Article Type
News
Changed
Tue, 12/11/2018 - 15:04
Display Headline
Benzodiazepines: A versatile clinical tool
Author(s)
Jolene R. Bostwick, PharmD, BCPS, BCPP

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
 

 

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.

Clinical Point

For treating social anxiety, benzodiazepines have better efficacy than SSRIs, MAOIs, and anticonvulsants

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

 

 

Clinical Point

Benzodiazepines have negligible action on core PTSD symptoms: re-experiencing, avoidance, and hyperarousal

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

Clinical Point

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of 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

Tapering benzodiazepines

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms, such as rebound anxiety, agitation, insomnia, or seizures, particularly when use exceeds 8 weeks. The onset of withdrawal symptoms varies, depending on the medication used. Withdrawal symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives.33Table 2 lists recommended durations for tapering benzodiazepines.33,34 In general, decrease the total daily dose by 25% the first week, another 25% the second week, then 10% a week until discontinuation. When benzodiazepine use exceeds 1 year, a slower taper is recommended; for example, decrease 10% every 1 to 2 weeks. When 20% of the dosage remains, begin a 5% dose reduction every 2 to 4 weeks. Monitor patients for withdrawal symptoms or symptom exacerbation. If either occur, consider maintaining the current benzodiazepine dose or increasing the dose for 1 to 2 weeks or longer, if necessary, then continue to taper at a slower rate.34

Table 2

Recommendations for tapering benzodiazepines

Duration of useRecommended taper lengthComments
<6 to 8 weeksTaper may not be requiredDepending on clinical judgment and patient stability/preference, consider implementing a taper, particularly if using a high-dose benzodiazepine or an agent with a short or intermediate half-life, such as alprazolam or triazolam
8 weeks to 6 monthsSlowly over 2 to 3 weeksGo slower during latter half of taper. Tapering will reduce, not eliminate, withdrawal symptoms. Patients should avoid alcohol and stimulants during benzodiazepine withdrawal
6 months to 1 yearSlowly over 4 to 8 weeks
>1 yearSlowly over 2 to 4 months
Source: References 33,34
 

 

Risks of benzodiazepine use

Clinical Point

Agents with shorter half-lives such as lorazepam and oxazepam are preferred for older patients

For most indications, benzodiazepine therapy should be short-term.35 Use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal. Tell patients to avoid alcohol while taking a benzodiazepine because this combination is potentially lethal. Benzodiazepines are commonly abused and abuse can lead to unintentional drug overdose. Benzodiazepines accounted for 37% of unintentional drug overdose deaths in West Virginia in 2006; in 46% of these cases, benzodiazepines were used for nonmedical purposes. Clinicians can help reduce the risk of diversion by limiting prescriptions to 30 days with no refills.36

Clinical Point

Benzodiazepine use should be short-term; use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal

Older patients taking benzodiazepines are at increased risk of falls and hip fractures.37 Lorazepam, oxazepam, and temazepam—agents with shorter half-lives that are not greatly affected by pharmacokinetic changes associated with aging—are preferred for these patients.34 Patients with dementia or other CNS-compromising conditions may become confused or delirious with regular benzodiazepine dosing. Educate patients to whom you prescribe benzodiazepines about the importance of gauging their level of sedation before driving or engaging in other tasks for which sedation could compromise their safety. Benzodiazepine use during pregnancy requires a careful discussion of risks and benefits (Box 2).38

Box 2

Using benzodiazepines during pregnancy

Benzodiazepine use during pregnancy has been associated with cleft palate and urogenital and neurologic malformations in the fetus.38 Although data are conflicting—particularly among recent meta-analyses that fail to demonstrate an association—some experts advise against benzodiazepine use in the first trimester. Participate in shared decision making with your patients and educate them about the potential risks and benefits of benzodiazepine use during the first trimester and throughout pregnancy. After delivery, newborns may develop “floppy baby syndrome”—which is associated with lethargy, difficulty eating, and respiratory depression—or withdrawal.38 To minimize this risk, consider tapering the benzodiazepine as the patient approaches delivery.

