Zolpidem: a masked hero. A reply to ZORRO study
Dear Editor,
we have read the article by Istvan & colleagues, which recently
appeared on your Journal1, with great interest. The
use of zolpidem has been driven by the still-widespread false belief
among doctors that, since zolpidem is chemically not a benzodiazepine,
it cannot lead to addiction and tolerance. Indeed, it took almost 30
years from when the drug was introduced for pharmacovigilance
authorities of various countries to start taking action, as described by
Istvan & colleagues. However, we would like to contribute to better
highlight certain characteristics of zolpidem and its potential as a
substance of abuse due to the fact that our operating unit, which is
entirely dedicated to medication abuse, has described among the most
numerous cases of addiction to high doses of benzodiazepines and related
hypnotics.
- Istvan & colleagues hint at the similarities between the regulation
policies of flunitrazepam to draw conclusions about zolpidem. Italy
has enacted the most restrictive regulations in the world on
flunitrazepam, although this didn’t avoid that use and abuse would
overflow towards other molecules, starting from lormetazepam. Indeed,
of about 1400 cases of hospitalization for addiction to high doses of
benzodiazepines and the like in our institution, none were due to
flunitrazepam, while more than half were due to lormetazepam. Zolpidem
was in fourth place among the 29 molecules present on the Italian
market2.
- We believe it’s now time to drop the term “Z-drugs”: zolpidem,
zopiclone e zaneplon all have different chemical structures, they bind
to different receptors and have completely different abuse
potentials3. In our case history, both zopiclon and
zaneplon were virtually absent, albeit being commonly used in Italy.
- Lormetazepam, towards which most prescriptions by French doctors
turned, deserves a separate discussion. Reports about its peculiar
addictiveness are quite scarce in literature and virtually only come
from Italy and Spain, the only countries to our knowledge in which the
drug is sold in the form of drops. In our case history, 99% of the
abusers that were hospitalized for addiction to lormetazepam were
addicted to its soluble formula, unlike all other molecules for which
tablets were prevalent2. This phenomenon is still
unclear, but it’s so evident in Italy that other countries should
beware of introducing such a formula 4. In Italy,
lormetazepam has also shown to be the most abused intravenous drug for
heroin addicts5.
- Istvan & colleagues highlight the fact that addiciton and abuse are
prevalent in samples suffering from mental illness. In our case
history this hasn’t been confirmed: about half of our patients had no
history of psychiatric illnesses, nor a history of addiction to
illicit substances or alcohol2,6.
- Lastly, regarding zolpidem’s hazardousness, we would like to report
the fact that the drug was significantly preferred by addicts with a
positive ADHD test result7. This data should be kept
in mind by services that handle neurodevelopment.
We would like to conclude with an appeal to those handling policies
regarding drug regulations.
The 2000s saw solid confirmation of the effectiveness of partial
agonists in the treatment of some common addictions, such as
buprenorphine, varenicline, cytisine. This didn’t happen for BZs despite
the fact that some drugs (e.g. abecarnil) have been the subject of
research for years. The pharmaceutical market has pushed the use of
molecules, such as zolpidem, which are similar to benzodiazepines and
have thus gained significant market share, but that have often shown the
same problems.
The same could be said about therapies that are offered to those
suffering from addiction to high doses of BZs and zolpidem. Although
studies on slow-infusion flumazenil have proven to be the most promising
for thirty years, there are very few facilities in the world that offer
this practice8.
We hope that these points will stimulate a discussion about the most
common off-label pharmaceutical usage in the world: that of BZs.
Conflict of interest: none.
The authors would like to remember Malcolm Lader (1936-2020), our mentor
for pharmacological research about benzodiazepines and their misuse.
Bibliografia.
- Istvan M, Caillet P, Rousselet M, et al. Change in the regulatory
framework for zolpidem: what is the impact on the landscape of the
prescription of sedative medications? The French national ZORRO study.
Br J Clin Pharmacol. 2021 Epub ahead of print. doi: 10.1111/bcp.14753.
- Faccini M, Tamburin S, Casari R, et al. High-dose lormetazepam
dependence: strange case of Dr. Jekyll and Mr. Hyde. Intern Emerg Med.
2019 14:1271-8. doi: 10.1007/s11739-019-02101-8.
- Rousselet M, Feuillet F, Gerardin M, ET AL. The French
addictovigilance network clinical assessment: Z-drugs, true false
twins. Expert Opin Drug Saf. 2017;16:1063-9. doi:
10.1080/14740338.2017.1346084.
- Costa E, Sterzi E, Tedeschi F, Casari R, ET AL. Can oral formulation
increase the risk of lormetazepam abuse? Intern Emerg Med. 2020 Epub
ahead of print. doi: 10.1007/s11739-020-02538-2.
- Lugoboni F, Bertoldi A, Casari R, et al. Adult
Attention-Deficit/Hyperactivity Disorder and Quality of Life in
High-Dose Benzodiazepine and Related Z-Drug Users. Eur Addict Res.
2020;26 :274-82. DOI: 10.1159/000507852
- Lugoboni F, Mirijello A, Morbioli L, ET AL. Zolpidem high-dose abuse:
what about the liver? Results from a series of 107 patients. Expert
Opin Drug Saf. 2019;18:753-8. DOI: 10.1080/14740338.2019.1628216
- Lugoboni F, Bertoldi A, Casari R, et al. Adult
Attention-Deficit/Hyperactivity Disorder and Quality of Life in
High-Dose Benzodiazepine and Related Z-Drug Users. Eur Addict Res.
2020;26:274-82. DOI: 10.1159/000507852.
- Hood SD, Norman A, Hince DA, et al. Benzodiazepine dependence and its
treatment with low dose flumazenil. Br J Clin Pharmacol.
2014;77:285-94. DOI: 10.1111/bcp.12023.