Need for a realistic appraisal of benzodiazepines
Authors: Richard Balon, Giovanni A. Fava, Karl Rickels
Journal: World Psychiatry (2015)

Some recent articles on benzodiazepine use 1, 2 have been followed by one more wave of negative publicity about these medications, sometimes calling for more regulations of their prescribing 3 Is this criticism deserved and what is its basis? The recent article by Olfson et al 1 does not really provide any new information about benzodiazepines. It simply informs us about the approximate percentage of U.S. adults who used these drugs in 2008, and differences between genders and age groups. It does not suggest any rising epidemics in prescribing of benzodiazepines, as there is none. Indeed, prescribing of benzodiazepines for mood and anxiety disorders decreased in the U.S. between 2001 (90 mil prescriptions) and 2007 (85 mil prescriptions), while population had increased. Regarding insomnia, Olfson et al 1 only echo some concerns raised in the past. They quote a 11 year old National Institute for Clinical Excellence (NICE) guidance 4 for the use of zaleplon, zolpidem and zopiclone (not benzodiazepines), recommending the use of hypnotics only on short-term basis for severe and impairing insomnia and only after careful consideration of nonpharmacological options. The recommendation of using nonpharmacological options is fine for brief, situational, intermittent insomnia. Yet, recommending only a short-term treatment for severe impairing insomnia is not clinically suitable. Insomnia is now considered a chronic disorder: its definition specifies duration of at least 3 months. In clinical practice, we usually do not treat chronic illness for a brief period of time. The requirement of only a brief use of hypnotics in insomnia was removed from most regulatory materials. Actually, we do not have enough long-term studies available. Some "long-term" studies (only 6 months) actually suggest that prolonged treatment with eszopiclone 5 and zolpidem 6 improves daytime concentration, work performance and patient satisfaction. Unfortunately, we do not have similar studies with benzodiazepines, but their long-standing use for this indication by clinicians suggests similar conclusions. Last but not least, the relationship between insomnia and depression is bidirectional 7, since untreated insomnia may lead to depression. Benzodiazepines provide an effective treatment of anxiety disorders 8-10. Their use has been in part supplanted by selective serotonin reuptake inhibitors (SSRIs), interestingly without any supporting evidence of superior efficacy or better safety data. Indeed, when benzodiazepines and antidepressants were directly compared in controlled trials, a superiority of the former in both efficacy and side effect profile emerged 11. For instance, in Nardi et al's comparison of clonazepam vs. paroxetine in panic disorder 12, 13, the benzodiazepine was not only faster and better during the short-term treatment, but remained effective in long-term (3 years) treatment, when tolerance developed to its sedative effect, while side effects of paroxetine such as sexual dysfunction and weight gain remained an issue. The original observation of non-responsiveness of panic disorder to benzodiazepines (in contrast to imipramine) was probably mainly due to the usage of subtherapeutic doses of those drugs. The potentials for dependency, toxicity and abuse of benzodiazepines have been emphasized in the literature, yet the percentage of abuse is really low in relation to the number of people using them 14. Also, as Greenblatt et al 8 pointed out, since benzodiazepines do not cure neither anxiety nor insomnia, symptom recurrence can be anticipated after their discontinuation, and many critics may have mixed in their observations symptoms of withdrawal with recurrence of the anxiety disorder symptomatology. Furthermore, the withdrawal phenomena that occur with SSRIs 15 and atypical antipsychotics 16 have been frequently ignored. In the case of SSRIs, these phenomena have been termed "discontinuation syndromes", but are in no way milder or less troublesome than those entailed by benzodiazepines 15. Concerns have been also raised about relationships between benzodiazepines and events such as risk of falling and car accidents, and dementia 2, 3. However, at least some of these relationships could be spurious 17, and it seems premature to conclude that benzodiazepines are a causative factor in a multidimensional disorder such as Alzheimer's disease. These concerns also ignore the fact that benzodiazepine side effect profile is in many aspects very favorable compared to the long-term use of SSRIs and antipsychotics. Unfortunately, the use of antipsychotics in generalized anxiety disorder has greatly increased in the U.S., as it seems that general practitioners falsely believe that these drugs are safer than benzodiazepines. There have been also calls for more restrictions on prescribing benzodiazepines. More control and restrictions do not usually work well, as we have seen in the case of boxed warning about suicidality associated with antidepressants. Benzodiazepines are actually controlled substances under the Controlled Substances Act in the U.S.. Further regulation of prescribing benzodiazepines using so-called triplicate prescriptions was abandoned in some U.S. states after this regulation led to an increase in prescriptions of barbiturates, meprobamate and other more toxic medications. Many concerns have been also raised about prescribing benzodiazepines for the elderly. However, as pointed out by Salzman and Shader, "experienced geriatric clinicians often find that judicious use of low-dose, short half-life benzodiazepines reduces stress, promotes daytime functioning, and assists in sleep onset; elderly patients themselves report that they would gladly forgo short-term memory reduction in exchange for a calmer daytime and reliable sleep onset" (17, p. 2). How and why did we get to our profession's negative view of benzodiazepines, a view which is not necessarily shared by other disciplines? A part of the problem is a different perspective by different clinicians. As noticed by Starcevic 10, clinicians working in settings for the treatment of substance use disorders tend to take a "harsh" stand on long-term use of benzodiazepines, while clinicians working with patients with anxiety and related disorders may be more willing to see the "good side". We would like to add that, unfortunately, when new medications are introduced, their "superior" profile is suddenly promoted and marketed, even if the evidence concerning their superiority to existing medications is unclear or not available, especially since comparison to a gold standard is no longer required by the U.S. Food and Drug Administration (FDA), and superiority to placebo is considered satisfactory. It is worth mentioning that a provision in the U.S. Affordable Care Act that the pharmaceutical industry successfully defeated was the plan to compare efficacy of cheap vs. expensive medications. Is it possible that cheap benzodiazepines would fare better in anxiety disorders than some expensive new antidepressants and antipsychotics? We can probably guess the answer, but we would prefer systematic studies to be done. In conclusion, clinicians know that benzodiazepines, like any other medications, are unlikely to entail permanent and definitive solutions to chronic anxiety states, insomnia and other conditions. However, as stated by Starcevic (10, p. 1283), "the likely reasons for their ongoing popularity include their consistent and reliable effectiveness for the most prominent symptoms of anxiety, relatively good tolerability, quick onset of action, possibility of using them on an 'as-needed' basis and the realization that the newer antidepressants have not been as useful for anxiety and related disorders as they had initially seemed to be". Physicians should remain free to prescribe benzodiazepines like any other psychotropic medications. Suggesting simplistic measures for complex clinical issues is not an answer. Informed prescribing rooted in critical thinking is. Richard Balon1, Giovanni A. Fava2, Karl Rickels3 1Departments of Psychiatry and Behavioral Neurosciences and Anesthesiology, Wayne State University, Detroit, MI, USA; 2Department of Psychology, University of Bologna, Bologna, Italy and Department of Psychiatry, State University of New York at Buffalo, Buffalo, NY, USA; 3Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA