Control Board) who estimates global supply and demand for controlled substances across the world.  According to that report, global production in 2018 was 199 tons and increase of 24% from 2017 (p. 36). The INCB also estimates the total benzodiazepine use by country for clinical and scientific use.

Additional resources in this area include this post that looks at a selective study of several states that agreed to disclose prescription levels for the purpose of this study.  There is significant variation in both opioids and benzodiazepine use from state to state.  My initial thoughts about pharmacosurveillance and pharmacovigilance still apply.  A robust system of following medication side effects and utilization can no longer depend on inadequate snapshots and voluntary reporting.

With regard to the specific change in black box warning the three main bullet points are all very reasonable and I would be shocked if any physician is not aware of these problems.  The first bullet point, highlights that the epidemiology of overdoses clearly shows a correlation of deaths with concurrent use of benzodiazepines and a shift to more potent fentanyl based illicit opioids.  A trend that has not received any comment yet is the use of fentanyl to produce counterfeit benzodiazepine tablets.  The second bullet point is necessary for the informed consent discussion with any patient.  Unless the addictive potential is openly discussed patient concerns about their past experience with addictive drugs and their family history is never mentioned.  The severity of addiction and withdrawal effects including the potential for protracted withdrawal also need to be openly discussed. The third bullet point is basically a necessary extension of the warning about tolerance and withdrawal. In clinical practice it is common to talk with patients who decided that they wanted to discontinue benzodiazepine on their own and experienced seizures and/or severe withdrawal after abrupt discontinuation.

The associated concern about the black box warning is whether it will change physician behavior or not. The experience with the black box warning on antidepressants and suicidality in patients less than 25 years of age had a significant effect on decreased prescriptions in that age group. The black box warning on benzodiazepines is really nothing new and it will be interesting to see if there are any effects. The lack of comprehensive prescription information restricts any study of that phenomena to local effects. A useful outcome may be a more comprehensive discussion of the risks and benefits before benzodiazepines are prescribed.        


George Dawson, MD, DFAPA



1:  Silberman E, Balon R, Starcevic V, Shader R, Cosci F, Fava GA, Nardi AE, Salzman C, Sonino N. Benzodiazepines: it's time to return to the evidence. Br J Psychiatry. 2021 Mar;218(3):125-127. doi: 10.1192/bjp.2020.164. PMID: 33040746.

2:  Balon R, Starcevic V, Silberman E, Cosci F, Dubovsky S, Fava GA, Nardi AE, Rickels K, Salzman C, Shader RI, Sonino N. The rise and fall and rise of benzodiazepines: a return of the stigmatized and repressed. Braz J Psychiatry. 2020;42(3):243-244. doi: 10.1590/1516-4446-2019-0773. Epub 2020 Mar 9. PMID: 32159714; PMCID: PMC7236156.

3:  Jones CM.  The latest prescription trends for controlled prescription drugs. FDA presentation. September 1, 2015

4:  International Narcotics Control Board.  Psychotropics 2019 Statistics for 2018 Assessments of Annual Medical and Scientific Requirements.  Link.


All graphics made by me.  As far as I know package inserts are public information. Click on any graphic to enlarge.

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