Prescribing Benzodiazepines in Clinical Practice

Raymond Pary, MD, University of Louisville School of Medicine and Veterans Affairs Medical Center; and Susan Lewis, ARNP, PhD, Veterans Affairs Medical Center, Louisville, Ky

Published Online: January 16, 2008 - 9:56:06 PM (CST)

About 15% of Americans have taken benzodiazepines in any given year. This class of medications activates the gamma-aminobutyric acid?benzodiazepine receptor complex, causing an influx of chloride ions in neurons throughout the central nervous system. This results in increased membrane polarization, neuronal inhibition, and subsequent central nervous system depression. Benzodiazepines are indicated for anxiety disorders and may be used in combination with other drugs indicated for the treatment of anxiety. They are ordinarily not used as monotherapy for obsessive-compulsive disorder or for posttraumatic stress disorder. When taken with alcohol, benzodiazepines substantially increase the risk for accident-related injuries. The risk for injury and cognitive dysfunction must be weighed against possible symptom recurrence with medication discontinuation. The newer benzodiazepine agonists are primarily used as hypnotics, have greater sedating activity, and reduced muscle relaxant and anticonvulsant effects compared with the traditional compounds.

Classified as sedative-hypnotics or tranquilizers, benzodiazepines became available in the 1960s and were soon the most frequently prescribed drugs in the United States. It is estimated that about 15% of Americans have received benzodiazepine prescriptions.¹ Although the extent of actual use is not known, about 100 million benzodiazepine prescriptions were written in 1999.²

The age-group with the highest lifetime prevalence of sedative-hypnotic or tranquilizer use is that of 26- to 34-year-old persons. Individuals between the ages of 18 and 25 years are most likely to have used these types of drugs within the past year.³ Women outnumber men as users of sedative-hypnotics by 3 to 1, and whites outnumber blacks by 2 to 1. Benzodiazepine use rates in the elderly exceed those in younger patients. The elderly fill a disproportionately greater percentage of prescriptions for benzodiazepines and they constitute the largest group of long-term users.³

Benzodiazepines are also taken by individuals who are not under medical care. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision estimates that about 6% of Americans have used either sedatives or tranquilizers illicitly.⁴

Mechanism of Action

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter of the central nervous system (CNS) that is central to the experience of anxiety. The receptor complex associated with GABA has several subunits.⁵ Activation of the GABA?benzodiazepine receptor complex causes an influx of chloride ions into the neurons, resulting in increased membrane polarization and neuronal inhibition.⁵ Benzodiazepines amplify the frequency of ion channel openings that facilitate the action of GABA.⁵ The overall effect of this mechanism is CNS depression.

By binding to the GABA?benzodiazepine receptor complex, the effect of GABA is enhanced,⁶ and therefore neurons are hyperpolarized and have reduced excitability. The inhibitory tone of the CNS is thereby increased by benzodiazepines. The result is decreased agitation, muscle relaxation, and an antiseizure effect, which can all be observed clinically.

Zolpidem (Ambien) and zaleplon (Sonata) are newer benzodiazepine-agonists that are selective for 1 of 3 benzodiazepine binding sites on the GABA?benzodiazepine receptor complex.⁷ This may account for their greater sedating activity and reduced muscle relaxant and anticonvulsant effects compared with the older nonselective benzodiazepines (Table 1).

Indications for Benzodiazepines

Generalized anxiety disorder
Early misconceptions about anxiety were based on the belief that it was transient, a part of the human condition, or a symptom of another illness.⁸ Most patients who receive benzodiazepines have a high level of distress and therefore qualify for a diagnosis of an anxiety disorder.

After the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the late 1980s, there was a decrease in the use of benzodiazepines and an increase in the use of antidepressants for patients with anxiety. This trend was demonstrated in an evaluation of pharmacotherapeutic prescribing patterns in 1996 compared with those in 1989.⁹ The same study showed that about one third of patients with anxiety disorder were not prescribed any medication in 1989 or in 1996.

