Antonio E. Nardi, Richard Balon, Guy Chouinard, Fiammetta Cosci, Steven Dubovsky, Giovanni A. Fava, Rafael C. Freire, David J. Greenblatt, John H. Krystal, Karl Rickels, Thomas Roth, Carl Salzman, Richard I. Shader, Edward K. Silberman, Nicoletta Sonino, Vladan Starcevic and Steven J. Weintraub: The value of long-term clinical experience with benzodiazepines. International Task Force on Benzodiazepines
Hector Warnes’ comments

           I must congratulate the Task Force on the conclusion reached on the use of benzodiazepines (BZD). Benzodiazepines are considered to be versatile, safe, easy to use and with an important margin of tolerance in recommended doses. Differences in absorption, half-life, liposolubility, distribution in the CNS, co-administration with other drugs, elimination and pharmacological background of the patient have to be considered in each individual case. Chouinard (2004) clearly defined the relationship between potency, withdrawal and rebound effects of the BZD.

           We all have seen cases of psychological dependence and even physical dependence when the patient, over time, increases the tolerance and the doses required in order to control his/her symptoms. There are many observed cases with rebound anxiety, abstinence when not following the gradual discontinuation of the drug (about 25% per week) and far more infrequently memory disturbances. Madhusoodanan and Bogunovic (2004) have shown that in elderly patients with co-morbid medical and psychiatric conditions who are most likely taking multiple medications, BZD side effects are frequently seen, including nocturnal disorientation, falling and fractures.

           Pompeia et al. (2005) demonstrated clearly that not all BZD are the same in a classical paper (What makes lorazepam different from other benzodiazepines?). It has been shown that most BZD shortened the sleep latency, reduce the number of awakenings or microarousal during sleep, increase the stage II sleep along with sleep spindles and K complexes and invariably decrease delta sleep or the depth of sleep generally, restorative sleep (which occurs during the first third of the night). The effect on REM sleep is variable and the sudden discontinuation of BZD can produce nightmares, sudden awakenings and strange dreams. In individuals with sleep apneas BZD increase their frequency, as well as the snoring which precedes them.

           The overdose of these compounds with suicidal intent, and when not combined with other drugs, are successfully treated particularly with flumazenil, a competitive antagonist given IV. Because flumazenil has a very rapid half-life it must be given two or more times. Most fatalities seen with the use of BZD occur when they are taken in what is called combined drug intoxication particularly with alcohol, opioids, antidepressants, cocaine, fentanyl, propofol, antihistaminics and so on. Reynaud et al. (1998) reported six deaths linked to concomitant use of buprenorphine and BZD, just to mention one of many cases reported in the literature. Soumerai et al. (2003) reported on 2,440 patients taking BZD over time that there was a lack of relationship between long-term use and escalation to high dosage.

           Benzodiazepines have a shifting duration of action on account of possible tolerance, liposolubility, relative potencies, drug interactions and varying metabolism from patient to patient.

           Since the mechanism of action of the BZD is through the GABA-A receptors which are widely distributed in the central nervous system each BZP may have a specific inhibitory action affecting more its anxiolytic, hypnotic, anticonvulsant, muscle relaxant and so on. Therefore, studies on the predominant site of action are still unclear but may be on the spinal cord, the limbic system, the locus coeruleus, the cortex or the brain stem. Also, it has been shown that BZD may affect the cerebellum (ataxia), the central reticular formation (hypnotic effects) and the hippocampus and frontal cortex (memory dysfunction). Anterograde amnesia (useful in anesthesia) is seen in the BZD with high potency and ultra-rapid half-life (Midazolam and Triazolam), the half-life of which is approximately 1-4 hours. When Triazolam is used as a hypnotic, with alcohol the risk of anterograde amnesia is greater. The half-life is the time taken for the blood concentration to fall to half its peak values after a single dose. Mintzer et al. (2006) have demonstrated, using PET scanning, triazolam changes in the temporal lobe and prefrontal cortex associated with dysfunction of memory encoding.

           There has been a trend to replace the BZD for pregabalin which in some cases proved to be unsuccessful in controlling anxiety and its multiple derivatives (panic, insomnia, neurovegetative dysfunction, multiple somatization, etc.). In many cases patients were able to be switched to a serotoninergic antidepressant or to mirtazapine with successful outcome. It appears to be an individual response specifically linked to pharmaco-genetics, drug metabolism, drug interaction in the hepatic Cytochrome P450 enzymes, pharmacokinetic, diet, illness profile or as yet not well understood factors.

References:

Chouinard G. Issues in the clinical use of benzodiazepines: potency, withdrawal and rebound. J. Clin. Psychiatry 2004; 65: 7-12.

Madhusoodanan S, Bogunovic OJ. Safety of benzodiazepines in the geriatric population. Expert opinions Drug Safety. 2004; 3: 485-93.

Mintzer MZ, Kuwabara H, Alexander M, Brasic JR, Ye W, Ernst M, Griffiths RR, Wong DF. Dose effects of triazolam in brain activity during episodic memory encoding: a PET study. Psychopharmacology 2006; 188: 445-61.

Pompeia S, Manzano GM, Tufik S, Bueno OFA. What makes lorazepam different from other benzodiazepines? J. Physiology 2005; 569: 709.

Reynaud M, Petit G, Polard D, Courty P. Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Addiction 1998; 93: 1385-92.

Soumerai SB, Simoni-Waslila L, Singer C, Mah C, Gao X, Salzman C, Ross-Degnan D. Lack of relationship between long term use of benzodiazepines and escalation to high dosages. Psychiatric Serv. 2003; 54: 1006-11.

Mintzer MZ, Kuwabara H, Alexander M, Brasic JR, Ye W, Ernst M, Griffiths RR, Wong DF. Dose effects of triazolam in brain activity during episodic memory encoding: a PET study. Psychopharmacology 2006; 188: 445-61.

January 3, 2019