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Evidence-Based Reviews


Benzodiazepines: A versatile clinical tool

Evidence supports their use for alcohol withdrawal, insomnia, anxiety disorders, and other conditions

Vol. 11, No. 04 / April 2012
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Since the discovery of chlordiazepoxide in the 1950s, benzodiazepines have revolutionized the treatment of anxiety and insomnia, largely because of their improved safety profile compared with barbiturates, formerly the preferred sedative-hypnotic.1 In addition to their anxiolytic and sedative-hypnotic effects, benzodiazepines exhibit anterograde amnesia, anticonvulsant, and muscle relaxant properties.1 Psychiatrists use benzodiazepines to treat anxiety and sleep disorders, acute agitation, alcohol withdrawal, catatonia, and psychotropic side effects such as akathisia. This article highlights the evidence for using benzodiazepines in anxiety and other disorders and why they generally should not be used for obsessive-compulsive disorder and posttraumatic stress disorder (Box 1).

Box 1

When not to use benzodiazepines: OCD and PTSD

Current evidence indicates little support for using benzodiazepines for obsessive-compulsive disorder (OCD). The American Psychiatric Association (APA) and the World Federation of Biological Psychiatry do not recommend benzodiazepines for treating OCD because of a lack of evidence for efficacy.a,b An earlier study suggested clonazepam monotherapy was effective for OCDc; however, a more recent study did not show a benefit on rate of response or degree of symptom improvement.d Augmentation strategies with benzodiazepines also do not appear to be beneficial for OCD management. A recent double-blind, placebo-controlled study failed to demonstrate faster symptom improvement by augmenting sertraline with clonazepam, although the study had a small sample size and high drop-out rate.e

Because benzodiazepines have negligible action on core posttraumatic stress disorder (PTSD) symptoms (re-experiencing, avoidance, and hyperarousal), selective serotonin reuptake inhibitors and other agents largely have supplanted them for PTSD treatment.f Use of benzodiazepines for PTSD is associated with withdrawal symptoms, more severe symptoms after discontinuation, and possible disinhibition, and may interfere with patients’ efforts to integrate trauma experiences. Although benzodiazepines may reduce distress associated with acute trauma, there is evidence—in clinical studies and animal models—that early benzodiazepine administration fails to prevent PTSD and may increase its incidence.g The International Consensus Group on Depression and Anxiety, the APA, and the British Association for Psychopharmacology all highlight the limited role, if any, for benzodiazepines in PTSD.h-j

References

  1. Bandelow B, Zohar J, Hollander E, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders - first revision. World J Biol Psychiatry. 2008;9(4):248-312.
  2. American Psychiatric Association. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Arlington, VA: American Psychiatric Publishing, Inc.; 2007.
  3. Hewlett WA, Vinogradov S, Agras WS. Clomipramine, clonazepam, and clonidine treatment of obsessive compulsive disorder. J Clin Psychopharmacol. 1992;12(6):420-430.
  4. Hollander E, Kaplan A, Stahl SM. A double-blind, placebo-controlled trial of clonazepam in obsessive-compulsive disorder. World J Biol Psychiatry. 2003;4(1):30-34.
  5. Crockett BA, Churchill E, Davidson JR. A double-blind combination study of clonazepam and sertraline in OCD. Ann Clin Psychiatry. 2004;16(3):127-132.
  6. Argyropoulos SV, Sandford JJ, Nutt DJ. The psychobiology of anxiolytic drugs. Part 2: pharmacological treatments of anxiety. Pharmacol Ther. 2000;88(3):213-227.
  7. Matar MA, Zohar J, Kaplan Z, et al. Alprazolam treatment immediately after stress exposure interferes with the normal HPA-stress response and increases vulnerability to subsequent stress in an animal model of PTSD. Eur Neuropsychopharmacol. 2009;19(4):283-295.
  8. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement update on posttraumatic stress disorder from the international consensus group on depression and anxiety. J Clin Psychiatry. 2004;65(suppl 1):55-62.
  9. Ursano RJ, Bell C, Eth S, et al. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am J Psychiatry. 2004;161(11 suppl):3-31.
  10. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19(6):567-596.

Pharmacokinetic properties

Most benzodiazepines are considered to have similar efficacy; therefore, selection is based on pharmacokinetic considerations. Table 1 compares the indication, onset, and half-life of 12 commonly used benzodiazepines.2-6 Although Table 1 lists approximate equivalent doses, studies report inconsistent data. These are approximations only and should not be used independently to make therapy decisions.