Related Resources

Drug Brand Names

  • Alprazolam • Xanax
  • Chlordiazepoxide • Librium, Limbitrol
  • Clonazepam • Klonopin
  • Clorazepate • Tranxene
  • Diazepam • Valium
  • Diphenhydramine • Benadryl, others
  • Estazolam • ProSom
  • Flumazenil • Romazicon
  • Flurazepam • Dalmane
  • Haloperidol • Haldol
  • Lithium • Lithobid
  • Lorazepam • Ativan
  • Olanzapine • Zyprexa
  • Oxazepam • Serax
  • Paroxetine • Paxil
  • Pregabalin • Lyrica
  • Propranolol • Inderal, InnoPran XL, others
  • Quazepam • Doral
  • Ramelteon • Rozerem
  • Sertraline • Zoloft
  • Temazepam • Restoril
  • Triazolam • Halcion
  • Valproic acid • Depakene, Stavzor, others

Disclosures

Drs. Bostwick and Yasugi report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca and Sunovion Pharmaceuticals.

Clinical Point

Benzodiazepine use during pregnancy has been associated with cleft palate and urogenital and neurologic malformations

References

1. Mihic SJ, Harris RA. Hypnotics and sedatives. In: Brunton LL Chabner BA, Knollmann BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. New York, NY: McGraw Hill and Company; 2011:457-480.

2. Facts and comparisons Web site. 2011 Wolters Kluwer Health Inc. http://online.factsandcomparisons.com. Accessed August 16, 2011.

3. DuPont RL, Greene W, Lydiard RB. Sedatives and hypnotics: pharmacology and epidemiology. In: Gold MS Hermann R, eds. UpToDate. http://www.uptodate.com/contents/sedatives-and-hypnotics-abuse-and-dependence-pharmacology-and-epidemiology. Accessed August 16, 2011.

4. U.S. Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed August 16, 2011.

5. Chouinard G. Issues in the clinical use of benzodiazepines: potency withdrawal, and rebound. J Clin Psychiatry. 2004;65(suppl 5):7-12.

6. Shader RI, Greenblatt DJ. Can you provide a table of equivalencies for benzodiazepines and other marketed benzodiazepine receptor agonists? J Clin Psychopharmacol. 1997;17(4):331.-

7. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacologic interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev. 2011;15(6):CD008537.-

8. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.

9. Foral P, Dewan N, Malesker M. Insomnia: a therapeutic review for pharmacists. Consult Pharm. 2011;26(5):332-341.

10. Riemann D, Perlis ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev. 2009;13(3):205-214.

11. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments of generalized anxiety disorder. J Psychopharmacol. 2007;21(8):864-872.

12. Davidson JR, Zhang W, Connor KM, et al. A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J Psychopharmacol. 2010;24(1):3-26.

13. 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.

14. American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. 2nd ed. Arlington VA: American Psychiatric Publishing, Inc.; 2009.

15. Pollack MH, Simon NM, Worthington JJ, et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol. 2003;17(3):276-282.

16. Watanabe N, Churchill R, Furukawa TA. Combined psychotherapy plus benzodiazepines for panic disorder. Cochrane Database Syst Rev. 2009;(1):CD005335.-

17. Otto MW, McHugh RK, Simon NM, et al. Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation. Behav Res Ther. 2010;48(8):720-727.

18. Davidson JR. Use of benzodiazepines in social anxiety disorder generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65(suppl 5):29-33.

19. Argyropoulos SV, Sandford JJ, Nutt DJ. The psychobiology of anxiolytic drugs Part 2: pharmacological treatments of anxiety. Pharmacol Ther. 2000;88(3):213-227.

20. Connor KM, Davidson JR, Potts NL, et al. Discontinuation of clonazepam in the treatment of social phobia. J Clin Psychopharmacol. 1998;18(5):373-378.

21. Miller CH, Fleischhacker WW. Managing antipsychotic-induced acute and chronic akathisia. Drug Saf. 2000;22(1):73-81.

22. Rodnitzky RL. Drug-induced movement disorders. Clin Neuropharmacol. 2002;25(3):142-151.

23. Arbaizar B, Gómez-Acebo I, Llorca J. Postural induced tremor in psychiatry. Psychiatry Clin Neurosci. 2008;62(6):638-645.

24. Casher MI, Bess JD. Manual of inpatient psychiatry. New York NY: Cambridge University Press; 2010.

25. Battaglia J. Pharmacological management of acute agitation. Drugs. 2005;65(9):1207-1222.

26. Physicians’ desk reference. Montvale NJ: PDR Network, LLC; 2010.

27. Rosebush PI, Mazurek MF. Catatonia and its treatment. Schizophr Bull. 2010;36(2):239-242.

28. Ungvari GS, Kau LS, Wai-Kwong T, et al. The pharmacological treatment of catatonia: an overview. Eur Arch Psychiatry Clin Neurosci. 2001;251(suppl 1):I31-I34.

