High-dose opioid utilization and mortality among individuals initiating hemodialysis.

BACKGROUND: Individuals undergoing hemodialysis in the United States frequently report pain and receive three-fold more opioid prescriptions than the general population. While opioid use is appropriate for select patients, high-dose utilization may contribute to an increased risk of death due to possible accumulation of opioid metabolites. METHODS: We studied high-dose opioid utilization (≥120 morphine milligram equivalents [MME] per day) among adults initiating hemodialysis in the United States between 2007 and 2014 using national registry data. We calculated the cumulative incidence (%) of high-dose utilization and depicted trends in the average percentage of days individuals were exposed to opioids. We used adjusted Cox proportional hazards models to identify which opioid doses were associated with mortality. RESULTS: Among 327,344 adults undergoing hemodialysis, the cumulative incidence of high-dose utilization was 14.9% at 2 years after initiating hemodialysis. Among patients with ≥1 opioid prescription during follow-up, the average percentage of days exposed to high-dose utilization increased from 13.9% in 2007 to 26.1% in 2014. Compared to 0MME per day, doses < 60MME were not associated with an increased risk of mortality, but high-dose utilization was associated with a 1.63-fold (95% CI, 1.57, 1.69) increased risk of mortality. The risk of mortality associated with opioid dose was highest in the first year after hemodialysis initiation. CONCLUSIONS: The risk of mortality associated with opioid utilization among individuals on hemodialysis increases as doses exceed 60MME per day and is greatest during periods of high-dose utilization. Patients and clinicians should carefully weigh the risks and benefits of opioid doses exceeding 60MME per day.

Benzodiazepines, Codispensed Opioids, and Mortality among Patients Initiating Long-Term In-Center Hemodialysis.

BACKGROUND AND OBJECTIVES: Mortality from benzodiazepine/opioid interactions is a growing concern in light of the opioid epidemic. Patients on hemodialysis suffer from a high burden of physical/psychiatric conditions, which are treated with benzodiazepines, and they are three times more likely to be prescribed opioids than the general population. Therefore, we studied mortality risk associated with short- and long-acting benzodiazepines and their interaction with opioids among adults initiating hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The cohort of 69,368 adults initiating hemodialysis (January 2013 to December 2014) was assembled by linking US Renal Data System records to Medicare claims. Medicare claims were used to identify dispensed benzodiazepines and opioids. Using adjusted Cox proportional hazards models, we estimated the mortality risk associated with benzodiazepines (time varying) and tested whether the benzodiazepine-related mortality risk differed by opioid codispensing. RESULTS: Within 1 year of hemodialysis initiation, 10,854 (16%) patients were dispensed a short-acting benzodiazepine, and 3262 (5%) patients were dispensed a long-acting benzodiazepine. Among those who were dispensed a benzodiazepine during follow-up, codispensing of opioids and short-acting benzodiazepines occurred among 3819 (26%) patients, and codispensing of opioids and long-acting benzodiazepines occurred among 1238 (8%) patients. Patients with an opioid prescription were more likely to be subsequently dispensed a short-acting benzodiazepine (adjusted hazard ratio, 1.66; 95% confidence interval, 1.59 to 1.74) or a long-acting benzodiazepine (adjusted hazard ratio, 1.11; 95% confidence interval, 1.03 to 1.20). Patients dispensed a short-acting benzodiazepine were at a 1.45-fold (95% confidence interval, 1.35 to 1.56) higher mortality risk compared with those without a short-acting benzodiazepine; among those with opioid codispensing, this risk was 1.90-fold (95% confidence interval, 1.65 to 2.18; Pinteraction<0.001). In contrast, long-acting benzodiazepine dispensing was inversely associated with mortality (adjusted hazard ratio, 0.84; 95% confidence interval, 0.72 to 0.99) compared with no dispensing of long-acting benzodiazepine; there was no differential risk by opioid dispensing (Pinteraction=0.72). CONCLUSIONS: Codispensing of opioids and short-acting benzodiazepines is common among patients on dialysis, and it is associated with higher risk of death.

Determinants of Generic Drug Substitution in the United States.

