Off-Label Use Efficacy

While some of the off-label uses of benzodiazepines appear to be effective, many common uses are ineffective. Several off-label uses for which benzodiazepines have been shown to be ineffective or to induce other serious problems are listed below. Note that a problem with benzodiazepines that is common across most of the off-label uses is the risk of physiological dependence.

 → Analgesia (Pain Control)
Benzodiazepine prescriptive practices have evolved to the point that they are widely prescribed as analgesics.  There are many guidelines for pain management, and they are mixed in their recommendations.   The majority recommend that benzodiazepines be used as analgesics only in special cases, such as surgery or palliative care.  Several studies^[7-9] have shown that benzodiazepines are ineffective as analgesics.  Since 2016, the FDA has required black box warnings on all benzodiazepines, stating that there is a high risk of death when combining benzodiazepines and opioids.

→ Insomnia Relief
Although it is an off-label use, benzodiazepines are commonly prescribed as sedatives.  Half-lives of benzodiazepines vary widely, with even the shortest-acting, oxazepam, having a half-life that varies between 3-21 hours.  Some of the benzodiazepines have half-lives of up to 100 hours.  At best, this makes them unpredictable sedatives.  At worst, it means that patients will be at least partially sedated for whole days after using a benzodiazepine as a sleep aid, leading to impaired judgment and increased risk of accidents.  A meta-study of benzodiazepine use in the treatment of insomnia^[10] determined that it is associated with an increase in average sleep duration of 61.8 minutes, but this gain is countered by a number of adverse effects, including cognitive function decline and memory impairment.  Representative of the drugs specifically marketed as sleeping aids, the benzodiazepine receptor agonist zopiclone was not found to be superior to benzodiazepines on any of the outcome measures examined, including negative outcomes.  Incidents of dangerous behavior while under the influence of z-drugs have been well documented. ^[11-13]   Note that sleep management techniques that are not based on benzodiazepines or non-benzodiazepines (Z-drugs) yield a similar increase in average sleep duration, without the undesirable effects of benzodiazepines.

→  Post-Traumatic Stress Disorder
According to the World Health Organization, “There is no evidence on the benefits of benzodiazepines, a common anti-anxiety drug, on symptoms of traumatic stress after a recent potentially traumatic event. Benzodiazepines may slow down the time to recover from potentially traumatic events.”^[14]  The British Association for Psychopharmacology has determined that benzodiazepines have no efficacy for treating post-traumatic stress disorder.  Indeed they may actually be contraindicated for use in PTSD, as it should be noted that benzodiazepines can be disinhibiting which could result in inappropriate or even violent behavior.

→  Depression
Most depression treatment guidelines emphasize treatment with antidepressant medication and recommend that benzodiazepine use be minimized, particularly among elderly patients. ^[15] Benzodiazepines are often co-prescribed with antidepressants to increase patient medication compliance levels. However, this strategy has been shown to be ineffective after six weeks, and the studies do not factor in the likelihood of becoming physically dependent on benzodiazepines.^[16] It has been shown that the combination of SSRIs and benzodiazepines should be avoided, and there is no anti-depressive advantage of adding benzodiazepines to tri-cyclic antidepressants. ^[17-18]  A study found that of 42 patients treated with alprazolam, up to a third of long-term users of alprazolam (Xanax®) develop depression.^[19] Studies have shown that long-term use of benzodiazepines and the benzodiazepine receptor agonists (nonbenzodiazepines or “Z-drugs”) are associated with causing depression as well as a markedly raised suicide risk and an overall increased mortality risk. ^[20-21]

→  Mania and Bipolar Disorder
Benzodiazepine use may be associated with greater risk for recurrence of a mood episode among patients with bipolar I and II disorder. The prescribing of benzodiazepines, at a minimum, appears to be a marker for a more severe course of illness. ^[22] Benzodiazepines are often prescribed to reduce the extremes of manic episodes, especially in the first week after onset of mania. However, the benzodiazepines themselves have been shown to induce manic symptoms, both during long-term use, as well as during and after withdrawal from benzodiazepines. For a more detailed discussion of this topic and pertinent references, click here.

→  Obsessive-compulsive disorder
A double-blind placebo-controlled study of the effectivity of clonazepam in OCD showed no statistically significant difference between treatment and placebo.^[23] In addition, a 2016 study showed that “OCD patients taking BDZs may be more complex and more difficult to manage”.^[24] According to the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines, “One should be aware that benzodiazepines were not found to be effective in acute stress disorder and in conditions with depression comorbidity, or OCD.”  Just as for PTSD, benzodiazepine use for OCD may not only be ineffective but also contraindicated.