Benzodiazepines are currently among a number of drug classes used for the treatment of anxiety. General clinical experience indicates that these drugs have greater efficacy and more rapid anxiety relief than other drugs used for the treatment of patients with moderate-to-severe anxiety disorders.¹⁰ Long-term outcomes have been favorable,¹⁰ and somatic symptoms are especially responsive to these drugs.¹¹

Posttraumatic stress disorder
Monotherapy with benzodiazepines may not be the best option for patients with posttraumatic stress disorder (PTSD).¹² One study reported an increased incidence of PTSD after 6 months in patients who received benzodiazepines soon after a traumatic event, compared with an untreated control group.¹³ In a similar investigation of trauma survivors, short-term benzodiazepine therapy in the early posttraumatic period alleviated distress but did not prevent subsequent PTSD.¹⁴

Obsessive?compulsive disorder
Clonazepam (Klonopin) has serotonergic properties and may be helpful for the anxiety component of obsessive?compulsive disorder. However, current evidence does not support benzodiazepine monotherapy for this condition.¹⁵

Panic disorder

Benzodiazepines are currently recommended by the American Psychiatric Association (APA) for the treatment of panic disorder, with or without agoraphobia.¹⁶ Benzodiazepines may be preferred when early symptom control is critical, as in the case of a recent stressful event. Between 55% and 70% of all patients with panic disorder will experience relapse after medication discontinuation.^16,17 Therefore, extended therapy for this condition is usually necessary. Patients do not appear to develop tolerance to the therapeutic effects of benzodiazepines.¹⁶ When benzodiazepines are initially prescribed in combination with antidepressants to patients with panic disorder, the therapeutic response is accelerated, and early anxiety is reduced.¹⁸ There is, however, no greater long-term benefit with a benzodiazepine plus an antidepressant regimen compared with antidepressant monotherapy.¹⁹

Social phobia
Drug therapy with benzodiazepines has been effective for patients with socialization problems. For example, clonazepam outperformed cognitive behavioral therapy for several measures of treatment success in one 12-week study.²⁰ Another study demonstrated that long-term (11-month) clonazepam therapy was safe and effective for patients with social phobia.²¹

Insomnia
Specific causes of insomnia must be identified and treated as early as possible. Consideration should always be given to making a referral to a sleep specialist and/or cognitive behavioral therapist. If these options are not accepted by the patient, zolpidem, zolpidem CR (Ambien CR), eszopiclone (Lunesta), or zaleplon may be tried for patients with sleep-onset problems. Intermediate-acting benzodiazepines, such as temazepam (Restoril), can be helpful for those who experience problems primarily with sleep maintenance. In the absence of a coexisting anxiety disorder, long-acting benzodiazepines are not advisable.

A study of sleep parameters in 25 patients who used benzodiazepines long-term to combat insomnia showed that sleep time and slow-wave sleep decreased in a 15-day period during which the agents were gradually withdrawn.²² However, after the benzodiazepines were discontinued, sleep quality, slow-wave sleep, and delta wave count improved.

Alcohol-related disorders
A meta-analysis of 57 trials that included 4051 people showed that benzodiazepines were effective against alcohol withdrawal symptoms, particularly seizures.²³ No comparison of the relative efficacy compared with other classes of drugs was possible because of the heterogeneity of the studies and the outcomes examined.

Does the prescription of a benzodiazepine promote alcohol use? In a prospective follow-up study of patients with anxiety disorders and a history of regular alcohol use, benzodiazepine use remained stable during the 12-year study period.²⁴ The use of these agents did not differ between patients who developed a new alcohol use disorder (n = 120) and those who did not (n = 425). Furthermore, benzodiazepine therapy did not predict recovery or recurrence of alcohol problems in those with a history of alcohol use disorder. The investigators found little association between the use of benzodiazepines and the occurrence of a newly acquired alcohol use disorder.

Comorbid anxiety and depression
The presence of an anxiety disorder and a depressive disorder concurrently increases the severity and chronicity of each illness, the likelihood of substance abuse, and the risk of suicide.²⁵ Benzodiazepines provide rapid relief of anxiety before the onset of the full therapeutic action of antidepressants. In a meta-analysis of 9 studies involving 679 patients, those treated with an antidepressant and a benzodiazepine were less likely to discontinue treatment and were more likely to respond to treatment compared with those treated with an antidepressant alone.²⁶

Clinical Scenarios

Patient 1
A 78-year-old man presents to the clinic as a new patient. He has been taking alprazolam (Xanax) 0.25 mg 3 times daily for the past 15 years. The medication was prescribed by a previous physician. He has never increased the dose, and there are no signs of medication abuse. He says that when he does not take the medicine, he becomes very anxious and physically ill.

