PTSD: National Center for PTSD

Use of Benzodiazepines for PTSD in Veterans Affairs

Key Points

• The VA/DoD Practice Guideline for PTSD recommends against the use of benzodiazepines for treatment of PTSD.
• The evidence is mounting on the harms associated with chronic benzodiazepine use in patients with PTSD.
• Prescriptions for benzodiazepines for VA PTSD patients have decreased from 30% in fiscal year (FY) 2012 to 9.1% in FY20 (Quarter 3; 1).
• The success seen in this reduction of use is primarily due to efforts of two initiatives, the Psychotropic Drug Safety Initiative (PDSI) and the National Academic Detailing Program.

Evidence on the Use of Benzodiazepines for PTSD

The VA/DoD 2017 Practice Guideline for the Management of PTSD strongly recommends against the routine use of benzodiazepines in Veterans with PTSD (2). The recommendation was based on unproven efficacy of benzodiazepines and well-known risks for abuse and dependence.

There have been two placebo-controlled randomized clinical trials of benzodiazepines for treating PTSD. Both had negative findings. Alprazolam (Xanax) had no benefit in alleviating PTSD symptoms (3), and clonazepam (Klonopin) had no benefit for the treatment of PTSD-related sleep dysfunction (4). Findings from research using VA administrative data of Veterans in care for co-occurring PTSD and substance use disorder (SUD) also do not support the use of benzodiazepines in PTSD (5). A recent meta-analysis of 18 studies with over 5,200 participants found benzodiazepines to be ineffective for PTSD treatment and concluded the risks associated with their use outweigh potential short-term benefits (6).

VA clinicians continue to prescribe benzodiazepines to some PTSD patients who may be seen as high risk—such as older Veterans or those on other sedative medications—presumably for symptomatic control of insomnia and anxiety due to the rapid short-term relief offered by benzodiazepines. However, it is now recognized that any benefit of benzodiazepines for these associated symptoms rapidly dissipates, leaving a patient to continue taking the medication to avoid withdrawal and rebound effects (7). The common practice of allowing patients to take benzodiazepines on an as-needed basis can lead to fluctuating blood levels that can worsen anxiety and cognitive impairment (8).

Problems Associated with Long-Term Benzodiazepine Use

There is a large literature documenting the harms of long-term benzodiazepine use (defined as > 3 months). This is especially true for older patients, who are at increased risk for motor vehicle crashes (9-10). Older patients taking benzodiazepines are also 2 to 3 times more likely to fall (11) and have 50% higher risk of hip fractures, even at modest doses with short-acting agents and short-term exposures (12-13). Cognitive dysfunction (including feelings of fogginess and confusion) is a common effect of long-term benzodiazepine use (14). Chronic benzodiazepine use can also cause anterograde amnesia (15) and is associated with elevated risk of dementia and Alzheimer’s disease (16-17). Importantly, there is a 50% increase in overall mortality rates associated with long-term benzodiazepine use (18).

There are also PTSD-specific problems. The cognitive effects of long-term benzodiazepine use among Veterans with PTSD are particularly concerning. PTSD itself is a risk factor for dementia, with older Veterans with PTSD nearly twice as likely as Veterans without PTSD to develop dementia (19). Increased disinhibition among those Veterans who are already high in aggression is another important concern. Increases in aggressive behavior were found among Veterans receiving benzodiazepines who were aggressive prior to treatment (20). Benzodiazepines are contraindicated in obstructive sleep apnea and chronic obstructive pulmonary disease (21), disorders commonly observed in Veterans with PTSD (22-24).

The long-recognized risks of abuse and dependence associated with use of benzodiazepines have particular relevance for Veterans with PTSD, who often have a co-occurring SUD. Pre-existing diagnosis of SUD may increase the risk of being prescribed high daily benzodiazepine doses for extended periods of time (25). Veterans who are on concurrent opioids and benzodiazepines are at increased risk for adverse effects including death from drug overdose (26-27).