29. Fink M, Taylor MA. Catatonia: a clinician’s guide to diagnosis and treatment. New York NY: Cambridge University Press; 2003.

30. Naguib N, Koorn R. Interactions between psychotropics anaesthetics and electroconvulsive therapy: implications for drug choice and patient management. CNS Drugs. 2002;16(4):229-247.

31. Boylan LS, Haskett RF, Mulsant BH, et al. Determinants of seizure threshold in ECT: benzodiazepine use, anesthetic dosage, and other factors. J ECT. 2000;16(1):3-18.

32. Krystal AD, Watts BV, Weiner RD, et al. The use of flumazenil in the anxious and benzodiazepine-dependent ECT patient. J ECT. 1998;14(1):5-14.

33. Melton ST, Kirkwood CK. Anxiety disorders I: generalized anxiety panic, and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. New York, NY: McGraw-Hill Companies; 2011:1209-1228.

34. Benzodiazepine toolkit. The Pharmacist’s Letter/Prescriber’s Letter. 2011;27(4):270406.-

35. Lader M. Benzodiazepines revisited – will we ever learn? Addiction. 2011;106(12):2086-2109.

36. Toblin RL, Paulozzi LJ, Logan JE, et al. Mental illness and psychotropic drug use among prescription drug overdose deaths: a medical examiner chart review. J Clin Psychiatry. 2010;71(4):491-496.

37. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249-255.

38. Menon SJ. Psychotropic medication during pregnancy and lactation. Arch Gynecol Obstet. 2008;277(1):1-13.

Article PDF
1104CP_Bostwick.pdf
Author and Disclosure Information

Jolene R. Bostwick, PharmD, BCPS, BCPP
Clinical Assistant Professor of Pharmacy, University of Michigan College of Pharmacy, Clinical Pharmacist, University of Michigan Health System, Ann Arbor, MI
Michael I. Casher, MD
Clinical Assistant Professor, Department of Psychiatry, University of Michigan Medical School, Director of Inpatient Adult Psychiatry, University of Michigan Health System, Ann Arbor, MI
Shinji Yasugi, MD
First-Year Psychiatry Resident, University of Michigan Health System, Ann Arbor, MI

Audio / Podcast
2012.04.April.Casher.mp3
Issue
Current Psychiatry - 11(04)
Publications
MDedge Psychiatry
Current Psychiatry
Topics
Anxiety Disorders
Addiction Medicine
Sleep Medicine
Page Number
54-64
Legacy Keywords
Benzodiazepines; alcohol withdrawal; insomnia; anxiety disorders; panic disorder; akathisia; catatonia; agitation
Sections
Evidence-Based Reviews
Reviews
Audio / Podcast
2012.04.April.Casher.mp3
Audio / Podcast
2012.04.April.Casher.mp3
Author(s)
Jolene R. Bostwick, PharmD, BCPS, BCPP
Author(s)
Jolene R. Bostwick, PharmD, BCPS, BCPP
Author and Disclosure Information

Jolene R. Bostwick, PharmD, BCPS, BCPP
Clinical Assistant Professor of Pharmacy, University of Michigan College of Pharmacy, Clinical Pharmacist, University of Michigan Health System, Ann Arbor, MI
Michael I. Casher, MD
Clinical Assistant Professor, Department of Psychiatry, University of Michigan Medical School, Director of Inpatient Adult Psychiatry, University of Michigan Health System, Ann Arbor, MI
Shinji Yasugi, MD
First-Year Psychiatry Resident, University of Michigan Health System, Ann Arbor, MI

Author and Disclosure Information

Jolene R. Bostwick, PharmD, BCPS, BCPP
Clinical Assistant Professor of Pharmacy, University of Michigan College of Pharmacy, Clinical Pharmacist, University of Michigan Health System, Ann Arbor, MI
Michael I. Casher, MD
Clinical Assistant Professor, Department of Psychiatry, University of Michigan Medical School, Director of Inpatient Adult Psychiatry, University of Michigan Health System, Ann Arbor, MI
Shinji Yasugi, MD
First-Year Psychiatry Resident, University of Michigan Health System, Ann Arbor, MI

Article PDF
1104CP_Bostwick.pdf
Article PDF
1104CP_Bostwick.pdf

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
 

 

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.

