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The American Journal of Managed Care March 2018
False-Positive Mammography and Its Association With Health Service Use
Christine M. Gunn, PhD; Barbara Bokhour, PhD; Tracy A. Battaglia, MD, MPH; Rebecca A. Silliman, MD, PhD; and Amresh Hanchate, PhD
Incorporating Value Into Physician Payment and Patient Cost Sharing
Zirui Song, MD, PhD; Amol S. Navathe, MD, PhD; Ezekiel J. Emanuel, MD, PhD; and Kevin G. Volpp, MD, PhD
Development and Implementation of an Academic Cancer Therapy Stewardship Program
Amir S. Steinberg, MD; Anish B. Parikh, MD; Sara Kim, PharmD; Damaris Peralta-Hernandez, RPh; Talaat Aggour, BPharm; and Luis Isola, MD
Overuse and Insurance Plan Type in a Privately Insured Population
Meredith B. Rosenthal, PhD; Carrie H. Colla, PhD; Nancy E. Morden, MD; Thomas D. Sequist, MD; Alexander J. Mainor, JD; Zhonghe Li, MS; and Kevin H. Nguyen, MS
Patients Discharged From the Emergency Department After Referral for Hospitalist Admission
Christopher A. Caulfield, MD; John Stephens, MD; Zarina Sharalaya, MD; Jeffrey P. Laux, PhD; Carlton Moore, MD, MS; Daniel E. Jonas, MD, MPH; and Edmund A. Liles Jr, MD
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Trends in Opioid and Nonsteroidal Anti-Inflammatory Use and Adverse Events
Veronica Fassio, PharmD; Sherrie L. Aspinall, PharmD, MSc; Xinhua Zhao, PhD; Donald R. Miller, ScD; Jasvinder A. Singh, MD, MPH; Chester B. Good, MD, MPH; and Francesca E. Cunningham, PharmD
Improving Quality of Care in Oncology Through Healthcare Payment Reform
Lonnie Wen, RPh, PhD; Christine Divers, PhD; Melissa Lingohr-Smith, PhD; Jay Lin, PhD, MBA; and Scott Ramsey, MD, PhD
Assessing Medical Home Mechanisms: Certification, Asthma Education, and Outcomes
Nathan D. Shippee, PhD; Michael Finch, PhD; and Douglas R. Wholey, PhD
Patient-Reported Denials, Appeals, and Complaints: Associations With Overall Plan Ratings
Denise D. Quigley, PhD; Amelia M. Haviland, PhD; Jacob W. Dembosky, MPM; David J. Klein, MS; and Marc N. Elliott, PhD

Trends in Opioid and Nonsteroidal Anti-Inflammatory Use and Adverse Events

Veronica Fassio, PharmD; Sherrie L. Aspinall, PharmD, MSc; Xinhua Zhao, PhD; Donald R. Miller, ScD; Jasvinder A. Singh, MD, MPH; Chester B. Good, MD, MPH; and Francesca E. Cunningham, PharmD
Opioid use incidence and prevalence rates decreased with implementation of an opioid safety initiative, whereas nonsteroidal anti-inflammatory drug rates remained constant. Rates of adverse events were higher among opioid users.

Objectives: To describe the prevalence and incidence of opioid and nonsteroidal anti-inflammatory drug (NSAID) use before and since the start of the Veterans Health Administration (VHA) Opioid Safety Initiative (OSI) and to assess rates of adverse events (AEs).

Study Design: Historical cohort study.

Methods: The OSI began in August 2012 and was fully implemented by the end of fiscal year (FY) 2013. The study timeframe was categorized into baseline (FY 2011-2012), transition (FY 2013), and postimplementation (FY 2014-2015) phases. Prevalence and incidence rates were calculated for opioid and NSAID users by quarter between FY 2011 and FY 2015. For AEs among new users of an NSAID or opioid, Cox proportional hazards models with inverse probability weighting were used to adjust for potential confounding.

Results: There were 3,315,846 regular users of VHA care with at least 1 opioid and/or NSAID outpatient prescription between FYs 2011 and 2015. The quarterly opioid prevalence rate was approximately 21% during the baseline and transition phases, then decreased to 17.3% in the postimplementation phase. NSAID prevalence remained constant at about 16%. Opioid incidence rates gradually decreased (2.7% to 2.2%) during the study, whereas NSAID incidence rates remained about 2.2%. After inverse probability weighting, patients receiving opioids had a greater risk of cardiovascular events (hazard ratio [HR], 1.41; 95% CI, 1.36-1.47), acute kidney injury (HR, 2.60; 95% CI, 2.51-2.68), gastrointestinal bleeding (HR, 1.68; 95% CI, 1.56-1.81), and all-cause mortality (HR, 3.73; 95% CI, 3.60-3.87) than NSAID users.