BACKGROUND: Some classes of drugs have lower than optimal uptake of generic products. We aimed to understand the determinants of generic drug substitution across classes. METHODS: We conducted a cross-sectional analysis of data from the 2013 MarketScan Commercial Claims and Encounters Database from Truven Health Analytics. We quantified generic substitution rates (GSR) for 26 drug classes, choosing one representative week in November 2013. We used mixed-effects logistic regression to estimate the independent relationship between the determinants of interest and generic substitution for 8 classes with low generic utilization. RESULTS: The GSRs for most classes exceeded 90%, although some were much lower including thyroid hormones (64%), androgens (74%), estrogens (71%), and hydantoin-type anticonvulsants (72%). The determinants of generic substitution varied across classes, albeit with important patterns. Patients using a mail order pharmacy had significantly less generic substitution than patients filling at retail pharmacies for 5 of the 8 studied classes; two additional classes showed no relationship between pharmacy type and generic use. Men relative to women and patients taking more medications were more likely to use generics for most classes. State substitution laws and patient consent laws were largely inconsequential regarding generic substitution. CONCLUSIONS: Policies are needed to support the use of safe, effective and often lower cost generic drugs, when available. Mail order pharmacies, as often required by pharmacy benefits managers, lessen generic use for many classes. These pharmacies may require additional regulatory oversight if this adversely impacts patients.

Chronic Disease Medication Adherence After Initiation of Buprenorphine for Opioid Use Disorder.

BACKGROUND: Although buprenorphine is an evidence-based treatment for opioid use disorder (OUD), it is unknown whether buprenorphine use may affect patients' adherence to treatments for chronic, unrelated conditions. OBJECTIVES: To quantify the effect of buprenorphine treatment on patient adherence to 5 therapeutic classes: (1) antilipids; (2) antipsychotics; (3) antiepileptics; (4) antidiabetics; and (5) antidepressants. RESEARCH DESIGN: This was a retrospective cohort study. SUBJECTS: We started with 12,719 commercially ensured individuals with a diagnosis of OUD and the buprenorphine initiation between January 2011 and June 2015 using Truven Health's MarketScan data. Individuals using any of the 5 therapeutic classes of interest were included. MEASURES: Within the 180-day period post buprenorphine initiation, we derived 2 daily indicators: having buprenorphine and having chronic medication on hand for each therapeutic class of interest. We applied logistic regression to assess the association between these 2 daily indicators, adjusting for demographics, morbidity, and baseline adherence. RESULTS: Across the 5 therapeutic classes, the probability with a given treatment on hand was always higher on days when buprenorphine was on hand. After adjustment for demographics, morbidity, and baseline adherence, buprenorphine was associated with a greater odds of adherence to antilipids [odds ratio (OR), 1.27; 95% confidence interval (CI), 1.04-1.54], antiepileptics (OR, 1.22; CI, 1.10-1.36) and antidepressants (OR, 1.42; CI, 1.32-1.60). CONCLUSIONS: Using buprenorphine to treat OUD may increase adherence to treatments for chronic unrelated conditions, a finding of particular importance given high rates of mental illness and other comorbidities among many individuals with OUD.

Trends in Opioid Prescribing Among Hemodialysis Patients, 2007-2014.

BACKGROUND: Hemodialysis (HD) patients frequently experience pain. Previous studies of HD patients suggest increased opioid prescribing through 2010. It remains unclear if this trend continued after 2010 or declined with national trends. METHODS: Longitudinal cohort study of 484,745 HD patients in the United States Renal Data System/Medicare data. We used Poisson/negative binomial regression to estimate annual incidence rates of opioid prescribing between 2007 and 2014. We compared prescribing rates with the general US population using IQVIA's National Prescription Audit data. Outcomes included the following: percent of HD patients receiving an opioid prescription, rate of opioid prescriptions, quantity, days supply, morphine milligram equivalents (MME) dispensed per 100 person-days, and prescriptions per person. RESULTS: In 2007, 62.4% of HD patients received an opioid prescription. This increased to 63.2% in 2010 then declined to 53.7% by 2014. Opioid quantity peaked in 2011 at 73.5 pills per 100 person-days and declined to 62.6 pills per 100 person-days in 2014. MME peaked between 2010 and 2012 then declined through 2014. In 2014, MME rates were 1.8-fold higher among non-Hispanic patients and 1.6-fold higher among low-income patients. HD patients received 3.2-fold more opioid prescriptions per person compared to the general US population and were primarily prescribed oxycodone and hydrocodone. Between 2012 and 2014, HD patients experienced greater declines in opioid prescriptions per person (18.2%) compared to the general US population (7.1%). CONCLUSION: Opioid prescribing among HD patients declined between 2012 and 2014. However, HD patients continue receiving substantially more opioids than the general US population.