Clinical Point

For treating social anxiety, benzodiazepines have better efficacy than SSRIs, MAOIs, and anticonvulsants

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

 

 

Clinical Point

Benzodiazepines have negligible action on core PTSD symptoms: re-experiencing, avoidance, and hyperarousal

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

Clinical Point

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of 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

Tapering benzodiazepines

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms, such as rebound anxiety, agitation, insomnia, or seizures, particularly when use exceeds 8 weeks. The onset of withdrawal symptoms varies, depending on the medication used. Withdrawal symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives.33Table 2 lists recommended durations for tapering benzodiazepines.33,34 In general, decrease the total daily dose by 25% the first week, another 25% the second week, then 10% a week until discontinuation. When benzodiazepine use exceeds 1 year, a slower taper is recommended; for example, decrease 10% every 1 to 2 weeks. When 20% of the dosage remains, begin a 5% dose reduction every 2 to 4 weeks. Monitor patients for withdrawal symptoms or symptom exacerbation. If either occur, consider maintaining the current benzodiazepine dose or increasing the dose for 1 to 2 weeks or longer, if necessary, then continue to taper at a slower rate.34

Table 2

Recommendations for tapering benzodiazepines

Duration of useRecommended taper lengthComments
<6 to 8 weeksTaper may not be requiredDepending on clinical judgment and patient stability/preference, consider implementing a taper, particularly if using a high-dose benzodiazepine or an agent with a short or intermediate half-life, such as alprazolam or triazolam
8 weeks to 6 monthsSlowly over 2 to 3 weeksGo slower during latter half of taper. Tapering will reduce, not eliminate, withdrawal symptoms. Patients should avoid alcohol and stimulants during benzodiazepine withdrawal
6 months to 1 yearSlowly over 4 to 8 weeks
>1 yearSlowly over 2 to 4 months
Source: References 33,34
 

 

Risks of benzodiazepine use

Clinical Point

Agents with shorter half-lives such as lorazepam and oxazepam are preferred for older patients

For most indications, benzodiazepine therapy should be short-term.35 Use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal. Tell patients to avoid alcohol while taking a benzodiazepine because this combination is potentially lethal. Benzodiazepines are commonly abused and abuse can lead to unintentional drug overdose. Benzodiazepines accounted for 37% of unintentional drug overdose deaths in West Virginia in 2006; in 46% of these cases, benzodiazepines were used for nonmedical purposes. Clinicians can help reduce the risk of diversion by limiting prescriptions to 30 days with no refills.36

Clinical Point

Benzodiazepine use should be short-term; use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal

Older patients taking benzodiazepines are at increased risk of falls and hip fractures.37 Lorazepam, oxazepam, and temazepam—agents with shorter half-lives that are not greatly affected by pharmacokinetic changes associated with aging—are preferred for these patients.34 Patients with dementia or other CNS-compromising conditions may become confused or delirious with regular benzodiazepine dosing. Educate patients to whom you prescribe benzodiazepines about the importance of gauging their level of sedation before driving or engaging in other tasks for which sedation could compromise their safety. Benzodiazepine use during pregnancy requires a careful discussion of risks and benefits (Box 2).38

Box 2

Using benzodiazepines during pregnancy

Benzodiazepine use during pregnancy has been associated with cleft palate and urogenital and neurologic malformations in the fetus.38 Although data are conflicting—particularly among recent meta-analyses that fail to demonstrate an association—some experts advise against benzodiazepine use in the first trimester. Participate in shared decision making with your patients and educate them about the potential risks and benefits of benzodiazepine use during the first trimester and throughout pregnancy. After delivery, newborns may develop “floppy baby syndrome”—which is associated with lethargy, difficulty eating, and respiratory depression—or withdrawal.38 To minimize this risk, consider tapering the benzodiazepine as the patient approaches delivery.

Related Resources

Drug Brand Names

  • Alprazolam • Xanax
  • Chlordiazepoxide • Librium, Limbitrol
  • Clonazepam • Klonopin
  • Clorazepate • Tranxene
  • Diazepam • Valium
  • Diphenhydramine • Benadryl, others
  • Estazolam • ProSom
  • Flumazenil • Romazicon
  • Flurazepam • Dalmane
  • Haloperidol • Haldol
  • Lithium • Lithobid
  • Lorazepam • Ativan
  • Olanzapine • Zyprexa
  • Oxazepam • Serax
  • Paroxetine • Paxil
  • Pregabalin • Lyrica
  • Propranolol • Inderal, InnoPran XL, others
  • Quazepam • Doral
  • Ramelteon • Rozerem
  • Sertraline • Zoloft
  • Temazepam • Restoril
  • Triazolam • Halcion
  • Valproic acid • Depakene, Stavzor, others

Disclosures

Drs. Bostwick and Yasugi report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca and Sunovion Pharmaceuticals.