Table 1

Oral benzodiazepines: Indications, onset, half-life, and equivalent doses

Drug

FDA-approved indication(s)

Onset of action

Approximate half-life (hours) in healthy adults

Approximate equivalent dose (mg)a

Comments

Alprazolam

Anxiety disorders, panic disorder

Intermediate

6.3 to 26.9 (IR), 10.7 to 15.8 (XR)

0.5

Increased risk for abuse because of greater lipid solubility

Chlordiazepoxide

Anxiety disorders, acute alcohol withdrawal, preoperative apprehension and anxiety

Intermediate

24 to 48

10

Risk for accumulation because of long-acting metabolites (desmethyldiazepam, oxazepam)

Clonazepam

Seizure disorders, panic disorder

Intermediate

18 to 50

0.25 to 0.5

Use caution in patients with liver disease

Clorazepate

Anxiety, seizures, acute alcohol withdrawal

Fast

40 to 50

7.5

Risk for accumulation because of long-acting metabolites (desmethyldiazepam, oxazepam)

Diazepam

Anxiety disorders, acute alcohol withdrawal, muscle spasms, convulsive disorders

Very fast

20 to 100

5

Risk for accumulation because of long-acting metabolites (temazepam, desmethyldiazepam, oxazepam). Increased risk for abuse because of quick onset

Estazolam

Insomnia

Intermediate

10 to 24

0.3 to 2

None

Flurazepam

Insomnia

Intermediate

47 to 100

30

Avoid in geriatric patients or patients with liver impairment

Lorazepam

Anxiety

Intermediate

10 to 20

1

Preferred for patients with liver impairment and geriatric patients

Oxazepam

Anxiety, acute alcohol withdrawal

Slow to intermediate

5 to 20

30

Preferred for patients with liver impairment and geriatric patients

Quazepam

Insomnia

Intermediate

39 to 73

5 to 15

Risk for accumulation because of long-acting metabolites (desmethyldiazepam, oxazepam)

Temazepam

Insomnia

Intermediate

3.5 to 18.4

30

Preferred for patients with liver impairment and geriatric patients

Triazolam

Insomnia

Fast

1.5 to 5.5

0.25

Lacks active metabolites

IR: immediate release; XR: extended release
aInterpret with caution, conflicting data exist
Source: References 2-6

A diverse range of indications

Alcohol withdrawal. Benzodiazepines are the treatment of choice for alcohol withdrawal syndrome, particularly to prevent seizures.7 Research supports symptom-triggered therapy using the revised Clinical Institute Withdrawal Assessment for Alcohol. Benzodiazepines reduce CNS sympathetic hyperactivity to mitigate withdrawal from alcohol by decreasing tachycardia, tremor, insomnia, agitation, and anxiety. Furthermore, these agents provide prophylaxis against serious sequelae such as seizures and delirium.

Insomnia. The American Academy of Sleep Medicine considers benzodiazepine receptor agonists (BzRAs, which include benzodiazepines and non-benzodiazepines) and ramelteon first-line pharmacotherapy for primary insomnia.8 However, pharmacologic treatment should be short-term. Agents with short to intermediate half-lives and rapid onset, such as triazolam, can aid sleep initiation. Those with longer half-lives, such as temazepam, could address sleep maintenance. If a patient does not respond to the initial agent, try another medication within the same class, because patients may respond differently. Use lower starting doses in geriatric patients.9 Closely monitor for adverse effects, rebound insomnia, and potential abuse or tolerance. Identify comorbid conditions and medications that may impair sleep, and address them accordingly.

Psychological and behavioral treatments given over 4 to 8 weeks can yield stable sleep improvements for up to 2 years. If available, these interventions may be considered first-line for treating insomnia because of their lasting effects compared with BzRAs.10

Generalized anxiety disorder (GAD). Benzodiazepines effectively treat GAD because they work quickly and are well tolerated. However, there are better first-line treatment options when considering efficacy studies and dependence and tolerance concerns. One effect-size comparison of 21 double-blind, placebo-controlled trials showed that the efficacy of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and pregabalin are comparable to benzodiazepines.11 Benzodiazepines can be used in the first 2 to 3 weeks after initiating antidepressants to alleviate and prevent worsening of anxiety that may occur at the start of antidepressant therapy. Recent treatment guidelines recommend benzodiazepines as a second-line treatment or for treatment-resistant GAD in patients who do not have a substance abuse history.12,13

Panic disorder. Efficacy of benzodiazepines for panic disorder is comparable to SSRIs, SNRIs, and tricyclic antidepressants (TCAs). SSRIs and SNRIs are considered first-line treatments for panic disorder because of their favorable side effect profile.14 In practice, benzodiazepines often are combined with SSRIs, SNRIs, or TCAs. A randomized controlled trial demonstrated that paroxetine and clonazepam (mean dose 1.6 mg/d at 5 weeks) resulted in a more rapid response compared with paroxetine alone, although this difference lasted only a few weeks.15 Furthermore, this study suggested that brief treatment with clonazepam followed by a taper is as effective as sustained treatment with paroxetine and clonazepam.15