Dementia, Alzheimer's Disease, and Mortality after Hemodialysis Initiation.

BACKGROUND AND OBJECTIVES: Older patients with ESKD experience rapid declines in executive function after initiating hemodialysis; these impairments might lead to high rates of dementia and Alzheimer's disease in this population. We estimated incidence, risk factors, and sequelae of diagnosis with dementia and Alzheimer's disease among older patients with ESKD initiating hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied 356,668 older (age ≥66 years old) patients on hemodialysis (January 1, 2001 to December 31, 2013) from national registry data (US Renal Data System) linked to Medicare. We estimated the risk (cumulative incidence) of diagnosis of dementia and Alzheimer's disease and studied factors associated with these disorders using competing risks models to account for death, change in dialysis modality, and kidney transplant. We estimated the risk of subsequent mortality using Cox proportional hazards models. RESULTS: The 1- and 5-year risks of diagnosed dementia accounting for competing risks were 4.6% and 16% for women, respectively, and 3.7% and 13% for men, respectively. The corresponding Alzheimer's disease diagnosis risks were 0.6% and 2.6% for women, respectively, and 0.4% and 2.0% for men, respectively. The strongest independent risk factors for diagnosis of dementia and Alzheimer's disease were age ≥86 years old (dementia: hazard ratio, 2.11; 95% confidence interval, 2.04 to 2.18; Alzheimer's disease: hazard ratio, 2.11; 95% confidence interval, 1.97 to 2.25), black race (dementia: hazard ratio, 1.70; 95% confidence interval, 1.67 to 1.73; Alzheimer's disease: hazard ratio, 1.78; 95% confidence interval, 1.71 to 1.85), women (dementia: hazard ratio, 1.10; 95% confidence interval, 1.08 to 1.12; Alzheimer's disease: hazard ratio, 1.12; 95% confidence interval, 1.08 to 1.16), and institutionalization (dementia: hazard ratio, 1.36; 95% confidence interval, 1.33 to 1.39; Alzheimer's disease: hazard ratio, 1.10; 95% confidence interval, 1.05 to 1.15). Older patients on hemodialysis with a diagnosis of dementia were at 2.14-fold (95% confidence interval, 2.07 to 2.22) higher risk of subsequent mortality; those with a diagnosis of Alzheimer's disease were at 2.01-fold (95% confidence interval, 1.89 to 2.15) higher mortality risk. CONCLUSIONS: Older patients on hemodialysis are at substantial risk of diagnosis with dementia and Alzheimer's disease, and carrying these diagnoses is associated with a twofold higher mortality.

Effect of Direct-to-Consumer Advertising on Statin Use in the United States.

IMPORTANCE: The value of direct-to-consumer advertising (DTCA) of prescription drugs is widely debated, as is the effect of DTCA on prescription sales and health care utilization. OBJECTIVE: We examined the association between DTCA intensity for statin medications and prescription sales and cholesterol-related health care utilization. DESIGN, SETTING, AND PARTICIPANTS: We conducted an ecological study for 75 designated market areas from 2005 to 2009 in the United States using linked data regarding televised DTCA volume, non-DTCA marketing and promotion, retail, mail order and long-term care prescription drug sales, prescription drug and ambulatory care health care utilization, and contextual factors such as health care density and socioeconomic status. Main outcomes and measures were volume of sales, number of dispensed prescriptions, and high cholesterol-related outpatient visits. Analyses were conducted in 2016. RESULTS: The intensity of rosuvastatin and atorvastatin ad exposures per household varied substantially across designated market areas. After adjustment for socioeconomic, demographic, and clinical characteristics, each 100-unit increase in advertisement viewership was associated with a 2.22% [95% confidence interval (CI), 0.30%-4.19%] increase in statin sales. Similar patterns were observed between DTCA and statin dispensing among the commercially insured. DTCA was associated with increases in high cholesterol-related outpatient visits among adults 18-45 years of age (3.15% increase in visits per 100-unit increase in viewership, 95% CI, 0.98%-5.37%) but not among those 46-65 years of age (0.51%, 95% CI, -1.49% to 2.55%). CONCLUSION: DTCA for statins is associated with increases in statin utilization and hyperlipidemia-related outpatient visits, especially for young adults.

