Benzodiazepines as a First Line Treatment for Anxiety Disorders
Benzodiazepine tranquilizers have been around since 1960. These include: Xanax (alprazolam), Klonopin (clonazepam), Valium (diazepam), Ativan (lorazepam) and Librium (chlordiazepoxide).
These are the most effective medications with the least amount of side effects for the treatment of Anxiety Disorders: Generalized Anxiety Disorder, Panic Disorder, Agoraphobia, Social Phobia, School Phobia and brief periods of stress.
There are many myths and misconceptions about these very safe and useful medications from doctors, non-physician mental health workers and the media. The American Psychiatric Association, Nation Institute of Health and DEA have produced documents showing their safety. They are not addictive, do not produce tolerance (the need to continually increase the dose) and are rarely abused. Most of the abuse comes from mixing them with alcohol and street drugs. They have much fewer side effects compared to the SSRI, tricyclic and other
antidepressants. When they are dosed properly there are often no side effects. They can be safely used long term and even a lifetime.
Because of misinformation, doctors are reluctant to and even fear prescribing them. As a result, this useful class of medications, benzodiazepines, are currently underutilized.
This article helps to correct that misinformation and is a guide for your doctor to properly prescribe them.
Benzodiazepines as a First-Line Treatment for Anxiety Disorders
By Abbot Lee Granoff, MD Board Certified Psychiatrist
April 8, 2018
Many articles, medical presenters and the media perpetuate the myth about "addiction," dependence meaning addiction, building tolerance, inappropriate use of and abuse of benzodiazepines.(1,2,3,4) Physiologic adaptation and discontinuance syndrome can occur.(5,6,7,8) However, these can also occur with many drugs: steroids, anticoagulants, beta blockers, anti-inflammatories, many psychotropic drugs, sedative hypnotics, opioids.(6,7) Objectivity and consistency of terminology would lead us to use the same terminology for the same process, yet many physicians use the more pejorative terms of addiction, dependency, drug seeking and withdrawal when referring to the benzodiazepines.
Chronic use of a benzodiazepine for treating a medical condition is not an addiction. It is more appropriately considered dependence. Unfortunately, these terms are often used interchangeably. DSM-5 does not consider benzodiazepines taken appropriately under medical supervision a Substance Use Disorder.(7) Its essential feature is "continual use of the substance despite significant substance-related problems."(7) Pharmacological criteria requires tolerance, "a markedly increased dose of the substance to achieve the desired effect," in addition to withdrawal. (7) "Symptoms of tolerance and withdrawal occurring during appropriate medical treatment with prescribed medications are specifically notcounted when diagnosing Substance Use Disorder. Normal, expected pharmacological tolerance and withdrawal during the course of medical treatment has been known to lead to an erroneous diagnosis of addiction."(7)
Prevalence for Sedative, Hypnotic, or Anxiolytic Use Disorder is 0.5% or less among American adults with the exception of Native Americans and Alaska Natives at 0.8%.(7) Medical presenters, the medical literature and the media make it seem like abuse is rampant and out of control.
Using any medication long term or even a lifetime is not addiction. Patients are dependent on their medications to treat any chronic medical condition of any organ system. Benzodiazepines are no different. When a person develops Panic Disorder
which can lead to phobias, this author prescribes alprazolam as a first-line treatment. The average dose is 2-3mg per day with a range of 1/16-12mg per day. For Generalized Anxiety Disorder this author prescribes diazepam as a first-line treatment. The average dose is 10-20mg per day with a range of 2-60mg per day.(6,8) This author has successfully done this for over 40 years in his private psychiatric practice with a 98+% return to a full functioning life.(8) Panic Disorder, Agoraphobia, Social Phobia and Generalized Anxiety Disorder are usually lifetime conditions requiring lifetime treatment.
SSRIs do not cure Panic Disorder in 6 months to 2 years as first claimed by the manufacturers of paroxetine (FDA approved 1996) and sertraline (FDA approved 1997). They had to withdraw that claim. Alprazolam the last benzodiazepine produced became generic in 1993. The major anxiolytic marketing for the SSRIs began toward the end of the proprietary life of alprazolam. There was no pharmaceutical company left to counter those false claims. The manufacturers of SSRIs made billions with their supposedly non-addictive, temporarily used drugs that don't produce withdrawal. These usually have to be taken for a lifetime also.