Studies are mixed on whether benzodiazepines interfere with evidence-based cognitive-behavioral therapies (CBT) for PTSD, especially exposure-based therapies (28-30). There is some evidence that daytime dosing and long-acting benzodiazepines appear to interfere with the mental processes necessary to benefit from psychotherapy (6).

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Safe and Effective Treatment Options

The VA/DoD Clinical Practice Guideline recommends evidence-based psychotherapeutic interventions (1), including the two treatments disseminated in VA’s national evidence-based practice initiative, Prolonged Exposure and Cognitive Processing Therapy (31). A meta-analysis of treatments for PTSD suggests psychotherapy is more effective than medications (32). Recommended medications for PTSD include antidepressants such as sertraline (Zoloft) and paroxetine (Paxil) (1). Safer and more effective treatment options for the specific symptoms often targeted by clinicians with benzodiazepines exist (33). For anxiety, psychotherapy options include CBT, CBT for Anxiety, or Stress Inoculation Training. Medication options include selective-serotonin reuptake-inhibitor antidepressants such as sertraline (Zoloft) and paroxetine (Paxil) or the serotonin-norepinephrine reuptake-inhibitor venlafaxine (Effexor) (34). For insomnia, CBT for insomnia is highly effective (35). Other forms of CBT may be helpful. Medication options include older antidepressants such as trazodone, doxepin, or amitriptyline; prazosin for trauma-related nightmares; or diphenhydramine (Benadryl) (36).

Steps taken by VA to improve prescribing practices

As a result of efforts taken by VA, FY20 data from the Psychotropic Drug Safety Initiative indicate the overall percentage of Veterans with PTSD who received an outpatient benzodiazepine prescription is now at 9% (1). Given the lack of efficacy of benzodiazepines for the treatment of PTSD and the potential harms noted above, VA pharmacotherapy safety initiatives have identified potential subgroups of patients that are most at risk of adverse effects from long-term benzodiazepine use. These subgroups include patients with co-occurring TBI and co-occurring current or lifetime substance use disorder. Other high-risk groups include older Veterans and those with a history of chronic pain who are on other sedatives (37).

The Psychotropic Drug Safety Initiative is a nationwide psychopharmacology quality improvement program launched in 2013. The program supports Veterans Integrated Service Network (VISN) and facility psychopharmacology quality improvement initiatives by providing data on national, VISN, and facility-level performance on prescribing measures; facilitating clinical review of Veterans who may benefit from improvement in their psychotropic medication regimen via actionable patient lists on a Clinical Management Dashboard; providing feedback and technical assistance for quality improvement action planning; coordinating a national learning collaborative; and providing training and educational resources. One of the prescribing measures addressed in the program is use of benzodiazepines in patients with PTSD. There are also measures addressing use of benzodiazepines in older Veterans, regardless of PTSD diagnosis.

The Opioid Safety Initiative, established in 2012, has worked to support clinicians to reduce the use of opioids for chronic pain and offer safer, alternative treatment options. Co-prescribing of opioids and benzodiazepines has been a specific focus of these efforts because of the increased risk of overdose when these medications are taken together. As a result, the latest VA data from July 2012 to December 2014 indicate overall opioid use in the VA healthcare system is down, with 29,281 fewer patients receiving opioids and benzodiazepines together.

The National Academic Detailing Service, developed through Pharmacy Benefits Management, has also focused on benzodiazepine use in patients with PTSD. The Academic Detailing program works by having clinical pharmacists meet with individual clinicians to review caseloads and suggest options for specific patients. Suggestions may include safe tapering strategy guidance as well as information on recommended alternative treatment strategies. Development of PTSD-specific clinician dashboards and patient reports are in progress and are scheduled for national rollout by the end of 2015. The dashboards will provide clinicians the ability to conduct proactive, population level management of specific classes of pharmacotherapy for their patients with PTSD.