Patterns of Buprenorphine-Naloxone Treatment for Opioid Use Disorder in a Multistate Population.

BACKGROUND: Buprenorphine-naloxone treatment for opioid use disorder has rapidly expanded, yet little is known about treatment outcomes among patients in the general population. OBJECTIVE: To examine predictors of treatment duration, dosage, and continuity in a diverse community setting. RESEARCH DESIGN: We examined QuintilesIMS Real World Data, an all-payer, pharmacy claims database, to conduct an analysis of individuals age 18 years and above initiating buprenorphine-naloxone treatment between January 2010 and July 2012 in 11 states. We used logistic regression to assess treatment duration longer than 6 months. We used accelerated failure time models to assess risk of treatment discontinuation. We used ordinary least squares regression to assess mean daily dosage. For patients with ≥3 fills, we also used logistic regression to assess whether ;an individual had a medication possession ratio of <80% and/or gaps in treatment >14 days. Models adjusted for individual demographics, prescribing physician specialty, state, and county-level variables. RESULTS: Overall, 41% of individuals were retained in treatment for at least 6 months and the mean treatment length was 266 days. Compared with individuals who paid primarily for treatment with cash, adjusted odds of 6 month retention were significantly lower for individuals with primary payment from Medicaid fee-for-service, Medicare part D, and third-party commercial. There were substantial differences in 6-month retention across states with the lowest in Arizona and highest in New York. Low-possession ratios occurred for 30% of individuals and 26% experienced treatment episodes with gaps >14 days. Odds of low-possession and treatment gaps were largely similar across demographic groups and geographic areas. CONCLUSIONS: Current initiatives to improve access and quality of buprenorphine-naloxone treatment should examine geographic barriers as well as the potential role of insurance benefit design in restricting treatment length.

Non-buprenorphine opioid utilization among patients using buprenorphine.

BACKGROUND AND AIMS: Buprenorphine is commonly used to treat opioid use disorder; however, non-buprenorphine prescription opioid use among these patients is not well defined. We sought to estimate the prevalence of non-buprenorphine opioid use among incident buprenorphine users and quantify levels of opioid use prior to, during and after the first treatment episode. DESIGN: We used QuintilesIMS anonymized, individual-level, all-payer pharmacy claims to identify incident users of buprenorphine between January 2010 and July 2012 from a large cohort of approximately 50 million patients filling two or more prescriptions for any opioid during any calendar year between 2006 and 2013 in 11 states of interest. SETTING: Eleven states within the United States. PARTICIPANTS: Of the individuals who met our inclusion criteria (n = 38 096), 55% were female and half were aged between 29 and 54 years. Median length of the first treatment episode was 55 days [interquartile range (IQR) = 28-168 days]. MEASUREMENTS: We calculated four measures of non-buprenorphine opioid use: (1) number of prescriptions, (2) quantity dispensed, (3) days of supply and (4) total morphine milligram equivalents (MME) before, during and after the first treatment episode. Our primary outcome was the MME per opioid day supplied during each time period. FINDINGS: Approximately two-fifths (43%) of buprenorphine recipients filled an opioid prescription during the treatment episode and two-thirds (67%) filled an opioid prescription following treatment. The mean total of MME per opioid day supplied 12 months prior to treatment declined from 57 mg/per day [95% confidence interval (CI) = 57, 58] to 54 mg/per day (95% CI = 54, 55) during the treatment episode, then remained constant at 55 mg/per day (95% CI = 54, 56) following the treatment episode. CONCLUSIONS: The use of buprenorphine for the treatment of opioid use disorder has increased markedly in the United States. However, a substantial proportion of patients fill prescriptions for non-buprenorphine opioids during and following such treatment.

Effect of Prescription Drug Coupons on Statin Utilization and Expenditures: A Retrospective Cohort Study.