Recommendation: Continuing the alprazolam seems to be the best course of action. A discussion of the increased risk with benzodiazepines for falls and hip fracture in older people should also occur. A rapid tapering of this drug will most likely cause extreme distress for this patient, but he should be offered the chance to slowly discontinue the medication if he wishes.

Patient 2
A 40-year-old woman has symptoms of panic disorder. She mentions that she has tried taking her sister's lorazepam and found that it helped her symptoms. She has no history of drug or alcohol abuse.

Recommendation: Clonazepam is a good initial choice for this patient because of its long duration of action. Coprescribing an SSRI can also be helpful for panic and anxiety symptoms. The drugs should be started at different times to allow the patient to discriminate side effects that may occur from each new medicine. The physician may consider slowly tapering the clonazepam after a 2-month period if the SSRI is effective.

Patient 3
A 43-year-old woman with diagnoses of depression, anxiety, and chronic pain, as well as a history of polysubstance abuse, is discharged from the hospital by her primary care physician. He had been prescribing oxycodone HCl/acetaminophen 5/325 (Endocet, Percocet, Roxicet) every 6 hours, for her chronic pain. Other discharge medications include sertraline HCl (Zoloft) 150 mg/day and alprazolam 1 mg 4 times daily. During this hospital stay, her urine toxicity screen was positive for cocaine, cannabis, and opiates but negative for benzodiazepines. After hospital discharge she is scheduled for follow-up at the mental health clinic and asks for benzodiazepines.

Recommendation: Because this patient has been using illicit drugs and her urine toxicity screen was negative for benzodiazepines, we would recommend that benzodiazepines not be prescribed. If her toxicity screen had been positive for benzodiazepines, we would recommend a gradual taper of alprazolam because of her history of illicit drug abuse, especially because this use has been recent.

Dependence and Tolerance

Long-term use of benzodiazepines may cause biological dependence. Pharmacologic dependence, the physiologic adaptation accompanying sustained drug use, is the natural basis for withdrawal symptoms after drug discontinuation. Between 58% and 100% of patients who have taken benzodiazepines in daily, therapeutic doses for at least 1 year will experience clinically significant discontinuation symptoms upon abrupt withdrawal.²⁷ The 4 characteristics that increase the risk for benzodiazepine dependence are⁶:

1. History of dependence on sedative-hypnotics or on alcohol
2. Chronic medical or psychiatric illnesses
3. Chronic dysphoria and borderline or dependent personality disorders
4. Chronic insomnia.

Tolerance to the anxiolytic effects of benzodiazepines implies that increased dosages are necessary to maintain symptom remission. Long-term users of these drugs appear to develop tolerance to the sedative and psychomotor effects but not to the acute short-term memory effects.²⁸

Addiction requires evidence of compulsive drug-seeking with impairment of psychosocial functioning. Reports of addiction arising from legitimate benzodiazepine intake are uncommon.²⁸

Patients with combat-related PTSD may be particularly sensitive to discontinuation of long-term benzodiazepine therapy. A study of 8 combat veterans receiving benzodiazepine therapy for PTSD showed that all had severe anxiety, sleep disturbances, and hyperalertness when alprazolam therapy was discontinued after 1 to 5 years of treatment.²⁹

Withdrawal Symptoms

The severity of somatic symptoms after stopping benzodiazepines varies considerably in relation to average dose and duration of use. Mild discontinuation symptoms can occur after short-term use of fairly low doses. Compounds with short half-lives are more likely to cause withdrawal symptoms and have greater potential for abuse. The advantages of these brief-duration drugs, however, include little accumulation in the body, rapid clearance from the bloodstream, and flexible dosing alternatives (Table 2).