There is a lack of high-quality data on combining cognitive-behavioral therapy (CBT) and benzodiazepines for panic disorder, although a Cochrane Review found that adding a benzodiazepine to CBT did not lead to a significant difference in response compared with psychotherapy alone.16 A recent randomized controlled trial demonstrated that tapering benzodiazepines combined with CBT was associated with successful discontinuation of the drug and prevented return of panic symptoms.17

Social anxiety. A meta-analysis found that for treating social anxiety, benzodiazepines have better efficacy than SSRIs, monoamine oxidase inhibitors, and anticonvulsants.18 Longer-acting benzodiazepines may be more effective than shorter-acting agents. One study of patients with social anxiety showed a 38% response rate for alprazolam vs 20% for placebo over 12 weeks, and a similar 10-week study demonstrated a 73% recovery rate with clonazepam vs 22% for placebo.19 In addition, studies have observed that patients can be maintained on clonazepam for up to 2 years without symptom relapse and will tolerate slow-taper discontinuation.18,20 Sedation and drowsiness can be lessened by limiting clonazepam doses to 2 to 3 mg/d.

Akathisia and tremor. Akathisia, a syndrome of motor restlessness and inner turmoil, is associated with antipsychotics but can occur with SSRIs. Reducing the dosage or switching to another, usually less potent agent often can relieve akathisia. When these remedies are not tenable, consider benzodiazepines along with other medications—including beta blockers and anticholinergic agents—with demonstrated efficacy in reducing akathisia symptoms. Lorazepam, diazepam, and clonazepam have demonstrated efficacy for relieving akathisia in comparison studies with placebo, propranolol, and diphenhydramine.21,22

Drug-induced postural tremor can occur with several psychotropics, including lithium, valproic acid, antidepressants, and antipsychotics. A tremor is considered mild if a patient can drink a glass of water with 1 hand without spilling and severe if holding a glass with 2 hands is difficult. Propranolol is most commonly prescribed for these tremors, but alprazolam and clonazepam have demonstrated efficacy, either as monotherapy or coadministered with a beta blocker.23

Acute agitation. Agitated patients often have acute psychosis and/or mania or dyscontrol secondary to axis II disorders.24 Patients may be paranoid, hostile, disruptive, and combative. Rapidly initiating medication can prevent the need for more restrictive measures, such as seclusion or restraint. Antipsychotics—especially high-potency agents such as haloperidol—and benzodiazepines, as monotherapy or in combination, are a mainstay treatment. Although treatment protocols favor atypical antipsychotics over typical antipsychotics, benzodiazepines are a viable option because of their anxiolytic and sedative effects. Advantages of benzodiazepine monotherapy include decreased extrapyramidal symptoms, greater patient acceptance/preference, and increased sedation compared with antipsychotics. Lorazepam, 1 to 2 mg intramuscularly (IM) or orally, is well tolerated because of its favorable drug-drug interaction profile and lack of significant cardiac side effects. Benzodiazepines can cause respiratory depression in patients with chronic lung disease and additive sedation secondary to opiates, other sedatives/hypnotics, or alcohol. Behavioral disinhibition is rare and is associated with preexisting CNS pathology or mental retardation.25 The IM olanzapine package insert warns against coadministering IM lorazepam because of additive cardiorespiratory depressive effects and excessive somnolence.26

Catatonia. The characteristic symptoms of catatonia are immobility, negativism, muteness, and failure to eat or drink. Benzodiazepines improve these symptoms in approximately 70% to 80% of catatonic patients with affective disorders. Response rates are lower in catatonia in patients with schizophrenia.27 If catatonia in a patient with psychosis is missed, giving antipsychotics before benzodiazepines may worsen catatonic symptoms or precipitate neuroleptic malignant syndrome in some cases. When you suspect a patient has catatonia, start with lorazepam, 1 to 2 mg IV or IM, and examine the patient for diminishing catatonic signs within 1 to 2 hours. If catatonia signs lessen, begin regularly scheduled lorazepam, with dosing varying by age—be more cautious in geriatric patients—and symptom severity. Titrate benzodiazepines for stuporous patients more slowly (eg, 1 mg 3 times a day as a starting dose) than for excited catatonic patients. Lorazepam can be increased gradually as tolerated; it is not unusual for patients to require up to 8 to 12 mg/d. Electroconvulsive therapy (ECT) is the treatment of choice when catatonic patients respond poorly or partially to high-dose benzodiazepines.28,29

Benzodiazepine reversal for ECT

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of ECT.30 A multi-center study demonstrated that lorazepam (up to 4 mg/d as needed) in the 48 hours before the first ECT session was not associated with effects on seizure threshold or duration; however, larger lorazepam dosages were associated with briefer EEG seizure duration.31 Some patients may not tolerate withholding or tapering benzodiazepines in preparation for ECT. Studies investigating flumazenil for pre-ECT benzodiazepine reversal are lacking. One retrospective analysis showed that flumazenil administration immediately before and after ECT resulted in adequate seizures with no difference in clinical outcome compared with patients who were not receiving benzodiazepines or flumazenil.32

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