Héctor Warnes´comment on Silberman, Balon, Starcevic et al "Benzodiazepines: it’s time to return to the evidence"* 

       This is an excellent summary on benzodiazepines per se as long as we divorce them from the clinical trenches. It is a fact that benzodiazepines are very safe (lethal dose LD50: 1000mg/Kg up to 2000 mg/Kg) except in pregnancy; that misuse may lead to abuse and long term abuse may cause addiction (along with withdrawal symptoms) in vulnerable patients (particularly those consuming other addictive substances) and who endure high levels of neuroticism and stressful life events (Tan, Brown, Laboudé et al. 2010). There is little doubt that the use of benzodiazepines has increased in tandem perhaps it is a controversial subject or as Cahir, Fahey, Teeling et al. (2010) report, it may be due to inappropriate prescribing.

       Further, most patients are not prescribed just one benzodiazepine but are prescribed proton-pump inhibitors, non-steroidal anti-inflammatories and they may be smoking or consuming alcoholic beverages often (which alters sleep). We are aware that the comorbidity between anxiety and depressive disorders is more than 60% which drives psychiatrists to prescribe an antidepressant compound as well (Belzer and Schneier 2004; Cahir, Fahey, Teeling et al. 2010; Schmitz 2016; Maust, Lin and Blow 2019; Alnæs 2009).

       As the patient grows older the number of drugs prescribed are increased because of the mounting prevalence (with aging) of hypertension, obesity, cancer, cardiovascular disorders, metabolic syndromes, arthrosis, traumatic lesions, pulmonary diseases and so on. A patient over the age of 50 or 60 may be consuming at least five different medications (polypharmacy) given by at least six doctors. One would surmise that antibiotics, painkillers, antidepressants and anxiolytics are taken for a reasonable period of time but they are being used as often and for a long as necessary according to the clinical symptoms emerging. No wonder the antibiotic resistance to microorganisms are plaguing our clinical practice.

       Frequently, benzodiazepines are used for insomnia which is very prevalent particularly in the stressed-out patient who may be overweight, has snoring behaviour and sleep apnea (Netzer, Stoohs, Netzer et al. 1999). Like the opioid compounds (e.g., tramadol, oxycodone, hydrocodone) some benzodiazepines depress the respiratory centers during sleep. Patients with diminished respiratory functions should not be prescribed potential depressants of the respiratory centers unless they are carefully monitored for the levels of oxygen saturation during sleep while taking the drugs.

       It also depends on the half-life of the benzodiazepine: short, intermediate or intermediate long. With increased aging clonazepam and alprazolam are frequently prescribed. Most elderly patients wake up at least once during their sleep in order to urinate which may increase the risk of falling and fractures. It has been shown as well that cognitive lucidity decreases with the use of benzodiazepines particularly in those elderly patients who do not have a restorative sleep due to the known effect of benzodiazepines on sleep (they are likely to suppress theta and delta sleep which occurs during the first third of the night (during theta and delta sleep growth hormones reach a peak) and depending of the doses they also suppress REM sleep with a rebound effect should the medication be abruptly discontinued (Roehrs and Roth 2010; Mazza, Losurdo, Testani et al. 2014). Patients consuming benzodiazepines who are returning home late at night may experience "microsleeps," episodes which are a common cause of vehicle accidents (Bastien, LeBlanc, Carrier and Morin 2003).

       I also wanted to comment on Halcyon which was the first benzodiazepine that gave me an inkling on anterograde amnesia (Juhl, Daugherty and Kroboth 1984). Lately, I have seen patients who were abusing alprazolam up to 8 or 10 mg a night (obviously tolerance to the drug was significant). Once one of them drove the car and went to meet a friend; at times she was driving on the sidewalk (reported by observers) and had no recall of the events for about four hours.

* This editorial was published in The British Journal of Psychiatry (Silberman E, Balon R, Starcevic V, Shader R, Cosci F, Fava GA, Nardi AE, Salzman C, Sonino N. Br J Psychiatry, 2020;1-3).

References:

Alnæs STR. A 6-year follow-up study of anxiety disorders in psychiatric outpatients: Development and continuity with personality disorders and personality traits as predictors. Nordic Journal of Psychiatry, 2009;53(6):409-16. 

Bastien CH, LeBlanc M, Carrier J, Morin CU. Sleep EEG power spectra insomnia and chronic use of benzodiazepines. Sleep, 2003;26:313-7. 

Belzer K, Schneier F. Comorbidity of Anxiety and Depressive Disorders: Issues in Conceptualization, Assessment and treatment. Journal of Psychiatric Practice, 2004;10(5); 296-306. 

Cahir C, Fahey T, Teeling M, Teljeur C, Feely J, Bennett K. Potentially inappropriate prescribing and cost outcomes for older people: a national population study. Br J Clin Pharmacol, 2010;69(5):543–52. 

Juhl RP, Daugherty VM, Kroboth PD. Incidence of next-day anterograde amnesia caused by flurazepam hydrochloride and triazolam. Clin Pharm, 1984;3(6):622-5. 

Maust DT, Lin LA, Blow FC. Benzodiazepine use and misuse among adults in the USA. Psychiatr Serv, 2019;70(2):97–106.  

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Netzer NC, Stoohs, RA, Netzer CM, Clark K, Strohl KP. Using the Berlin questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med, 1999;131(7):485-91. 

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Tan KR, Brown M, Laboudé G, Yvon C, Creton C, Fritschy J-M, Rudolph U, Lüscher C. Neural bases for addictive properties of benzodiazepines. Nature, 2010;463:769-74.

March 4, 2021