Many Affective Disorders and Schizophrenia are also lifetime disorders requiring lifetime psychotropics. Literature directly comparing SSRIs with one another, other antidepressants and benzodiazepines is scarce.(4,8,9,10) No pharmaceutical company would want to fund studies of their proprietary drug compared to a generic one which would most likely be shown to be more effective and less costly.
Patients can become dependent on benzodiazepines and SSRIs and other antidepressants. The brain produces its own benzodiazepine. There are binding sites for it on the chloride ion channel and the GABA molecule. GABA also has a binding site on the chloride ion channel. When both are present the chloride channel opens wider to allow negatively charged chloride ions to flow from outside to inside the nerve cell membrane causing it to become less excitable which translates to less anxiety.(11) Since Anxiety Disorders have a strong genetic predisposition one can postulate that these patients cannot produce enough of their own benzodiazepine to prevent the occurrence of an Anxiety Disorder. This can be compared to diabetes. Adding a therapeutic dose of a benzodiazepine puts that part of the brain chemistry back into balance alleviating symptoms.
Withdrawal from benzodiazepines is often misunderstood. Benzodiazepine Discontiuance Syndrome can be divided into three categories: rebound, recurrence and withdrawal - Table 1.(7)
Benzodiazepine Discontinuance Syndrome
Table 1 (7)
Type of Symptom
Severity compared to original
Same as original
Rapid onset, temporary
Same as original
Very gradual onset, stays
Lasts 2-4 weeks
Benzodiazepines can produce withdrawal or rebound discontinuance syndrome if abruptly withdrawn because their half-life is relatively short. By reducing the dose slowly there is minimal or no rebound or withdrawal. The original symptoms will return. This is not withdrawal as is often falsely claimed. If a more rapid discontinuation is necessary benzodiazepines can be stopped abruptly. A tapering dose equivalent of phenobarbital over 10 days will prevent seizures and withdrawal as per this authors experience.
SSRI's can also produce severe withdrawal if discontinued. This happens less frequently because their half-life is much longer. However, it happens often enough to be considered a serious problem, especially with paroxetine and the SNRI venlafaxine, since their half-life is shorter.
Birth defects in humans using benzodiazepines is somewhat controversial. Some studies show no increased incidence.(12,13,14,15) Some show benzodiazepines to be safe.(16,17,18) Some studies show the information to be inconclusive.(15,19,20,21) The same rate of birth defects occurs in neonates of women who take a benzodiazepine vs those who don't.(12) They are the same types. No one type stands out.(12) The early reference to increased incidence to cleft palate with diazepam has been later shown to be incorrect.(18,19,22,23,24)
The seemingly higher level of benzodiazepine related birth defects vs other medications has been correlated with the higher number of women taking a benzodiazepine during pregnancy. When a birth defect occurs the first question asked the mother is to list the medications taken during pregnancy.
There is no clear correlation with neonatal lethargy, sedation or weight loss.(25) These can occur without the mother having taken a benzodiazepine.(14) There are a few reports in the literature showing a benzodiazepine blood level in a neonate from the placental blood where this has occurred. However, other drugs, alcohol or a combination might be the cause. One also has to consider the effect on the fetus of high cortisol and adrenalin levels in untreated women with an Anxiety Disorder.
This author has treated over 2,000 patients with Anxiety Disorders in his private psychiatric practice. He finds benzodiazepines to be the most effective and least toxic medications for Anxiety Disorders. In his extensive experience and the experience of others they do not result in tolerance to anxiolytic effects, requiring higher dosing to achieve the initial effect as often stated.(5,6,7,8,26,27,28,29,30,31,32,33,34,35,36)
The dosage remains stable at the patients usual therapeutic range as long as stress (physical, psychological and environmental) remains stable.(8,26) If stress increases the dose has to be increased to go into the new therapeutic range. It remains there as long as that increased stress remains. When that stress is alleviated the dose returns to the usual therapeutic range. Figure 1
Conversely, if stress decreases the dose can be decreased to a new lower therapeutic range without discontinuation syndrome.(Figure 1) Clinically this is seen when a patient becomes sedated at their usual therapeutic dose or begins skipping doses. Approximately 20% of this author's patients reduce or discontinue their dosage over time.(8) Not all benzodiazepine users become dependent and most discontinuance symptoms are not severe.(5,6,7,8,26) The therapeutic benefits from long-term use outweighs the risk.(26) Individuals who take a therapeutic doses of a benzodiazepine rarely increase their dose, or take drugs for pleasure.(5,6,7,8,26,34,36)
The misconception of "addiction" might come from the fact that patients do build some tolerance to the sedating effect after 3-5 days of a stable dose. The dose can then be increased if necessary to a therapeutic one. Intermittent usage does not produce that tolerance. This can lead to sub-therapeutic dosing for the Anxiety Disorders. Retaining their sedative effect when used for their hypnotic properties for sleep disorders is helpful.