IMPORTANCE: Drug coupons are widely used, but their effects are not well understood. OBJECTIVE: To quantify the effect of coupons on statin use and expenditures. DESIGN: Retrospective cohort analysis of IMS Health LRx LifeLink database. SETTING: U.S. retail pharmacy transactions. PARTICIPANTS: Incident statin users who initiated branded atorvastatin or rosuvastatin between June 2006 and February 2013. MAIN OUTCOMES AND MEASURES: Monthly statin utilization (pill-days of therapy), switching (filling a different statin), termination (failure to refill statin for 6 mo), and out-of-pocket and total costs. RESULTS: Of 1.1 million incident atorvastatin and rosuvastatin users, 2% used a coupon for at least one statin fill. At 1 year, compared with noncoupon users, those who used a statin coupon on their first fill were dispensed an equal number of monthly pill-days (23.7 vs 23.8), were less likely to switch statins (14.4% vs 16.3%), and were less likely to have terminated statin therapy (31.3% vs 39.2%). At 4 years, coupon users were more likely to have switched (45.5% vs 40.8%) and less likely to have terminated statin therapy (50.6% vs 61.1%) compared with noncoupon users. Those who used greater numbers of coupons were substantially less likely to switch and terminate statin therapies. Monthly out-of-pocket costs were lower among coupon than noncoupon users at 1 year ($9.7 vs $15.1), but total monthly costs were qualitatively similar ($115.5 vs $116.9). At 4 years, monthly out-of-pocket costs among coupon users remained lower ($14.3 vs $16.6) compared with noncoupon users. Sensitivity analyses supported the main results. CONCLUSIONS: Coupons for branded statins are associated with higher utilization and lower rates of discontinuation and short-term switching to other statin products.

Impact of prescription drug monitoring programs and pill mill laws on high-risk opioid prescribers: A comparative interrupted time series analysis.

BACKGROUND: Prescription drug monitoring programs (PDMPs) and pill mill laws were implemented to reduce opioid-related injuries/deaths. We evaluated their effects on high-risk prescribers in Florida. METHODS: We used IMS Health's LRx Lifelink database between July 2010 and September 2012 to identify opioid-prescribing prescribers in Florida (intervention state, N: 38,465) and Georgia (control state, N: 18,566). The pre-intervention, intervention, and post-intervention periods were: July 2010-June 2011, July 2011-September 2011, and October 2011-September 2012. High-risk prescribers were those in the top 5th percentile of opioid volume during four consecutive calendar quarters. We applied comparative interrupted time series models to evaluate policy effects on clinical practices and monthly prescribing measures for low-risk/high-risk prescribers. RESULTS: We identified 1526 (4.0%) high-risk prescribers in Florida, accounting for 67% of total opioid volume and 40% of total opioid prescriptions. Relative to their lower-risk counterparts, they wrote sixteen times more monthly opioid prescriptions (79 vs. 5, p<0.01), and had more prescription-filling patients receiving opioids (47% vs. 19%, p<0.01). Following policy implementation, Florida's high-risk providers experienced large relative reductions in opioid patients and opioid prescriptions (-536 patients/month, 95% confidence intervals [CI] -829 to -243; -847 prescriptions/month, CI -1498 to -197), morphine equivalent dose (-0.88mg/month, CI -1.13 to -0.62), and total opioid volume (-3.88kg/month, CI -5.14 to -2.62). Low-risk providers did not experience statistically significantly relative reductions, nor did policy implementation affect the status of being high- vs. low- risk prescribers. CONCLUSIONS: High-risk prescribers are disproportionately responsive to state policies. However, opioids-prescribing remains highly concentrated among high-risk providers.

Effect of a "pill mill" law on opioid prescribing and utilization: The case of Texas.

BACKGROUND: States have attempted to reduce prescription opioid abuse through strengthening the regulation of pain management clinics; however, the effect of such measures remains unclear. We quantified the impact of Texas's September 2010 "pill mill" law on opioid prescribing and utilization. METHODS: We used the IMS Health LRx LifeLink database to examine anonymized, patient-level pharmacy claims for a closed cohort of individuals filling prescription opioids in Texas between September 2009 and August 2011. Our primary outcomes were derived at a monthly level and included: (1) average morphine equivalent dose (MED) per transaction; (2) aggregate opioid volume; (3) number of opioid prescriptions; and (4) quantity of opioid pills dispensed. We compared observed values with the counterfactual, which we estimated from pre-intervention levels and trends. RESULTS: Texas's pill mill law was associated with declines in average MED per transaction (-0.57 mg/month, 95% confidence interval [CI] -1.09, -0.057), monthly opioid volume (-9.99 kg/month, CI -12.86, -7.11), monthly number of opioid prescriptions (-12,200 prescriptions/month, CI -15,300, -9,150) and monthly quantity of opioid pills dispensed (-714,000 pills/month, CI -877,000, -550,000). These reductions reflected decreases of 8.1-24.3% across the outcomes at one year compared with the counterfactual, and they were concentrated among prescribers and patients with the highest opioid prescribing and utilization at baseline. CONCLUSIONS: Following the implementation of Texas's 2010 pill mill law, there were clinically significant reductions in opioid dose, volume, prescriptions and pills dispensed within the state, which were limited to individuals with higher levels of baseline opioid prescribing and utilization.

