Benzodiazepines Are Efficacious and Safe for Long-Term Use

Any group of drugs that has been on the market for more than 60 years and is constantly being prescribed by physicians in their daily practice should have our attention and respect [1]. This is the case with benzodiazepines (BZ) as they have been on the market for a long time and deserve some degree of deference for surviving attacks from the media and the industry, have emerged from the classification era when the diagnostic criteria and particular diagnoses are linked with specific drug [1], and remain the most prescribed group of medications for anxiety disorders [2]. They continually deserve a comprehensive update of their pharmacological and clinical features. Dubovsky and Marshall [3] provided an excellent updated review that increased our self-confidence in prescribing BZ and criticizing the literature that is full of data involving conflicts of interest [4]. The savage marketing of serotonin selective reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor (SNRI) is among the worst episodes in the recent history of psychopharmacology [1]. Psychiatrists and physicians do not need to study and think about what they read or see in front of them; they should simply prescribe an antidepressant (AD) for every anxiety disorder. The illusion of guidelines sponsored by the SSRI and SNRI industry decided that they should demonize BZ, and physicians should prescribe an AD for every anxiety disorder without comparison to any other group or drug [1^, 5]. It is not possible that every anxiety disorder and post-traumatic stress disorder should have an AD as the first choice of treatment without any face-to-face clinical trial demonstrating these data.

BZ are effective and well-tolerated, and they should be prescribed as carefully and judiciously as any other medication [2^, 3]. They are efficacious for the short- and long-term treatment of anxiety disorders [6]. Clinicians and investigators have recognized their benefits for many anxious patients, but some medical “propagandists” have popularized a critical view of these medications, and this view has become entrenched in the media and general medical opinion [2^, 4]. For example, due to the possibility of withdrawal symptoms with BZ, most recent treatment guidelines recommend SSRI as the first-line choice for the treatment of anxiety [7]. Such recommendations are based on expert opinions and clinical trials of SSRI against placebo, but evidence coming from direct drug comparisons of BZ and SSRI in anxiety is rare, and in panic disorder (PD), one of the most prevalent anxiety disorders [8], it is always favorable to prescribe BZ with acute or long-term use [6^, 9]. This conflict-of-interest-based preference for SSRI treatments deprives individuals with anxiety disorders of potentially valuable treatment with BZ. Even worse, some physicians avoid prescribing them, and some patients take every pill feeling guilty or as if they are doing something against their health [2^, 4].

Studies comparing approved BZ with approved SSRI in PD patients have been conducted, but they did not reach the impact of SSRI marketing [1^, 2^, 6]. Our research team [6] compared the efficacy and safety of clonazepam and paroxetine in PD patients during acute and long-term drug treatment and during drug discontinuation. The frequency of panic attacks decreased in patients receiving both medications beginning in the first treatment week, with a marginal advantage of clonazepam. After 8 weeks of treatment, 90% of patients receiving clonazepam and 82% of patients on paroxetine were free from panic attacks. All participants were invited to continue the treatment during a long-term study [6]. Patients with a good primary response to the monotherapy continued with the same drug and dose. At the end of 3 years of treatment, patients treated with clonazepam monotherapy were less likely to experience recurrence of panic attacks, and clonazepam had a safer side-effect profile during the acute, long-term, and withdrawal phases of treatment than those patients who were treated with paroxetine [6^, 9]. Therefore, our data show that BZ was not only faster and better during the PD short-term treatment but remained effective in long-term (3 years) treatment [6^, 9]. Some other studies evaluated AD and BZ in short- and long-term treatment in different anxiety disorders. For instance, a recent review [10] examined generalized anxiety disorder treatment and demonstrated that patients’ most improvement with a BZ was obtained by 4 weeks of treatment, suggesting that BZ treatment longer than 4 weeks should only be offered to patients maximally improved at 4 weeks. In contrast, ADs may have to be prescribed for 3–6 months to obtain maximal benefit [10].

BZ have long been used to treat anxiety disorders, sleep disturbances, and a variety of medical illnesses such as epilepsy and alcohol withdrawal [11]. Their high number of prescriptions stimulated considerable concerns and initiatives to limit their use [3]. The development of second-generation AD has resulted in more expensive treatment options for anxiety disorders [12]. BZ were clearly replaced with SSRI and SNRI [11]. Such a path would have been impossible if new drugs had to be compared to a gold standard because direct comparisons clearly show that BZ outperformed AD in efficacy and tolerability [12]. In fact, BZ present to be superior over AD in generalized anxiety disorders, complex phobias, and mixed anxiety depressive disorders [11]. Furthermore, BZ were better tolerated than SSRI and SNRI, leading to fewer dropouts and adverse reactions [11].

