Evidence-Based Reviews

Benzodiazepines: A versatile clinical tool

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


 

References

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

DrugFDA-approved indication(s)Onset of actionApproximate half-life (hours) in healthy adultsApproximate equivalent dose (mg)aComments
AlprazolamAnxiety disorders, panic disorderIntermediate6.3 to 26.9 (IR), 10.7 to 15.8 (XR)0.5Increased risk for abuse because of greater lipid solubility
ChlordiazepoxideAnxiety disorders, acute alcohol withdrawal, preoperative apprehension and anxietyIntermediate24 to 4810Risk for accumulation because of long-acting metabolites (desmethyldiazepam, oxazepam)
ClonazepamSeizure disorders, panic disorderIntermediate18 to 500.25 to 0.5Use caution in patients with liver disease
ClorazepateAnxiety, seizures, acute alcohol withdrawalFast40 to 507.5Risk for accumulation because of long-acting metabolites (desmethyldiazepam, oxazepam)
DiazepamAnxiety disorders, acute alcohol withdrawal, muscle spasms, convulsive disordersVery fast20 to 1005Risk for accumulation because of long-acting metabolites (temazepam, desmethyldiazepam, oxazepam). Increased risk for abuse because of quick onset
EstazolamInsomniaIntermediate10 to 240.3 to 2None
FlurazepamInsomniaIntermediate47 to 10030Avoid in geriatric patients or patients with liver impairment
LorazepamAnxietyIntermediate10 to 201Preferred for patients with liver impairment and geriatric patients
OxazepamAnxiety, acute alcohol withdrawalSlow to intermediate5 to 2030Preferred for patients with liver impairment and geriatric patients
QuazepamInsomniaIntermediate39 to 735 to 15Risk for accumulation because of long-acting metabolites (desmethyldiazepam, oxazepam)
TemazepamInsomniaIntermediate3.5 to 18.430Preferred for patients with liver impairment and geriatric patients
TriazolamInsomniaFast1.5 to 5.50.25Lacks active metabolites
IR: immediate release; XR: extended release
aInterpret with caution, conflicting data exist
Source: References 2-6

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