Conclusions: Opioid use declined following implementation of the OSI, whereas NSAID use remained constant. Rates of AEs were higher among opioid users, which provides additional rationale for efforts to use NSAIDs for pain management when appropriate.

Am J Manag Care. 2018;24(3):e61-e72
Takeaway Points

The percentages of patients receiving new and continuing opioid prescriptions decreased with implementation of an opioid safety initiative (OSI), whereas the percentages of nonsteroidal anti-inflammatory drug (NSAID) users remained constant. However, patients receiving opioids had greater risks of cardiovascular events, acute kidney injury, gastrointestinal bleeding, and all-cause mortality than NSAID users.
  • Our concern was the potential for expanded NSAID use among patients at increased risk for NSAID-related adverse drug events (eg, older patients) as an unintended consequence of the OSI; it is reassuring that an increase in adverse events was not identified among incident NSAID users.
  • The results provide support for ongoing efforts to use nonopioid strategies, such as NSAIDs, for pain management as appropriate.
  • Further research is needed to examine the incidence of serious adverse outcomes, and causes of death, with opioids.
Opioid safety continues to receive widespread attention given the ongoing increase in the number of opioid-related deaths.1,2 In August 2012, the Veterans Health Administration (VHA) implemented its Opioid Safety Initiative (OSI) to improve the safe and effective use of opioids. This comprehensive initiative included implementation of a national dashboard to help providers identify patients at risk of serious adverse events (AEs) related to high-dose opioid use and practice guideline-concordant use of opioid therapy in the management of chronic pain. The OSI dashboard includes data on pharmacy patients dispensed an opioid, patients on long-term opioids who received a urine drug screen, patients who received an opioid and a benzodiazepine in the same quarter of a fiscal year (FY), and the average morphine-equivalent daily dose of opioids. In addition, the VHA National Pain Management Program Office developed an OSI Toolkit that includes advice for tapering opioids and benzodiazepines, nonpharmacologic and nonopioid treatment alternatives, consent for long-term opioid therapy, and patient educational materials.3 Given the emphasis on decreasing high-risk opioid use, prescribing of nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), may have increased after the OSI. NSAIDs have their own risks, however, including adverse cardiovascular, renal, and gastrointestinal (GI) effects.4-9 Because the VHA patient population includes a high proportion of elderly patients with multiple comorbidities, NSAID-related AEs might increase if these medications are used inappropriately either to replace an existing opioid or to avoid initiating an opioid.

Various multifaceted interventions (eg, stakeholder involvement, education, and audit and feedback) have been effective in improving the safety of opioid prescribing.10-14 However, it is unclear how these safety initiatives may affect the utilization of other analgesics, such as NSAIDs, and the subsequent rate of AEs. We examined VHA databases to describe the prevalence and incidence of opioid and NSAID use and assess the rates of adverse outcomes typically associated with NSAIDs among incident opioid and NSAID users, before and since the OSI.


Study Setting and Population

Study patients were 18 years or older and regular users of VHA care. We further identified patients with at least 1 prescription for an opioid or NSAID during the study timeframe of FY 2011 (October 1, 2010-September 30, 2011) through FY 2015. “Regular users” were defined as patients with at least 2 VHA outpatient visits and/or inpatient stays during the FY containing their index date (date of first opioid or NSAID prescription during the study period) and the prior FY. The OSI started in August 2012 and was fully implemented by the end of FY 2013; therefore, the study timeframe was categorized into baseline (FY 2011-2012), transition (FY 2013), and postimplementation (FY 2014-2015) phases (Figure 1). The study was approved by the institutional review board for the Hines/North Chicago VA Medical Centers; protected health information was used.

Data Collection and Source

To characterize patients at the index date, we obtained data from the Outpatient and Inpatient National Medical SAS datasets during the year prior to the index date for demographics, VHA care utilization, and diagnosis codes. Comorbidities were defined using the Deyo et al adaptation of the Charlson Comorbidity Index15 and included other disease states that could influence opioid or NSAID use. We linked patient zip code to Federal Information Processing Standard county code and then mapped county code to the Area Health Resource File for describing the patient’s county of residence as urban, rural, or highly rural and classifying its Census region. Outpatient opioid and NSAID use and concomitant medications at index date were obtained from the VHA Pharmacy Benefits Management (PBM) Services database (version 3.0). Adverse outcomes typically associated with NSAIDs were primarily based on International Classification of Diseases, Ninth Revision (ICD-9) codes from the National Medical SAS datasets; serum creatinine values from PBM laboratory data were also included to identify acute kidney injury (AKI). Mortality data were obtained from the Vital Status file.