Due to the significant risks associated with benzodiazepines and the lack of evidence for their effectiveness in the treatment of PTSD, it is worthwhile to implement strategies to carefully assess and consider alternate treatment options and to minimize new benzodiazepine prescriptions whenever possible. Strategies to taper existing benzodiazepine prescriptions are effective despite the fact that it is difficult and time-consuming work (38-42). Ultimately, the results of VA’s efforts should result in continued decreases in utilization of these potentially harmful medications and facilitate effective treatment options among Veterans with PTSD who use VA care.

Printable Booklet

Benzodiazepines and PTSD: Do you know about this risky combination?

Download the PDF booklet to share with patients. It promotes shared decision-making by increasing knowledge for the risks of chronic benzodiazepine use in those with PTSD. It is based upon the original EMPOWER trial that was significantly effective in reducing benzodiazepine use in elderly adults (42).

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References

1. U.S. Department of Veterans Affairs. (2020). Mental Health Information System: Psychotropic Drug Safety Initiative Dashboard. [Data set]. Program Evaluation and Research Center. https://spsites.dev.cdw.va.gov/sites/OMHO_PEC/Pages/MHIS.aspx
2. U.S. Department of Veterans Affairs and Department of Defense. (2017). VA/DoD Clinical Practice Guideline for Management of Post-Traumatic Stress Disorder. Author. https://www.healthquality.va.gov/Post_Traumatic_Stress_Disorder_PTSD.asp
3. Braun, P., Greenberg, D., Dasberg, H., & Lerner, B. (1990). Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. Journal of Clinical Psychiatry, 51(6), 236-238.
4. Cates, M. E., Bishop, M. H., Davis, L. L., Lowe, J. S., & Woolley, T. W. (2004). Clonazepam for treatment of sleep disturbances associated with combat-related posttraumatic stress disorder. Annals of Pharmacotherapy, 38(9), 1395-1399. https://doi.org/10.1345/aph.1E043
5. Kosten, T. R., Fontana, A., Sernyak, M. J., et al. (2000). Benzodiazepine use in posttraumatic stress disorder among Veterans with substance abuse. Journal of Nervous and Mental Disease, 188(7), 454-459.
6. Guina, J., Rossetter, S. R., De, Rhodes, B., Nahhas, R., & Welton, R. S (2015). Benzodiazepines for PTSD: A systematic review and meta-analysis. Journal of Psychiatric Practice, 21(4), 281-303. https://doi.org/10.1097/PRA.0000000000000091
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11. Glass, J., Lanctôt, K. L., Herrmann, N., Sproule, B. A., & Busto, U. E. (2005). Sedative hypnotics in older people with insomnia: Meta-analysis of risks and benefits. BMJ, 331(7526), 1169. https://doi.org/10.1136/bmj.38623.768588.47
12. Wang, P. S., Bohn, R. L., Glynn, R. J., Mogun, H. & Avorn, J. (2001). Hazardous benzodiazepine regimens in the elderly: Effects of half-life, dosage, and duration on risk of hip fracture. American Journal of Psychiatry, 158(6), 892-898. https://doi.org/10.1176/appi.ajp.158.6.892
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17. de Gage, S. B., Moride, Y., Ducruet, T., Kurth, T., Verdoux, H., Tournier, M., Pariente, A., & Bègaud, B (2014). Benzodiazepine use and risk of Alzheimer’s disease: Case-control study. BMJ, 349, g5205. https://doi.org/10.1136/bmj.g5205
