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 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
References:
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.
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