Clinical Point

Benzodiazepine use during pregnancy has been associated with cleft palate and urogenital and neurologic malformations

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
 

 

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.

Clinical Point

For treating social anxiety, benzodiazepines have better efficacy than SSRIs, MAOIs, and anticonvulsants

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

 

 

Clinical Point

Benzodiazepines have negligible action on core PTSD symptoms: re-experiencing, avoidance, and hyperarousal

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

Clinical Point

Benzodiazepines have anticonvulsant properties that may interfere with the therapeutic efficacy of 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

Tapering benzodiazepines

Slow discontinuation of benzodiazepines is recommended to avoid withdrawal symptoms, such as rebound anxiety, agitation, insomnia, or seizures, particularly when use exceeds 8 weeks. The onset of withdrawal symptoms varies, depending on the medication used. Withdrawal symptoms may appear in 1 to 2 days for agents with shorter half-lives, but may not appear until 3 to 7 days for agents with longer half-lives.33Table 2 lists recommended durations for tapering benzodiazepines.33,34 In general, decrease the total daily dose by 25% the first week, another 25% the second week, then 10% a week until discontinuation. When benzodiazepine use exceeds 1 year, a slower taper is recommended; for example, decrease 10% every 1 to 2 weeks. When 20% of the dosage remains, begin a 5% dose reduction every 2 to 4 weeks. Monitor patients for withdrawal symptoms or symptom exacerbation. If either occur, consider maintaining the current benzodiazepine dose or increasing the dose for 1 to 2 weeks or longer, if necessary, then continue to taper at a slower rate.34

Table 2

Recommendations for tapering benzodiazepines

Duration of useRecommended taper lengthComments
<6 to 8 weeksTaper may not be requiredDepending on clinical judgment and patient stability/preference, consider implementing a taper, particularly if using a high-dose benzodiazepine or an agent with a short or intermediate half-life, such as alprazolam or triazolam
8 weeks to 6 monthsSlowly over 2 to 3 weeksGo slower during latter half of taper. Tapering will reduce, not eliminate, withdrawal symptoms. Patients should avoid alcohol and stimulants during benzodiazepine withdrawal
6 months to 1 yearSlowly over 4 to 8 weeks
>1 yearSlowly over 2 to 4 months
Source: References 33,34
 

 

Risks of benzodiazepine use

Clinical Point

Agents with shorter half-lives such as lorazepam and oxazepam are preferred for older patients

For most indications, benzodiazepine therapy should be short-term.35 Use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal. Tell patients to avoid alcohol while taking a benzodiazepine because this combination is potentially lethal. Benzodiazepines are commonly abused and abuse can lead to unintentional drug overdose. Benzodiazepines accounted for 37% of unintentional drug overdose deaths in West Virginia in 2006; in 46% of these cases, benzodiazepines were used for nonmedical purposes. Clinicians can help reduce the risk of diversion by limiting prescriptions to 30 days with no refills.36

Clinical Point

Benzodiazepine use should be short-term; use exceeding 2 to 4 weeks increases the risk for dependence and withdrawal

Older patients taking benzodiazepines are at increased risk of falls and hip fractures.37 Lorazepam, oxazepam, and temazepam—agents with shorter half-lives that are not greatly affected by pharmacokinetic changes associated with aging—are preferred for these patients.34 Patients with dementia or other CNS-compromising conditions may become confused or delirious with regular benzodiazepine dosing. Educate patients to whom you prescribe benzodiazepines about the importance of gauging their level of sedation before driving or engaging in other tasks for which sedation could compromise their safety. Benzodiazepine use during pregnancy requires a careful discussion of risks and benefits (Box 2).38

Box 2

Using benzodiazepines during pregnancy

Benzodiazepine use during pregnancy has been associated with cleft palate and urogenital and neurologic malformations in the fetus.38 Although data are conflicting—particularly among recent meta-analyses that fail to demonstrate an association—some experts advise against benzodiazepine use in the first trimester. Participate in shared decision making with your patients and educate them about the potential risks and benefits of benzodiazepine use during the first trimester and throughout pregnancy. After delivery, newborns may develop “floppy baby syndrome”—which is associated with lethargy, difficulty eating, and respiratory depression—or withdrawal.38 To minimize this risk, consider tapering the benzodiazepine as the patient approaches delivery.