18. Kripke, D. F., Langer, R. D., & Kline, L. E. (2012). Hypnotics' association with mortality or cancer: A matched cohort study. BMJ Open, 2(1), e000850. https://doi.org/10.1136/bmjopen-2012-000850
19. Yaffe, K., Vittinghoff, E., Lindquist, K., Barnes, D., Covinsky, K. E., Neylan, T., Kluse, M., & Marmar, C. (2010). Posttraumatic stress disorder and risk of dementia among US Veterans. Archives of General Psychiatry, 67(6), 609-613. https://doi.org/10.1001/archgenpsychiatry.2010.61
20. Shin, H. J., Rosen, C. S., Greenbaum, M. A., & Jain, S. (2012). Longitudinal correlates of aggressive behavior in help-seeking U.S. Veterans with PTSD. Journal of Traumatic Stress, 25(6), 649-656. https://doi.org/10.1002/jts.21761
21. Mazza, M., Losurdo, A., Testani, E., Marano, G., Di Nicola, M., Dittoni, S., Gnoni, V., Di Blasi, C., Giannontoni, N. M., Lapenta, L., Brunetti, V., Bria, P., Janiri, L., Mazza, S., & Marca, G. D. (2014). Polysomnographic findings in a cohort of chronic insomnia patients with benzodiazepine abuse. Journal of Clinical Sleep Medicine, 10(1), 35. https://doi.org/10.5664/jcsm.3354
22. Hawkins, E. J., Malte, C. A., Grossbard, J. R., & Saxon, A. J. (2015). Prevalence and trends of concurrent opioid analgesic and benzodiazepine use among Veterans Affairs patients with post-traumatic stress disorder, 2003-2011. Pain Medicine. 16(10), 1943-1954. https://doi.org/10.1111/pme.12787
23. Spitzer, C., Koch, B., Grabe, H. J., Ewert, R., Barnow, S., Felix, S. B., Ittermann, T., Obst, A., Völzke, H., Gläser, S., & Schäper. (2011). Association of airflow limitation with trauma exposure and post-traumatic stress disorder. The European Respiratory Journal, 37(5), 1068-1075. https://doi.org/10.1183/09031936.00028010
24. Williams, S. G., Collen, J., Orr, N., Holley, A. B., & Lettieri, C. J. (2015). Sleep disorders in combat-related PTSD. Sleep and Breathing, 19(1), 175-182. https://doi.org/10.1007/s11325-014-0984-y
25. Hermos, J. A., Young, M. M., Lawler, E. V., Rosenbloom, D., & Fiore, L. D. (2007). Long-term, high-dose benzodiazepine prescriptions in Veteran patients with PTSD: Influence of preexisting alcoholism and drug-abuse diagnoses. Journal of Traumatic Stress, 20(5), 909-914. https://doi.org/10.1002/jts.20254
26. Park, T. W., Saitz, R., Ganoczy, D., Ilgen, M. A., & Bohnert, A. S (2015). Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: Case-cohort study. BMJ, 350, h2698. https://doi.org/10.1136/bmj.h2698
27. Hawkins, E. J., Malte, C. A., Grossbard, J., Saxon, A. J., Imel, Z. E., & Kivlahan, D. R (2013). Comparative safety of benzodiazepines and opioids among Veterans Affairs patients with posttraumatic stress disorder. Journal of Addiction Medicine, 7(5), 354-362. https://doi.org/10.1097/ADM.0b013e31829e3957
28. van Minnen, A., & Hagenaars, M. (2002). Fear activation and habituation patterns as early process predictors of response to prolonged exposure treatment in PTSD. Journal of Traumatic Stress, 15(5), 359-367. https://doi.org/10.1023/A:1020177023209
29. Rosen, C. S., Greenbaum, M. A., Schnurr, P. P., Holmes, T. H., & Brennan, P. L (2013). Do benzodiazepines reduce the effectiveness of exposure therapy for posttraumatic stress disorder? Journal of Clinical Psychiatry, 74(12), 1241-1248. https://doi.org/10.4088/JCP.13m08592
30. Rothbaum, B. O., Price, M., Jovanovic, T., Norrholm, S. D., Gerardi, M., Dunlop, B., Davis, M., Bradley, B., Duncan, E. J., Rizzo, A., & Ressler, K. J (2014). A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War Veterans. American Journal of Psychiatry, 171(6), 640-648. doi:10.1176/appi.ajp.2014.13121625