Any person who takes benzodiazepines for a long time will develop physical dependence or tolerance to the medication effects and withdrawal symptoms upon discontinuing the drug. This is not considered addiction in the sense that psychosocial functioning is not impaired and the patient who uses these drugs as prescribed can carry out his usual routines in life. Our clinical experience suggests that most people who are physically dependent on prescribed benzodiazepines usually do not abuse these drugs or take excessive quantities. The elderly seem to follow the recommended prescriptions and do not call in for extra prescriptions because someone allegedly stole their medication. However, it is also true that different sources would provide different information.³

In the elderly, experienced physicians favor the use of short-acting benzodiazepines at low dosages and for brief periods of time.³⁰ Doses that are therapeutic for patients aged 65 to 70 years may produce serious adverse events in those older than 75 years.³⁰ Because a discontinuation syndrome is more likely to occur after the abrupt cessation of benzodiazepines, this approach is not recommended. Symptoms of a benzodiazepine discontinuation syndrome may include insomnia, irritability, anxiety, tremor, sweating, impaired concentration, nausea, palpitations, headache, and perceptual changes.

Withdrawal symptoms generally occur within about 2 to 3 days after stopping the medication. With the shorter-acting benzodiazepines, withdrawal manifestations occur sooner. After drug termination or dose lowering, patients may experience agitation, insomnia, dysphoria, increased awareness of sensory stimuli, and perceptual disturbances.³⁰ Delirium and seizures are possible but are more often seen in medical inpatients. Abnormal vital signs may be noted as well.

Adverse Reactions

Sedation
The most common side effect of benzodiazepines is sedation. For example, according to the APA practice guideline on the treatment of panic disorder, the incidence rate of sedation/drowsiness with alprazolam ranges between 38% and 75% compared with between 11% and 21% with placebo.¹⁶ Sedation/drowsiness can include daytime drowsiness from a previous night's medication.

Hip fracture
The benzodiazepines have been associated with an increased risk for hip fracture, especially in older people. A review of 6 studies showed that the risk for fracture with benzodiazepines increased between 50% and 110%.³¹ No difference was found between short- and long-acting drugs in terms of the potential for harm. The risk for hip fracture appears to be greatest in the first 2 weeks after starting treatment.³²

A 5-year prospective assessment of physical damage associated with benzodiazepines looked at 69,791 new users older than 65 years, 17.7% of whom were treated for at least 1 traumatic event, most often fractures.³³ Higher doses of oxazepam (Serax), flurazepam (Dalmane), and chlordiazepoxide (Librium) were associated with the greatest risk for injury.

Combining benzodiazepines with other drugs more than doubles the potential for injury.³⁴ This was borne out in a 3-year study of 13,745 veterans, in which the use of benzodiazepines plus concomitant medications was linked to increased treatment of injuries.³⁴

If a benzodiazepine is combined with alcohol, the potential for accidents increases substantially. In a study of 1611 trauma patients, those injured in violent accidents were more likely to have increased blood levels of alcohol and benzodiazepines.³⁵

Cognitive dysfunction
It is well-known that benzodiazepines have an adverse effect on memory. Tolerance to memory difficulties usually develops with long-term use. Older people may be especially vulnerable to developing cognitive dysfunction from taking benzodiazepines because they may have preexisting cognitive dysfunction related to aging. For example, in one study, the cognitive function of 104 elderly adults who were withdrawn from long-term benzodiazepine therapy improved compared with matched controls who continued taking benzodiazepines.³⁶

A meta-analysis of 13 studies demonstrated cognitive dysfunction in long-term users of benzodiazepines.³⁷ Although cognition improved after withdrawing these drugs, it did not return to the level observed in drug-free controls. And although the overall impact was generally minor, persistent cognitive impairments were seen during the first 6 months after stopping therapy.³⁷

Disinhibition is a potential but rare drug effect. There is a paradoxical increase in hostility, aggression, or violence with use of benzodiazepines.⁷ Teratogenic effects are also uncommon but possible; therefore, benzodiazepines should not be used during pregnancy.⁷

Treatment Duration and Discontinuation

The use of a therapeutic dose of a benzodiazepine for more than 2 months is generally considered to be longterm.³⁸ The strongest determinant for prescribing extended benzodiazepine therapy is previous use.³⁹ Although addiction is infrequent, patients are more likely to become physically dependent on a drug in this class when daily use continues for more than several months.