Related Resources

Drug Brand Names

  • Alprazolam • Xanax
  • Chlordiazepoxide • Librium, Limbitrol
  • Clonazepam • Klonopin
  • Clorazepate • Tranxene
  • Diazepam • Valium
  • Diphenhydramine • Benadryl, others
  • Estazolam • ProSom
  • Flumazenil • Romazicon
  • Flurazepam • Dalmane
  • Haloperidol • Haldol
  • Lithium • Lithobid
  • Lorazepam • Ativan
  • Olanzapine • Zyprexa
  • Oxazepam • Serax
  • Paroxetine • Paxil
  • Pregabalin • Lyrica
  • Propranolol • Inderal, InnoPran XL, others
  • Quazepam • Doral
  • Ramelteon • Rozerem
  • Sertraline • Zoloft
  • Temazepam • Restoril
  • Triazolam • Halcion
  • Valproic acid • Depakene, Stavzor, others

Disclosures

Drs. Bostwick and Yasugi report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca and Sunovion Pharmaceuticals.

Clinical Point

Benzodiazepine use during pregnancy has been associated with cleft palate and urogenital and neurologic malformations

References

1. Mihic SJ, Harris RA. Hypnotics and sedatives. In: Brunton LL Chabner BA, Knollmann BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. New York, NY: McGraw Hill and Company; 2011:457-480.

2. Facts and comparisons Web site. 2011 Wolters Kluwer Health Inc. http://online.factsandcomparisons.com. Accessed August 16, 2011.

3. DuPont RL, Greene W, Lydiard RB. Sedatives and hypnotics: pharmacology and epidemiology. In: Gold MS Hermann R, eds. UpToDate. http://www.uptodate.com/contents/sedatives-and-hypnotics-abuse-and-dependence-pharmacology-and-epidemiology. Accessed August 16, 2011.

4. U.S. Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed August 16, 2011.

5. Chouinard G. Issues in the clinical use of benzodiazepines: potency withdrawal, and rebound. J Clin Psychiatry. 2004;65(suppl 5):7-12.

6. Shader RI, Greenblatt DJ. Can you provide a table of equivalencies for benzodiazepines and other marketed benzodiazepine receptor agonists? J Clin Psychopharmacol. 1997;17(4):331.-

7. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacologic interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev. 2011;15(6):CD008537.-

8. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.

9. Foral P, Dewan N, Malesker M. Insomnia: a therapeutic review for pharmacists. Consult Pharm. 2011;26(5):332-341.

10. Riemann D, Perlis ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev. 2009;13(3):205-214.

11. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments of generalized anxiety disorder. J Psychopharmacol. 2007;21(8):864-872.

12. Davidson JR, Zhang W, Connor KM, et al. A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J Psychopharmacol. 2010;24(1):3-26.

13. 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.

14. American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. 2nd ed. Arlington VA: American Psychiatric Publishing, Inc.; 2009.

15. Pollack MH, Simon NM, Worthington JJ, et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol. 2003;17(3):276-282.

16. Watanabe N, Churchill R, Furukawa TA. Combined psychotherapy plus benzodiazepines for panic disorder. Cochrane Database Syst Rev. 2009;(1):CD005335.-

17. Otto MW, McHugh RK, Simon NM, et al. Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation. Behav Res Ther. 2010;48(8):720-727.

18. Davidson JR. Use of benzodiazepines in social anxiety disorder generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65(suppl 5):29-33.

19. Argyropoulos SV, Sandford JJ, Nutt DJ. The psychobiology of anxiolytic drugs Part 2: pharmacological treatments of anxiety. Pharmacol Ther. 2000;88(3):213-227.

20. Connor KM, Davidson JR, Potts NL, et al. Discontinuation of clonazepam in the treatment of social phobia. J Clin Psychopharmacol. 1998;18(5):373-378.

21. Miller CH, Fleischhacker WW. Managing antipsychotic-induced acute and chronic akathisia. Drug Saf. 2000;22(1):73-81.

22. Rodnitzky RL. Drug-induced movement disorders. Clin Neuropharmacol. 2002;25(3):142-151.

23. Arbaizar B, Gómez-Acebo I, Llorca J. Postural induced tremor in psychiatry. Psychiatry Clin Neurosci. 2008;62(6):638-645.