Effects of Televised Direct-to-Consumer Advertising for Varenicline on Prescription Dispensing in the United States, 2006-2009.

INTRODUCTION: Televised direct-to-consumer advertising (DTCA) for prescription drugs is controversial, especially for tobacco cessation products such as varenicline, given safety concerns that arose only after its market approval. We aim to quantify the extent to which DTCA influenced varenicline use. METHODS: We linked monthly DTCA television ratings with monthly prescription data from IMS Health's National Prescription Audit across top 75 media markets in 2006-2009. We used Poisson models with Generalized Estimating Equations to analyze effects of exposures to DTCA for both varenicline and nicotine replacement therapies on rate of dispensed varenicline prescriptions among smokers, controlling for population characteristics and varenicline-related events. RESULTS: Varenicline prescriptions increased dramatically following DTCA launch and declined sharply after safety risks were publicized and US Food and Drug Administration (FDA) issued an advisory. DTCA had significant impact on new prescription dispensing in the subsequent month: before the FDA advisory, one additional exposure to varenicline DTCA was associated with a 1.8% (rate ratio [RR] = 1.018 [1.015-1.021]) higher rate of new prescriptions; no effect was observed after the advisory (RR = 1.000 [0.997-1.003]). Prior to the advisory, cross-product effects of nicotine replacement therapy advertising on varenicline prescribing were negligible (RR = 1.002 [0.999-1.004]); after the advisory, effects were positive (RR = 1.015 [1.012-1.019]). CONCLUSIONS: DTCA for varenicline had a significant impact on varenicline prescribing when the drug's safety profile was not well characterized, supporting arguments to limit DTCA for newly approved products whose real-world safety is unclear. IMPLICATIONS: We examined the fluctuations in varenicline use in association with DTCA for varenicline and other tobacco cessation aids. To our knowledge this is the first study to quantify the effects of televised DTCA for varenicline and other tobacco cessation aids on varenicline prescription dispensing. We believe that understanding these relationships is critical for formulating effective public health policy and interventions.

Effect of Florida's Prescription Drug Monitoring Program and Pill Mill Laws on Opioid Prescribing and Use.

IMPORTANCE: Prescription Drug Monitoring Program (PDMP) and pill mill laws are among the principal means states use to reduce prescription drug abuse and diversion, yet little high-quality evidence exists regarding their effect. OBJECTIVE: To quantify the effect of Florida's PDMP and pill mill laws on overall and high-risk opioid prescribing and use. DESIGN, SETTING, AND PARTICIPANTS: We applied comparative interrupted time-series analyses to IMS Health LifeLink LRx data to characterize the effect of PDMP and pill mill law implementation on a closed cohort of prescribers, retail pharmacies, and patients from July 2010 through September 2012 in Florida (intervention state) compared with Georgia (control state). We conducted sensitivity analyses, including varying length of observation and modifying requirements for continuous observation of individuals throughout the study period. MAIN OUTCOMES AND MEASURES: Total opioid volume, mean morphine milligram equivalent (MME) per transaction, mean days' supply per transaction, and total number of opioid prescriptions dispensed. Analyses were conducted per prescriber and per patient, in aggregate and after stratifying by volume of baseline opioid prescribing for prescribers and use for patients. RESULTS: From July 2010 through September 2012, a cohort of 2.6 million patients, 431,890 prescribers, and 2829 pharmacies was associated with approximately 480 million prescriptions in Florida and Georgia, 7.7% of which were for opioids. Total monthly opioid volume, MME per transaction, days' supply, and prescriptions dispensed were higher in Florida than Georgia before implementation. Florida's laws were associated with statistically significant declines in opioid volume (2.5 kg/mo, P<.05; equivalent to approximately 500,000 5-mg tablets of hydrocodone bitartrate per month) and MME per transaction (0.45 mg/mo, P<.05), without any change in days' supply. Twelve months after implementation, the policies were associated with approximately a 1.4% decrease in opioid prescriptions, 2.5% decrease in opioid volume, and 5.6% decrease in MME per transaction. Reductions were limited to prescribers and patients with the highest baseline opioid prescribing and use. Sensitivity analyses, varying time windows, and enrollment criteria supported the main results. CONCLUSIONS AND RELEVANCE: Florida's PDMP and pill mill laws were associated with modest decreases in opioid prescribing and use. Decreases were greatest among prescribers and patients with the highest baseline opioid prescribing and use.