How long should benzodiazepines be prescribed? In primary care settings, these agents are generally used long-term for patients with psychiatric disorders. In a 6-month survey of 1156 patients aged 65 to 84 years, 90% of benzodiazepine users said that they had been taking the drugs for many years.⁴⁰ Long-term therapy for chronically anxious patients is often valuable, although this is arguable.⁷

A decision to reduce or taper the dose of a benzodiazepine should be made on an individualized basis. The increased risk for injury and potential for cognitive dysfunction should be weighed against the possibility that symptoms will return when the drug is stopped. In one study of 47 older adults who had discontinued long-term benzodiazepine therapy for insomnia, 43% of patients relapsed during the 2-year follow-up period.⁴¹

When tapering after long-term use, the drug should be reduced by approximately one eighth to one tenth of the daily dose every 2 weeks.⁴² To achieve success, some patients may require more than 1 year of slow dose-reductions. Alternatively, the dose may be lowered by one half tablet daily at 2-week intervals.

For patients who have been taking such drugs for less than 1 year, faster tapering may be possible. For example, the daily dose of lorazepam (Ativan) may be lowered by 1 mg/week or of alprazolam (Xanax) by 0.5 mg/week.³⁸ Patients need to be evaluated frequently during such rapid dose reductions.

One advantage of diazepam (Valium) over lorazepam and alprazolam is that it is eliminated slowly. When this drug is tapered, patients will experience a gradual decrease in blood concentrations. Another advantage of diazepam is its availability in a low-dose form. Therefore, reductions in 2-mg increments can be easily prescribed. For example, to achieve a very gradual taper of diazepam in a patient who has been on a high dosage (30 mg/d) for many years, the total daily dose can be lowered by 2 mg at monthly intervals.

Physicians should counsel patients regularly about avoiding the use of benzodiazepines and alcohol on the same day. Additional advice would be to skip doses when feeling calm and not anxious. To evaluate readiness to discontinue these drugs, patients may be asked to try decreasing the daily dose by 1 tablet until the next visit. If this proves successful, the patient may continue to reduce the dose. Negotiating dose changes with the patient is of paramount importance.

Conclusion

Benzodiazepines are effective for the treatment of anxiety disorders, alcohol withdrawal, and insomnia. These drugs provide greater efficacy and more rapid symptom relief than other medications for moderate-to-severe anxiety disorders. Benzodiazepines should be prescribed with careful consideration of the potential long-term consequences. Dependence and tolerance are of concern with extended use. In the elderly, benzodiazepines can contribute to falls and injuries, mental confusion, and cognitive decline. Because benzodiazepines are cross-tolerant with alcohol, patients with a history of alcohol dependence are at increased risk for addiction, and other classes of medications may be more favorable for sustained treatment. Benzodiazepines are not recommended as monotherapy for patients with PTSD, but there are times when a benzodiazepine is the drug of choice. Such a patient might be a very anxious individual with longstanding PTSD that is poorly responsive to antidepressants. Close patient monitoring and an awareness of current guidelines are recommended.

Acknowledgment

The authors wish to thank Gene Haynes for her assistance in the preparation of this manuscript.

SELF-ASSESSMENT TEST

1. Which of the following statements about benzodiazepines is true?
   
   1. Long-term use of therapeutic doses often results in dependence
   2. Most patients eventually develop tolerance to the therapeutic effects
   3. Early benzodiazepine treatment after a traumatic event does not help prevent PTSD
   4. Patients with panic disorder have better outcomes when treated with a benzodiazepine and an antidepressant than with an antidepressant alone


2. Benzodiazepine monotherapy would be an appropriate treatment for all these conditions, except:
   
   1. Social phobia
   2. Generalized anxiety disorder
   3. Panic disorder
   4. Obsessive?compulsive disorder


3. Long-term benzodiazepine therapy is defined by which of the following durations?
   
   1. ≥1 year
   2. ≥6 months
   3. ≥3 months
   4. ≥2 months


4. Which agent would be best for a patient whose primary complaint is insomnia?
   
   1. Chlordiazepoxide
   2. Flurazepam
   3. Alprazolam
   4. Oxazepam


5. Which tapering strategy would be best for a patient who has taken a benzodiazepine for more than 1 year?
   
   1. Reduce the daily dose by one tenth weekly
   2. Reduce the daily dose by one half tablet daily at 1-week intervals
   3. Reduce the daily dose by one eighth every 2 weeks
   4. Reduce the daily dose by 50% every 2 weeks

(Answers at end of references list)

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Answers: 1. C; 2. D; 3. D; 4. B; 5. C.