Several medications such as ACE-inhibitors have been associated with a
negative influence on COVID-19 based on their potential pharmacological
activity to interfere with viral cell invasion, however the causality
and clinical relevance have not been proven yet and this is subject of
investigation.[1] At our helpdesk for clinical decision support, we
received questions from health care professionals if benzodiazepines
could negatively influence the course of non-intubated COVID-19 patients
by their side effects, and hence should better be avoided.
Benzodiazepines are frequently used for indications such as sleep and
anxiety, also in seriously ill patients. In this letter, we comment on
the relevance of respiratory depression as side effect of
benzodiazepines in patients with COVID-19 from a pharmacological and
epidemiological perspective.
Benzodiazepines are GABAA-agonists, and respiratory
depression is a well-known side effect mentioned in the official product
information. Their main effect on respiratory function is depression of
the central respiratory drive and lowering of the responsiveness to
hypercapnia.[2] Other hypothesised pathways include direct
activation of GABAA-receptors in the peripheral nervous
system resulting in reduced respiratory muscle strength, and
contribution to local inflammation.[2] However, the findings on
respiratory depression in humans are inconclusive and contradictory, and
it is unclear how benzodiazepines are involved in the pathways behind
these processes.[3]
From an epidemiological perspective, the use of high (but not low) dose
benzodiazepines in patients with severe (oxygen dependent) COPD
increases the risk for mortality, but prospective trials have not shown
effects on gas exchange or breathing rate.[4] Epidemiological
studies are hampered by residual confounding, and therefore they might
overestimate the effect of benzodiazepines, yet these studies advise in
agreement with prescribing guidelines to be cautious with
benzodiazepines, especially when co-prescribed with opioids.[5] In
end-of-life care, the use of benzodiazepines can be indicated for
anxiety or the relief of dyspnoea.[6,7]
In the course of COVID-19, benzodiazepines are feared to worsen the
respiratory function in patients who experience shortness of breath in
the second week of illness, that may further develop to acute
respiratory distress syndrome in about 10-20% of the severe
patients.[8] However, as the respiratory problems in COVID-19 are
caused by a type 1 respiratory failure, and as the risk of
benzodiazepines is predominantly associated with hypercapnia, the
expected risk is limited. However, future epidemiological analyses that
will investigate the use of medication as factor contributing to the
course of COVID-19, should also study the use of benzodiazepines.
In conclusion, the pharmacological profile of benzodiazepines includes
respiratory depression, and theoretically benzodiazepines might
contribute to respiratory dysfunction. There are currently no data that
indicate that benzodiazepines are problematic in COVID-19, and the risk
is expected to be limited. Benzodiazepines are effective and frequently
used, and if there is a clear indication in patients with COVID-19 there
is insufficient reason to avoid benzodiazepines based on respiratory
depression as side effect.
References
- Vaduganathan
M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD.
Renin-Angiotensin-Aldosterone System Inhibitors in Patients with
Covid-19. N Engl J Med. 2020 Mar 30. doi: 10.1056/NEJMsr2005760.
- Vozoris NT. Do benzodiazepines contribute to respiratory problems?
Expert Rev Respir Med. 2014 Dec;8(6):661-3. doi:
10.1586/17476348.2014.957186.
- Masneuf S, Buetler J, Koester C, Crestani F. Role of α1- and
α2-GABA(A) receptors in mediating the respiratory changes associated
with benzodiazepine sedation. Br J Pharmacol. 2012 May;166(1):339-48.
doi:10.1111/j.1476-5381.2011.01763.x.
- Ekström
MP, Bornefalk-Hermansson A, Abernethy AP, Currow DC. Safety of
benzodiazepines and opioids in very severe respiratory disease:
national prospective study. BMJ 2014; 348: g445.
- UK Medicines & Healthcare products Regulatory Agency. Benzodiazepines
and opioids: reminder of risk of potentially fatal respiratory
depression. Drug Safety Update volume 13, issue 8: March 2020: 5.
- Salt S, Mulvaney CA, Preston NJ. Drug therapy for symptoms associated
with anxiety in adult palliative care patients. Cochrane Database Syst
Rev. 2017 May 18;5:CD004596. doi: 10.1002/14651858.CD004596.pub3.
- Kloke M, Cherny N; ESMO Guidelines Committee. Treatment of dyspnoea in
advanced cancer patients: ESMO Clinical Practice Guidelines. Ann
Oncol. 2015 Sep;26 Suppl 5:v169-73. doi: 10.1093/annonc/mdv306.
- Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): a clinical
update. Front Med. 2020 Apr 2. doi: 10.1007/s11684-020-0767-8. [Epub
ahead of print]