Effect of Direct-to-Consumer Advertising on Asthma Medication Sales and Healthcare Use.

RATIONALE: The United States is one of only two countries that permit direct-to-consumer advertising (DTCA) of prescription drugs, and many questions remain regarding its effects. OBJECTIVES: To quantify the association between asthma-related DTCA, pharmacy sales, and healthcare use. METHODS: This was an ecological study from 2005 through 2009 using linked data from Nielsen (DTCA television ratings), the IMS Health National Prescription Audit (pharmacy sales), and the MarketScan Commercial Claims data (healthcare use) for 75 designated market areas in the United States. We used multilevel Poisson regression to model the relationship between DTCA and rates of prescriptions and use within and across designated market areas. Main outcome measures include (1) volume of total, new, and refilled prescriptions for advertised products based on pharmacy sales; (2) prescription claims for asthma medications; and asthma-related (3) emergency department use, (4) hospitalizations, and (5) outpatient encounters among the commercially insured. MEASUREMENTS AND MAIN RESULTS: Four Food and Drug Administration-approved asthma medicines were advertised during the period examined: (1) fluticasone/salmeterol (Advair), (2) mometasone furoate (Asmanex), (3) montelukast (Singulair), and (4) budesonide/formoterol (Symbicort). After adjustment, each additional televised advertisement was associated with 2% (incident rate ratio, 1.02; 95% confidence interval, 1.01-1.03) higher pharmacy sales rate from 2005 through 2009, although this effect varied across the three consistently advertised therapies examined. Among the commercially insured, DTCA was positively and significantly associated with emergency room visits related to asthma (incident rate ratio, 1.02; 95% confidence interval, 1.01-1.04), but there was no relationship with hospitalizations or outpatient encounters. CONCLUSIONS: Among this population, DTCA was associated with higher prescription sales and asthma-related emergency department use.

National trends in the ambulatory treatment of hypertension in the United States, 1997-2012.

IMPORTANCE: Hypertension is common and costly. Over the past decade, new antihypertensive therapies have been developed, several have lost patent protection and additional evidence regarding the safety and effectiveness of these agents has accrued. OBJECTIVE: To examine trends in the use of antihypertensive therapies in the United States between 1997 and 2012. DESIGN, SETTING AND PARTICIPANTS: We used nationally representative audit data from the IMS Health National Disease and Therapeutic Index to examine the ambulatory pharmacologic treatment of hypertension. OUTCOME MEASURES: Our primary unit of analysis was a visit where hypertension was a reported diagnosis and treated with a pharmacotherapy (treatment visit). We restricted analyses to the use of six therapeutic classes of antihypertensive medications among individuals 18 years or older. RESULTS: Annual hypertension treatment visits increased from 56.9 million treatment visits (95% confidence intervals [CI], 53.9-59.8) in 1997 to 83.3 million visits (CI 79.2-87.3) in 2008, then declined steadily to 70.9 million visits (CI 66.7-75.0) by 2012. Angiotensin receptor blocker utilization increased substantially from 3% of treatment visits in 1997 to 18% by 2012, whereas calcium channel blocker use decreased from 27% to 18% of visits. Rates of diuretic and beta-blocker use remained stable and represented 24%-30% and 14-16% of visits, respectively. Use of direct renin inhibitor accounted for fewer than 2% of annual visits. The proportion of visits treated using fixed-dose combination therapies increased from 28% to 37% of visits. CONCLUSIONS: Several important changes have occurred in the landscape of antihypertensive treatment in the United States during the past decade. Despite their novel mechanism of action, the adoption rate of direct renin inhibitors remains low.

Emergency department visits by adults for psychiatric medication adverse events.