24. Casher MI, Bess JD. Manual of inpatient psychiatry. New York NY: Cambridge University Press; 2010.

25. Battaglia J. Pharmacological management of acute agitation. Drugs. 2005;65(9):1207-1222.

26. Physicians’ desk reference. Montvale NJ: PDR Network, LLC; 2010.

27. Rosebush PI, Mazurek MF. Catatonia and its treatment. Schizophr Bull. 2010;36(2):239-242.

28. Ungvari GS, Kau LS, Wai-Kwong T, et al. The pharmacological treatment of catatonia: an overview. Eur Arch Psychiatry Clin Neurosci. 2001;251(suppl 1):I31-I34.

29. Fink M, Taylor MA. Catatonia: a clinician’s guide to diagnosis and treatment. New York NY: Cambridge University Press; 2003.

30. Naguib N, Koorn R. Interactions between psychotropics anaesthetics and electroconvulsive therapy: implications for drug choice and patient management. CNS Drugs. 2002;16(4):229-247.

31. Boylan LS, Haskett RF, Mulsant BH, et al. Determinants of seizure threshold in ECT: benzodiazepine use, anesthetic dosage, and other factors. J ECT. 2000;16(1):3-18.

32. Krystal AD, Watts BV, Weiner RD, et al. The use of flumazenil in the anxious and benzodiazepine-dependent ECT patient. J ECT. 1998;14(1):5-14.

33. Melton ST, Kirkwood CK. Anxiety disorders I: generalized anxiety panic, and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. New York, NY: McGraw-Hill Companies; 2011:1209-1228.

34. Benzodiazepine toolkit. The Pharmacist’s Letter/Prescriber’s Letter. 2011;27(4):270406.-

35. Lader M. Benzodiazepines revisited – will we ever learn? Addiction. 2011;106(12):2086-2109.

36. Toblin RL, Paulozzi LJ, Logan JE, et al. Mental illness and psychotropic drug use among prescription drug overdose deaths: a medical examiner chart review. J Clin Psychiatry. 2010;71(4):491-496.

37. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249-255.

38. Menon SJ. Psychotropic medication during pregnancy and lactation. Arch Gynecol Obstet. 2008;277(1):1-13.

References

1. Mihic SJ, Harris RA. Hypnotics and sedatives. In: Brunton LL Chabner BA, Knollmann BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. New York, NY: McGraw Hill and Company; 2011:457-480.

2. Facts and comparisons Web site. 2011 Wolters Kluwer Health Inc. http://online.factsandcomparisons.com. Accessed August 16, 2011.

3. DuPont RL, Greene W, Lydiard RB. Sedatives and hypnotics: pharmacology and epidemiology. In: Gold MS Hermann R, eds. UpToDate. http://www.uptodate.com/contents/sedatives-and-hypnotics-abuse-and-dependence-pharmacology-and-epidemiology. Accessed August 16, 2011.

4. U.S. Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed August 16, 2011.

5. Chouinard G. Issues in the clinical use of benzodiazepines: potency withdrawal, and rebound. J Clin Psychiatry. 2004;65(suppl 5):7-12.

6. Shader RI, Greenblatt DJ. Can you provide a table of equivalencies for benzodiazepines and other marketed benzodiazepine receptor agonists? J Clin Psychopharmacol. 1997;17(4):331.-

7. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacologic interventions for the treatment of the alcohol withdrawal syndrome. Cochrane Database Syst Rev. 2011;15(6):CD008537.-

8. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.

9. Foral P, Dewan N, Malesker M. Insomnia: a therapeutic review for pharmacists. Consult Pharm. 2011;26(5):332-341.

10. Riemann D, Perlis ML. The treatments of chronic insomnia: a review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Med Rev. 2009;13(3):205-214.

11. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments of generalized anxiety disorder. J Psychopharmacol. 2007;21(8):864-872.

12. Davidson JR, Zhang W, Connor KM, et al. A psychopharmacological treatment algorithm for generalised anxiety disorder (GAD). J Psychopharmacol. 2010;24(1):3-26.

13. 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.

14. American Psychiatric Association. Practice guideline for the treatment of patients with panic disorder. 2nd ed. Arlington VA: American Psychiatric Publishing, Inc.; 2009.

15. Pollack MH, Simon NM, Worthington JJ, et al. Combined paroxetine and clonazepam treatment strategies compared to paroxetine monotherapy for panic disorder. J Psychopharmacol. 2003;17(3):276-282.