Tolerance to sedation does not continue to occur with increasing dosage.(6,7,8,26) If the dose goes beyond the therapeutic range sedation will remain. This is one way to find the top of therapeutic range. If anxiety symptoms remain, the bottom of therapeutic range has not been achieved. When this author's patients are at therapeutic range they tell him they don't feel like they are taking any medication: no sedation, no anxiety, no side effects.(8)
The side effect profile for benzodiazepines includes sedation, cognitive impairment, psychomotor impairment and short-term memory loss. All of these are dose related and usually occur when the therapeutic dose has been surpassed. Lowering the dose to the therapeutic range generally eliminates them. The side-effect profile for SSRI antidepressants includes insomnia, sexual dysfunction, weight gain, sedation, agitation, fatigue. Tricyclic antidepressants most commonly produce anticholinergic side effects (dry mouth, constipation) and weight gain. Lowering the dose of either of these medication types does not eliminate them. In this author's experience they can exacerbate panic attacks in about 1/3 of patients, they are ineffective in another 1/3 and they do work in the final 1/3. The ones in which they work usually have an Affective Disorder or OCD as a primary diagnosis with an Anxiety Disorder as a secondary diagnosis.(8,9) Research does not take this into account when comparing medications which can lead to faulty conclusions.
According to the "APA Task Force Report on Benzodiazepines"(5) and the DEA(34) they are used appropriately by the greater majority of patients.(6,7,8,26,27,28,29,32,34,36) Few abuse them but abusers do so along with alcohol and street drugs at the same time. The media, public perception, non-physician mental health workers and physicians have fallen into the false belief that they are addictive and dosage has to be continually increased.(6,8) Patients who take benzodiazepines chronically at their therapeutic dose report few if any side effects but their panic and anxiety are gone. They can then desensitize to their phobias more easily in real life situations. CBT desensitization with benzodiazepines appears more effective than CBT without medications or CBT with antidepressants. This needs more long-term study. Slow breathing or relaxation techniques don't work when a panic attack occurs in the middle of a tunnel or on top of a bridge. Patients taking a benzodiazepine return to a fully productive life. It is therapeutically effective for patients to take PRNs to cover occasional brief periods of increased stress. If they do not, breakthrough panic attacks can occur. When that stress abates they can return to their therapeutic dose. (Figure1)
There is concern benzodiazepines are being under prescribed or ineffectively prescribed.
When using PRNs patients should take 1 or 2 pills, place them in plastic wrap and put them in their wallet which is always with them. If breakthrough anxiety or panic occurs they have it readily available. Placing it under the tongue helps get it into the system more rapidly. This puts them in control of their illness rather than their illness controlling them. This empowerment speeds recovery to a fully functional life and helps extinguish phobias. If this stress is alleviated before the higher dose has time to metabolize and sedation occurs, the patients can then use some caffeine to titrate the sedation down.(Figure 1) Otherwise, caffeine should be avoided. It will increase anxiety and panic and reduce the effectiveness of the benzodiazepine.
If PRN use is more frequent than weekly or bi-weekly, one may consider raising the daily dosage to put the patient into a higher level of therapeutic range. It is prudent for the prescriber to look for the etiology of the increased need in areas of stress (physical, psychological and environmental). Once found, appropriate treatment should ensue.