Outcome Measures

Prevalence and incidence rates. Prevalence (ie, continuing users) and incidence (ie, new users) rates were individually calculated for opioids and NSAIDs (eAppendix A [eAppendices available at]) by quarter between FY 2011 and FY 2015. Quarterly-specific prevalent users were patients who had a supply of the drug(s) during the quarter of interest. Patients receiving an NSAID and opioid appeared in both groups. Quarterly-specific incident users were subsets of prevalent users with no opioids and/or NSAIDs during the year prior to the index date. The denominator was regular users of VHA care during both the FY containing the quarter of interest and the preceding FY.

Adverse outcomes. Adverse outcomes included cardiovascular events, AKI, GI bleeding requiring hospitalization or an emergency department (ED) visit, and all-cause mortality. Serious events associated with opioids (eg, overdose) were not included because the focus was on adverse outcomes commonly seen with NSAIDs. All were defined by ICD-9 diagnosis codes associated with the hospitalization or ED visit, except death, and coronary revascularization was defined by Current Procedural Terminology and ICD-9 procedure codes (eAppendix B). To improve the identification of AKI not coded during an encounter, serum creatinine lab values were used as defined by Lafrance and Miller (eAppendix B).16

Statistical Analyses

For patients who were regular VHA users with a prescription(s) for opioids or NSAIDs during the study timeframe, we described patient characteristics at the index date. Analysis of variance or χ2 tests were used to compare differences across groups. Over the 5-year timeframe, we calculated the quarterly prevalence and incidence rates of opioid and NSAID users. We computed 95% CIs for all rates, and the lower and upper bounds were the same as the point estimates to the first decimal place, given the huge sample size. Therefore, we focused on rate changes with clinical significance rather than statistical significance.

AEs were identified among incident users of opioids or NSAIDs only when the patient was receiving the medication (ie, release date of the prescription + the day-supply). Results were calculated for the entire study period, at baseline prior to implementation of the OSI (FY 2011), and after implementation (FY 2014, to ensure time for follow-up). Only incident users were included, because prevalent users were tolerating the treatment.17 Patients were followed for a maximum of 1 year after the index date and were censored when a drug from the other group was initiated (eg, on an opioid, then NSAID started) or an AE occurred, including death. The exposure time was the number of days the patient received the medication during the follow-up period, which could vary across AEs. Patients could have multiple types of AEs, but they were censored when the first event of the same outcome occurred (eg, first admission for AKI). For the aggregate outcomes of total AEs and cardiovascular events, patients were censored when the first adverse outcome of any type or first cardiovascular event occurred, respectively. In sensitivity analyses, we extended the medication exposure window to 1.25 times the day-supply of the medication or the day-supply plus 15 days, whichever was less.

In order to address factors that may confound the effect of treatment on the occurrence of an AE, we used inverse probability of treatment weighting (IPW) with normalized weights.18 Weights were estimated using a logistic regression model, with receipt of an NSAID as the dependent variable and patient demographics, VHA healthcare utilization, comorbidities, concomitant medications, and FY at index date as independent variables. We assessed the range of weights; less than 0.2% were above 20. We then conducted a sensitivity analysis with weights truncated at 20 to prevent an inflated influence of outliers. The results of this analysis were very similar, with less than a 4% change in hazard ratio (HR) estimates (data not shown). After weighting, we assessed the balance of baseline characteristics between NSAID and opioid groups using standardized difference. A standard difference of less than 0.1 was considered negligible.19 Then, we used Cox proportional hazards models to assess the association between NSAID and opioid use and AEs, with and without application of IPW. We assessed whether the proportional hazards assumption held true. Analyses were carried out using SAS version 9.4 (SAS Institute Inc; Cary, North Carolina). Statistical tests were 2-sided, with a P value <.05 considered statistically significant.


Patient Characteristics

Of the 3,315,846 opioid and/or NSAID users during the study period, 50.4% had prescriptions for opioids only at the index date; 42.3% received NSAIDs only, and 7.4% received both opioids and NSAIDs (Table 1 [part A, part B, and part C]). Both prevalent and incident opioid and NSAID users had clinically similar characteristics; therefore, their characteristics are not presented separately in Table 1.

On average, opioid-only users were older than NSAID-only users (mean age of 62 vs 56 years) (Table 1). Patients in all groups were predominantly male (92%). Compared with NSAID users, opioid-only users had a higher proportion of white patients (67% vs 60%); more utilization of VHA care; a higher Charlson Comorbidity Index score (1.5 vs 0.7); greater proportions with diagnoses of cancer, AKI, GI bleeding, and cardiovascular comorbidities; and higher percentages receiving medications that could influence the decision to prescribe an opioid or NSAID (eg, potential decrease in NSAID use among patients receiving antithrombotic therapy). NSAID users had higher proportions with behavioral health conditions. The characteristics of opioid and NSAID users did not change much between FYs 2011 and 2015 (eAppendix C).

Prevalence and Incidence Rates

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