16. Watanabe N, Churchill R, Furukawa TA. Combined psychotherapy plus benzodiazepines for panic disorder. Cochrane Database Syst Rev. 2009;(1):CD005335.-

17. Otto MW, McHugh RK, Simon NM, et al. Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation. Behav Res Ther. 2010;48(8):720-727.

18. Davidson JR. Use of benzodiazepines in social anxiety disorder generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65(suppl 5):29-33.

19. Argyropoulos SV, Sandford JJ, Nutt DJ. The psychobiology of anxiolytic drugs Part 2: pharmacological treatments of anxiety. Pharmacol Ther. 2000;88(3):213-227.

20. Connor KM, Davidson JR, Potts NL, et al. Discontinuation of clonazepam in the treatment of social phobia. J Clin Psychopharmacol. 1998;18(5):373-378.

21. Miller CH, Fleischhacker WW. Managing antipsychotic-induced acute and chronic akathisia. Drug Saf. 2000;22(1):73-81.

22. Rodnitzky RL. Drug-induced movement disorders. Clin Neuropharmacol. 2002;25(3):142-151.

23. Arbaizar B, Gómez-Acebo I, Llorca J. Postural induced tremor in psychiatry. Psychiatry Clin Neurosci. 2008;62(6):638-645.

24. Casher MI, Bess JD. Manual of inpatient psychiatry. New York NY: Cambridge University Press; 2010.

25. Battaglia J. Pharmacological management of acute agitation. Drugs. 2005;65(9):1207-1222.

26. Physicians’ desk reference. Montvale NJ: PDR Network, LLC; 2010.

27. Rosebush PI, Mazurek MF. Catatonia and its treatment. Schizophr Bull. 2010;36(2):239-242.

28. Ungvari GS, Kau LS, Wai-Kwong T, et al. The pharmacological treatment of catatonia: an overview. Eur Arch Psychiatry Clin Neurosci. 2001;251(suppl 1):I31-I34.

29. Fink M, Taylor MA. Catatonia: a clinician’s guide to diagnosis and treatment. New York NY: Cambridge University Press; 2003.

30. Naguib N, Koorn R. Interactions between psychotropics anaesthetics and electroconvulsive therapy: implications for drug choice and patient management. CNS Drugs. 2002;16(4):229-247.

31. Boylan LS, Haskett RF, Mulsant BH, et al. Determinants of seizure threshold in ECT: benzodiazepine use, anesthetic dosage, and other factors. J ECT. 2000;16(1):3-18.

32. Krystal AD, Watts BV, Weiner RD, et al. The use of flumazenil in the anxious and benzodiazepine-dependent ECT patient. J ECT. 1998;14(1):5-14.

33. Melton ST, Kirkwood CK. Anxiety disorders I: generalized anxiety panic, and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: a pathophysiologic approach. New York, NY: McGraw-Hill Companies; 2011:1209-1228.

34. Benzodiazepine toolkit. The Pharmacist’s Letter/Prescriber’s Letter. 2011;27(4):270406.-

35. Lader M. Benzodiazepines revisited – will we ever learn? Addiction. 2011;106(12):2086-2109.

36. Toblin RL, Paulozzi LJ, Logan JE, et al. Mental illness and psychotropic drug use among prescription drug overdose deaths: a medical examiner chart review. J Clin Psychiatry. 2010;71(4):491-496.

37. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249-255.

38. Menon SJ. Psychotropic medication during pregnancy and lactation. Arch Gynecol Obstet. 2008;277(1):1-13.

Issue
Current Psychiatry - 11(04)
Issue
Current Psychiatry - 11(04)
Page Number
54-64
Page Number
54-64
Publications
MDedge Psychiatry
Current Psychiatry
Publications
MDedge Psychiatry
Current Psychiatry
Topics
Anxiety Disorders
Addiction Medicine
Sleep Medicine
Article Type
News
Display Headline
Benzodiazepines: A versatile clinical tool
Display Headline
Benzodiazepines: A versatile clinical tool
Legacy Keywords
Benzodiazepines; alcohol withdrawal; insomnia; anxiety disorders; panic disorder; akathisia; catatonia; agitation
Legacy Keywords
Benzodiazepines; alcohol withdrawal; insomnia; anxiety disorders; panic disorder; akathisia; catatonia; agitation
Sections
Evidence-Based Reviews
Reviews
Article Source

PURLs Copyright

Inside the Article

Article PDF Media