BACKGROUND/RATIONALE:
Substantial numbers of Veterans with PTSD present with multiple and complex symptomatology such as co-occurring pain, anxiety and insomnia, and are commonly prescribed opioid and benzodiazepine medications to treat these symptoms. Yet, potential interactions between opioids and benzodiazepines pose serious risks to patients who take them, with the most serious risks including fall-related injuries caused by over-sedation and death due to respiratory depression. Despite these known risks, limited information exists on the national prevalence of opioids and benzodiazepines prescribed concurrently, their use among patients at elevated risk of severe adverse events, such as those with problematic alcohol use, suicide risk and advanced age, or the comparative safety of these medications among those diagnosed with PTSD.

OBJECTIVE(S):
The specific aims of this project were to: 1a) estimate the annual prevalence of any (>30-days) and long-term (>90-days) concurrent opioid and benzodiazepine use among patients with documented PTSD, 1b) estimate the annual prevalence of alcohol misuse, suicide risk and advanced age (>65 years old) among patients with PTSD who are prescribed benzodiazepines and opioids concurrently, 2) assess whether VA patients with PTSD receiving opioids and benzodiazepines concurrently are at increased risk of all cause mortality and fractures, as compared to those receiving opioids only, benzodiazepines only and nonusers of these medications, and 3) test if alcohol misuse and advanced age are associated with increased risks of all cause mortality and fractures among VA patients with PTSD who are newly prescribed opioids and benzodiazepines concurrently, as compared to those who screen negative for alcohol misuse or who are <65 years old.

METHODS:
In this retrospective cohort study participants were eligible if they received care at a VA facility and were diagnosed with a PTSD diagnosis during fiscal years (FY) 2010-2011. Aim 1a used gender-specific logistic regressions to estimate the annual prevalence of any (>30-days) and long-term (>90-days) concurrent use of opioids and benzodiazepines among patients receiving VA care and diagnosed with PTSD (men: n=500,632, women: n=44,628). Aim 1b used gender-specific logistic regressions to estimate the prevalence of comorbid alcohol misuse, suicide risk and advanced age (> 65 years old) among concurrent opioid and benzodiazepine users with a valid Alcohol Use Disorder Identification Test - Consumption (AUDIT-C) score (men: n=55,783, women: n=6,306). Aim 2 estimated the 12-month relative risk of mortality and fractures among new concurrent opioid and benzodiazepine users (n=6,261), as compared to propensity score matched users of benzodiazepines only, opioids only and nonusers of these medications, using hazard ratios from Cox proportional regression models. Aim 3 tested if the risks of all cause mortality and fractures among patients who are newly prescribed opioids and benzodiazepines concurrently with valid AUDIT-C scores (n=5,901) are increased due to comorbid alcohol misuse and advanced age, after adjustment for demographic and clinical covariates, using Cox proportional regression models.

FINDINGS/RESULTS:
Aim 1a: For FY2011, the age-adjusted annual prevalence of any (>30-days) and long-term (>90-days) concurrent opioid and benzodiazepine use was 9.8% (95% Confidence Interval (CI): 9.7%-9.9%) and 5.2% (CI: 5.2%-5.3%), respectively, among men and 13.5% (CI: 13.1%-13.8%) and 6.6% (CI: 6.4%-6.9%) respectively, among women with PTSD. Aim 1b: Among patients who were co-prescribed these medications for >30-days, the prevalence of alcohol misuse was 11.4% and 9.1% in men and women, respectively. Further, 15.0% of men and 3.1% of women were >65 years old and 7.6% of men and 12.1% of women had documented suicide risk. Aim 2: The 12-month adjusted risk of mortality among concurrent users was 1.50 (CI: 1.15-1.96) and 1.92 (CI: 1.46-2.53) times greater than those prescribed benzodiazepines only and opioids only, respectively, and 1.63 (CI: 1.24-2.13) times greater than nonusers. The 12-month adjusted risk of fractures among concurrent users was 2.43 (CI: 2.00-2.96) and 2.53 (CI: 2.10-3.05) times greater than those receiving benzodiazepines only and nonusers, respectively. Differences were not detected in risk of fractures between concurrent and opioid only users. Aim 3: Among patients who were newly prescribed opioids and benzodiazepines concurrently with a valid AUDIT-C score , the risks of all cause mortality increased among patients aged 65 or older (Adjusted Hazard Ratio (AHR)=3.52, CI: 1.69-7.35) compared to those under 35. Alcohol misuse, as measured by the AUDIT-C, was not associated with increased risk of all-cause mortality. The risks of all-cause mortality were increased among patients with a Charlson Comorbidity Index (CCI) score of 2 or more (AHR=4.37, CI: 2.86-6.68) relative to a score of 0, a TBI diagnosis (AHR=2.63, CI: 1.47-4.71), dosages with daily morphine equivalents (DDME) >100mg (AHR=1.90, CI: 1.19-3.02) relative to DDME < 50mg. A service-connected disability percentage of 50% or higher was associated with a lower mortality risk (AHR=0.56, CI: 0.41-0.76). The risks of fractures were not increased among patients 65 and older or with documented alcohol misuse. Factors associated with increased fracture risk included alcohol use disorder only (AHR=2.05, CI: 1.53-2.74), drug use disorder only (AHR=1.81, CI: 1.30-2.51) and alcohol and drug use disorders (AHR=1.97, CI: 1.40-2.79, p<0.001) relative to no substance use disorder, and CCI score >2 (AHR=1.55, CI: 1.16-2.08) relative to a score of 0.

IMPACT:
Knowledge gained from this proposal supports VA efforts to reduce non-recommended prescribing practices, including concurrent prescribing of opioids and benzodiazepines, by identifying subsets of the population at greater risk of adverse events. Furthermore, results will educate patients and providers with respect to two of the most important adverse events, death and fractures, associated with these medications, thereby informing clinical care decisions.

---

External Links for this Project

NIH Reporter

Grant Number: I01HX001270-01A1
Link: https://reporter.nih.gov/project-details/8676423

---

PUBLICATIONS:

Journal Articles

1. Donovan LM, Malte CA, Spece LJ, Griffith MF, Feemster LC, Engelberg RA, Au DH, Hawkins EJ. Risks of Benzodiazepines in Chronic Obstructive Pulmonary Disease with Comorbid Posttraumatic Stress Disorder. Annals of the American Thoracic Society. 2019 Jan 1; 16(1):82-90. [view]

Conference Presentations

1. Hawkins EJ, Malte CA, Saxon AJ, Sayre G. Evaluating a Medication Alert to Reduce Concurrent Opioid and Benzodiazepine Use at a Single VA Health Care System. Paper presented at: Society for Implementation Research Collaboration Biennial Conference on Advancing Efficient Methodologies Through Community Partnerships and Team Science; 2015 Sep 10; Seattle, WA. [view]
2. Hawkins EJ. Leadership and Measurement Based Care Implementation in VHA Substance Use Disorder Programs. Paper presented at: National Institutes of Health / AcademyHealth Conference on the Science of Dissemination and Implementation; 2014 Dec 5; Bethesda, MD. [view]
3. Hawkins EJ, Malte CA, Grossbard JR, Saxon AJ. Prevalence and Trends of Concurrent Opioid Analgesic and Benzodiazepine Use Among Veterans Affairs Patients with PTSD 2003-2011. Poster session presented at: VA HSR&D / QUERI National Meeting; 2015 Jul 10; Philadelphia, PA. [view]

DRA: Mental, Cognitive and Behavioral Disorders
DRE: Treatment - Observational
Keywords: none
MeSH Terms: none