→  Schizophrenia
As of 2016, two studies have assessed the relationship between benzodiazepine use and mortality in treatment of schizophrenia, both with and without other medications. In both studies, benzodiazepine use was associated with an increase of 80% to 90% in mortality. ^[25-26]

^→   Epilepsy
Benzodiazepines are the first-line treatment of status epilepticus. Adverse effects of chronic benzodiazepine use are sedation, tolerance, and potential for addiction in some patients. ^[27]

→  Dementia
A late 2016 Harvard study showed that benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association. ^[28] Despite known harms, benzodiazepines continue to be used for a variety of conditions, including the management of neuropsychiatric symptoms associated with dementia. Canadian data show that the rate of benzodiazepine use is 15% in the community; the rate increases to more than 30% in long-term care facilities, where at least half of residents aged 80 years and older have dementia. ^[29] In a controlled study, benzodiazepine treatment was gradually discontinued from a group of elderly nursing home residents. In comparison with similar residents who continued on benzodiazepines, measures of memory and cognitive functioning showed significant improvement following discontinuance. There was no associated increase in anxiety, agitation, or sleeplessness. ^[30]

→  Severe geriatric agitation
There are many recommendations in the literature advising against the use of benzodiazepines in the elderly. Elderly demented patients with chronic agitation treated with benzodiazepines are at an increased risk of falls, sedation and cognitive impairment. ^[21-33] However, these adverse effects are probably not relevant to the acute temporary management of an agitated patient.

→  Pediatric anxiety disorders
An Agency for Healthcare Research and Quality review was conducted with 20 random controlled trials that compared drugs to placebo for the treatment of anxiety disorders in youth (2,466 patients, age range 5-17 years old, mean age: 11.6 years old). Benzodiazepines did not show statistically significant improvements in anxiety symptoms over placebo. ^[34]

→  Restless leg syndrome
A systematic review done by the American Academy of Sleep Medicine stated that benzodiazepines should not be used as a first-line treatment for restless leg syndrome.   An association between many reported adverse reactions to benzodiazepines and the common syndrome of restless legs or nocturnal myoclonus is suggested. In one study, a patient with incapacitating restless leg syndrome had suffered from repetitive confusional states exclusively after use of short-acting benzodiazepines. Complete removal of symptoms was achieved discontinuing the benzodiazepines and administering levodopa. ^[35]

^→   Attention deficit hyperactivity disorder
Although there have been no controlled studies supporting their use, benzodiazepines, most notably Xanax®, are often part of the prescription mix used for treating ADHD. There is a fundamental problem with treating some of the symptoms concomitant to ADHD with benzodiazepines. Although they are highly variable, the symptoms of ADHD typically are chronic and require long-term treatment. Meanwhile, for benzodiazepines, anxiolysis decreases and physical dependency increases when used beyond the 2-4 week window for which they were approved.

→  Specific phobias
Benzodiazepines are often used to blunt the anxiety associated with phobias. While this has sometimes been shown to be effective for single situational phobias, the administration of benzodiazepines has not been shown to produce any long-term reduction in phobia. On the other hand, treatments such as CBT often produce lasting change. In one study, 50 dental phobic patients were allocated either to psychological treatment, benzodiazepine, or no treatment for anxiety. Both psychological and benzodiazepine treatment conditions led to less anxiety during dental surgery than did the control condition. Phobic patients in the benzodiazepine condition showed a relapse after dental treatment, whereas those in the psychological treatment condition showed further improvement until the follow-up 2 months later. Of the latter group, 70% continued dental treatment; only 20% and 10% returned in the benzodiazepine and control conditions, respectively. ^[36]

→  Fluvoxamine co-prescription problems
Fluvoxamine will inhibit the metabolism of alprazolam, midazolam, triazolam and diazepam causing increased sedation and potential toxicity. Since Fluvoxamine (Luvox®) is often used to treat obsessive-compulsive disorder (OCD), panic disorder, post-traumatic stress disorder and social anxiety disorder, benzodiazepine co-prescription should be avoided when it is used. ^[37]

→  Delusions
Daily users of benzodiazepines are at a higher risk of experiencing psychotic symptomatology such as delusions and hallucinations. ^[38]

References