31. Karlin, B. E., Ruzek, J. I., Chard, K. M., Eftekhari, A., Monson, C. M., Hembree, E. A., Resick, P. A., & Foa, E. B. (2010). Dissemination of evidence-based psychological treatments for posttraumatic stress disorder in the Veterans Health Administration. Journal of Traumatic Stress, 23(6), 663-673. https://doi.org/10.1002/jts.20588
32. Lee, D. J., Schnitzlein, C. W., Wolf, J. P., Vythilingam, M., Rasmusson, A. M., & Hoge, C. W. (2016). Psychotherapy versus pharmacotherapy for posttraumatic stress disorder: Systematic review and meta-analyses to determine first-line treatments. Depression and Anxiety, 33(9), 792-806. https://doi.org/10.1002/da.22511
33. Bernardy, N. C., & Friedman, M. J. (2015). Psychopharmacological strategies in the management of posttraumatic stress disorder (PTSD): What have we learned? Current Psychiatry Reports, 17(4), 564. https://doi.org/10.1007/s11920-015-0564-2
34. Baldwin, D. S., Anderson, I. M., Nutt, D. J., Bandelow, B., Bond, A., Davidson, J. R. T., den Boer, J. A., Fineberg, N. A., Knapp, M., Scott, J., & Wittchen, H. U. (2005). Evidence-based guidelines for the pharmacological treatment of anxiety disorders: Recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology, 19(6), 567-596. https://doi.org/10.1177/0269881105059253
35. Morin, C. M. (2015). Cognitive behavioral therapy for chronic insomnia: State of the science versus current clinical practices. Annals of Internal Medicine, 163(3), 236-237. https://doi.org/10.7326/M15-1246
36. Rosini, J. M., & Dogra, P. (2015). Pharmacology for insomnia: Consider the options. Nursing, 45(3), 38-45. https://doi.org/10.1097/01.NURSE.0000460712.06302.19
37. Bernardy, N. C., Lund, B. C., Alexander, B., & Friedman, M. J. (2014). Increased polysedative use in veterans with posttraumatic stress disorder. Pain Medicine, 15(7), 1083-1090. https://doi.org/10.1111/pme.12321
38. Morin, C. M., Bastien, C., Guay, B., Radouco-Thomas, M., Leblanc, J., & Vallières, A. (2014). Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. American Journal of Psychiatry, 161(2), 332-342. https://doi.org/10.1176/appi.ajp.161.2.332
39. Tannenbaum, C. (2015). Inappropriate benzodiazepine use in elderly patients and its reduction. Journal of Psychiatry & Neuroscience, 40(3), E27-28. https://doi.org/10.1503/jpn.140355
40. Pollmann, A. S., Murphy, A. L., Bergman, J. C., & Gardner, D. M. (2015). Deprescribing benzodiazepines and Z-drugs in community-dwelling adults: A scoping review. BMC Pharmacology and Toxicology, 16(1), 19. https://doi.org/10.1186/s40360-015-0019-8
41. Vicens, C., Bejarano, F., Sempere, E., Mateu, C., Fiol, F., Socias, I., Aragonès, E., Palop, V., Beltran, J. L., Piñol, J. L., Lera, G., Folch, S., Mengual, M., Basora, J., Esteva, M., Llobera, J., Roca, M., Gili, M., & Leiva, At. (2014). Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: Cluster randomized controlled trial in primary care. The British Journal of Psychiatry, 204(6), 471-479. https://doi.org/10.1192/bjp.bp.113.134650
42. Tannenbaum, C., Martin, P., Tamblyn, R., Benedetti, A., & Ahmed, S (2014). Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: The EMPOWER cluster randomized trial. JAMA Internal Medicine, 174(6), 890-898. https://doi.org/10.1001/jamainternmed.2014.949

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