IMPORTANCE: In 2011, an estimated 26.8 million US adults used prescription medications for mental illness. OBJECTIVE: To estimate the numbers and rates of adverse drug event (ADE) emergency department (ED) visits involving psychiatric medications among US adults between January 1, 2009, and December 31, 2011. DESIGN AND SETTING: Descriptive analyses of active, nationally representative surveillance of ADE ED visits using the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance system and of drug prescribing during outpatient visits using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. PARTICIPANTS: Medical records from national probability samples of ED and outpatient visits by adults 19 years or older were reviewed and analyzed. EXPOSURES: Antidepressants, antipsychotics, lithium salts, sedatives and anxiolytics, and stimulants. MAIN OUTCOMES AND MEASURES: National estimates of ADE ED visits resulting from therapeutic psychiatric medication use and of psychiatric medication ADE ED visits per 10,000 outpatient visits at which psychiatric medications were prescribed. RESULTS: From 2009 through 2011, there were an estimated 89,094 (95% CI, 68,641-109,548) psychiatric medication ADE ED visits annually, with 19.3% (95% CI, 16.3%-22.2%) resulting in hospitalization and 49.4% (95% CI, 46.5%-52.4%) involving patients aged 19 to 44 years. Sedatives and anxiolytics, antidepressants, antipsychotics, lithium salts, and stimulants were implicated in an estimated 30,707 (95% CI, 23,406-38,008), 25,377 (95% CI, 19,051-31,704), 21,578 (95% CI, 16,599-26,557), 3620 (95% CI, 2311-4928), and 2779 (95% CI, 1764-3794) respective ADE ED visits annually. Antipsychotics and lithium salts were implicated in 11.7 (95% CI, 10.1-13.2) and 16.4 (95% CI, 13.0-19.9) ADE ED visits per 10,000 outpatient prescription visits, respectively, compared with 3.6 (95% CI, 3.2-4.1) for sedatives and anxiolytics, 2.9 (95% CI, 2.3-3.5) for stimulants, and 2.4 (95% CI, 2.1-2.7) for antidepressants. The commonly used sedative zolpidem tartrate was implicated in 11.5% (95% CI, 9.5%-13.4%) of all adult psychiatric medication ADE ED visits and in 21.0% (95% CI, 16.3%-25.7%) of visits involving adults 65 years or older, in both cases significantly more than any other psychiatric medication. CONCLUSIONS AND RELEVANCE: Psychiatric medications are implicated in many ADEs treated in US EDs. Efforts to reduce ADEs should include adults of all ages but might prioritize medications causing high numbers and rates of ED visits.

Prevalence and treatment of pain in EDs in the United States, 2000 to 2010.

OBJECTIVES: To describe changes in the prevalence and severity of pain and prescribing of non-opioid analgesics in US emergency departments (EDs) from 2000 to 2010. METHODS: Analysis of serial cross-sectional data regarding ED visits from the National Hospital Ambulatory Medical Care Survey. Visits were limited to patients ≥18 years old without malignancy. Outcome measures included annual volume of visits among adults with a primary symptom or diagnosis of pain, annual rates of patient-reported pain severity, and predictors of non-opioid receipt for non-malignant pain. RESULTS: Rates of pain remained stable, representing approximately 45% of visits from 2000 through 2010. Patients reported pain as their primary symptom twice as often as providers reported a primary pain diagnosis (40% vs 20%). The percentage of patients reporting severe pain increased from 25% (95% confidence intervals [CI] 22%-27%) in 2003 to 40% (CI 37%-42%) in 2008. From 2000 to 2010, the proportion of pain visits treated with pharmacotherapies increased from 56% (CI 53%-58%) to 71% (CI 69%-72%), although visits treated exclusively with non-opioids decreased 21% from 28% (CI 27%-30%) to 22% (CI 20%-23%). The adjusted odds of non-opioid rather than opioid receipt were greater among visits for patients 18 to 24 years old (odds ratio [OR] 1.35, CI 1.24-1.46), receiving fewer medicines (OR 2.91, CI 2.70-3.15) and those with a diagnosis of mental illness (OR 2.24, CI 1.99-2.52). CONCLUSIONS: Large increases in opioid utilization in EDs have coincided with reductions in the use of non-opioid analgesics and an unchanging prevalence of pain among patients.