The advantages and disadvantages of BZ and AD are related to some hypothetical biological substrates for the different side effects observed with these drugs. Dubovsky and Marshall [3] discussed comprehensively BZ mechanisms of action and the possible side effects of this drug class. One important approach into BZ prescription is instead of grouping all BZ together, as is commonly done, physicians must consider each medication as its own. BZ differences and similarities should be evaluated based on relative lipid solubility, binding affinity, and half-life [13]. Drugs having high lipid solubility, such as triazolam and alprazolam, would be linked with increased dependency liability, cognitive impairment, and anterograde amnestic effects [13]. However, BZ having low affinity for the BZ receptor and lipid solubility, such as clonazepam, on the other hand, would be associated with lower dependence liability and amnestic potential [13]. Consequently, it is clear that not all BZ are the same, and this must be considered when we are prescribing this medication [13].

There is an emerging awareness of the deleterious and bothersome adverse events that may ensue specially with long-term treatment with AD, such as high rates of sexual dysfunction, bleeding, hyponatremia, weight gain, and osteoporosis [7]. Furthermore, a recent study [14] shows that the risks of excessive mood elevation during AD treatment, including mania-hypomania, were much greater than with placebo, and similar in juvenile anxiety and depressive disorders, calling for caution and monitoring for potential risk of future bipolar disorder in children and adolescents. The tolerance induced by AD may predispose patients who have never been depressed before more vulnerable to depression as well as hypomania/mania, particularly in younger people [12]. Young patients who begin taking AD for anxiety disorders and continue this treatment forever without receiving any sort of psychotherapy should be especially cautious, since there is no evidence regarding the long-term impact of AD disruptions in young people, and we still do not know if tolerance will emerge, resulting in refractoriness [12^, 14]. These worries were pointed out by Fava [12] and originated the belief that AD use may be acceptable in the context of a significant depressive episode coexisting with an anxiety disorder. In all other circumstances, unless psychotherapy alternatives are unavailable or ineffective, or BZ fails to offer adequate relief, treatment with AD should be carefully evaluated [12]. To better evaluate this matter, studies directly comparing AD and BZ in different life stages should be conducted.

Most patients with anxiety disorders need long-term treatment to prevent recurrence of the disease. Two key issues in long-term treatment are the tolerability of pharmacological agents and withdrawal symptoms [15]. Drug-related adverse events are the most common reason for premature cessation of treatment, especially with SSRI [7]. Abrupt discontinuation of any anti-anxiety agent, both BZ and AD, is generally to be avoided. However, not only abrupt discontinuation of AD might cause severe discontinuation symptoms, but this can also be seen with AD slow and ultra-slow tapering [15]. This is especially true of medications that do not have a long half-life. Good tolerability is therefore pivotal for long-term success. Dependence after prolonged use of BZ and difficulties in managing withdrawal symptoms during their discontinuation were mentioned in nearly all publications on therapeutic use of BZ that appeared in the 1990s and at the beginning of this century [16]. Indeed, severe withdrawal symptoms, including seizures, were observed in PD patients following drug discontinuation with BZ and AD [16^, 17].

The rates of response and remission with AD are very low when considering the treatment of anxiety disorders [18]. In a trial evolving patients with social anxiety disorder treated with sertraline, low rates of remission (13%) and response (32%) were found [19]. However, these results failed to enter a discussion about sertraline being considered a first line of treatment for social anxiety disorder. Furthermore, drug treatment of anxiety disorders results in almost automatic relapse upon discontinuation, even after 1 year of treatment with AD [18^, 20]. Therefore, psychotherapy should be considered as a first line of evidence for anxiety disorders treatment and should be performed independent of the drug choice.

Since present-day anxiety disorders’ treatment guidelines are not yet supported by controlled clinical trials, therefore, questions have been raised regarding the quality of evidence for first-line medications for anxiety specifically whether data exist that imply that BZ should be regarded as worse and, thus, second-line in anxiety treatment [21^-23]. Dubovsky and Marshall [3] provided an excellent review that improved our understanding of prescribing BZ and corroborates the available evidence that does not support the trend in prescribing patterns favoring SSRIs over BZ in the treatment of anxiety [22^, 23]. Therefore, it may be time to reassess the use of BZ in the long-term treatment of anxiety disorders. Several patients may benefit from BZ as first-line therapy. Rather than placing restrictions on the use of BZ, the indications for their usage should be thoroughly evaluated.

Conflict of Interest Statement

The authors have no conflicts of interest to declare. A.E.N. is a member of the International Task Force on Benzodiazepines, an organization of clinical researchers without any economic support.

Funding Sources

Both authors received grants for research from the National Council for Scientific and Technological Development (CNPq) from the Federal Government of Brazil and from the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) from the State Government of Rio de Janeiro, Brazil.

Author Contributions

Both authors equally worked on the manuscript, discussing the project, colecting the references, writing the drafts, and approving the final version.