The most common reason for treatment failure with benzodiazepines is too low a dose that is taken too infrequently.(8) Often times this occurs because of the fear of prescribing them in the first place. Physicians who do not understand how they work and properly prescribe them come to faulty conclusions about their effectiveness. They often scare the patient by telling them the benzodiazepines are addictive and should be used sparingly. This often leads to the prescription of an SSRI or tricyclic with more significant side effects. PRN benzodiazepines are also often needed here.
It is generally not appropriate to prescribe benzodiazepines to alcoholics or drug abusers. They are the most likely to abuse them. However, some patients who are self- medicating with alcohol to treat their Anxiety Disorders might benefit from them. Antabuse should be given along with the benzodiazepine especially in the early stages of treatment to prevent alcohol use.
It may be potentially dangerous to combine a benzodiazepine with an opiate. This is theorized to cause respiratory depression and death. This conclusion needs more study since this combination is often taken at appropriately prescribed doses without adverse sequelae. Research literature on this speculation is sparse and opioid overdose is the more likely primary cause of death. Fentanyl is more potent and deadlier than opiates and is often added to opiates to increase their effect. It is not included in the reports in opioid deaths. There are limited animal studies. More are definitely needed.
The conclusion about combining benzodiazepines and opiates is similar to the one regarding teratogenicity. Just because a benzodiazepine is present does not mean it is causal to any adverse event that occurs. The negative bias toward the benzodiazepines seem to make them causal even without proof. This is speculation not science. Science must prove that speculation.
As people age they must be observed for dementia. If they have it, reduce or discontinue their dosage of benzodiazepine as needed. Clinical judgement is necessary. The myth that they cause dementia including Alzheimer's Disease is perpetuated by poorly designed research. Read the British Medical Journal article 2014; 349:g 5205 "Benzodiazepine use and risk of Alzheimer's disease: case-control study."(37) At the end of the article the authors themselves state this "might not be causal." Read this authors critique of that study in the BMJ. You will find it under "Response."(38) These critiques only appear online and are somewhat difficult to locate which minimizes their corrective effect. Psychiatric News picked up on this article in their Oct 2014 edition "Long Term Use of Benzodiazepines May Be Linked to Alzheimer's."(39) They did not publish this author's critique letter to them. Major TV news along with the NYTimes and other newspapers picked up on this faulty conclusion as though it was fact, needlessly scaring the public and physicians and starting a new myth.
Patients should always have a 10-14 day supply so they won't run short and experience discontinuance syndrome if they have to cancel an appointment due to illness, weather or other unforeseen circumstances. This prevents their fear of running out of them. Insurance companies and many physicians often won't let patients have this buffer amount of their prescription. This might be causing some of the unnecessary desperation seen in patients fomenting the myth of addiction. If missing appointments happens too often consider abuse. If it is present switch to an SSRI.
In order to discontinue a benzodiazepine, slowly reduce the dosage by perhaps 10-15% every 1-3 weeks. To discontinue more quickly, prescribe an equivalent Phenobarbital dosage and taper it over 10 days to cover withdrawal and seizures. Premorbid anxiety symptoms usually return. This is not withdrawal as is often incorrectly concluded. This withdrawal myth is too prevalent. Withdrawal lasts 1-4 weeks. Benzodiazepines can produce withdrawal but so can SSRIs. Proper prescribing can minimize or alleviate it.
If there is an increased street use of benzodiazepines, this author speculates that it may be because physicians have become fearful of prescribing them. Patients with Anxiety Disorders where SSRIs or other treatments are ineffective and benzodiazepines are may seek them on the street. This could happen when they can't find a physician willing to prescribe them or experienced enough to prescribe at proper therapeutic levels.
There are few studies comparing benzodiazepines to antidepressants in treating Anxiety Disorders. When they do occur they are usually short-term, 5-8 weeks and they don't take into account comorbid Affective Disorders or OCD. These are usually lifetime disorders that can wax and wane. Brief studies along with comorbid illness may produce inaccurate conclusions. Since we are yet unable to fix the gene(s) that cause them, lifetime treatment is often necessary.
When comparing benzodiazepines to antidepressants to treat Anxiety Disorders for side effects, efficacy and tolerability, the benzodiazepines win hands down. To perpetuate the myths of addiction, abuse and dementia scares physicians and the public from these very safe and useful medications. They have been available since 1960 and have been safely prescribed to millions of patients. They are currently underutilized. This can be corrected with knowledge and training.
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