Barbara K. Zedler

Risk Factors for Serious Prescription Opioid-Related Toxicity or Overdose among Veterans Health Administration Patients

OBJECTIVE Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids. DESIGN Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data. SUBJECTS Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987). METHODS Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome. RESULTS The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated. CONCLUSIONS Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids.

Does Packaging with a Calendar Feature Improve Adherence to Self-Administered Medication for Long-Term Use? A Systematic Review

BACKGROUND The therapeutic benefit of self-administered medications for long-term use is limited by an average 50% nonadherence rate. Patient forgetfulness is a common factor in unintentional nonadherence. Unit-of-use packaging that incorporates a simple day-and-date feature (calendar packaging) is designed to improve adherence by prompting patients to maintain the prescribed dosing schedule. OBJECTIVE To review systematically, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, randomized controlled trial evidence of the adherence benefits and harms of calendar blister packaging (CBP) and calendar pill organizers (CPO) for self-administered, long-term medication use. METHODS Data sources included the MEDLINE and Web of Science and Cochrane Library databases from their inception to September 2010 and communication with researchers in the field. Key search terms included blister-calendar pack, blister pack, drug packaging, medication adherence, medication compliance, medication compliance devices, medication containers, medication organizers, multicompartment compliance aid, persistence, pill-box organizers, prescription refill, randomized controlled trials, and refill compliance. Selected studies had an English-language title; a randomized controlled design; medication packaged in CBP or CPO; a requirement of solid, oral medication self-administered daily for longer than 1 month in community-dwelling adults; and at least 1 quantitative outcome measure of adherence. Two reviewers extracted data independently on study design, sample size, type of intervention and control, and outcomes. RESULTS Ten trials with a total of 1045 subjects met the inclusion criteria, and 9 also examined clinical outcomes (seizures, blood pressure, psychiatric symptoms) or health care resource utilization. Substantial heterogeneity among trials precluded meta-analysis. In 3 studies, calendar packaging was part of a multicomponent adherence intervention. Six of 10 trials reported higher adherence, but it was associated with clinically significant improvement in only 1 study: 50% decreased seizure frequency with a CPO-based, multicomponent intervention. No study reported sufficient information to examine conclusively potential harms related to calendar packaging. LIMITATIONS All trials had significant methodological limitations, such as inadequate randomization or blinding, or reported insufficient information regarding enrolled subjects and attrition, which resulted in a moderate-to-high risk of bias and, in 2 studies, unevaluable outcome data. Trials were generally short and sample sizes small, with heterogeneous adherence outcome measures. CONCLUSIONS Calendar packaging, especially in combination with education and reminder strategies, may improve medication adherence. Methodological limitations preclude definitive conclusions about the effect size of adherence and clinical benefits or harms associated with CBP and CPO. High-quality trials of adequate size and duration are needed to assess the clinical effectiveness of such interventions.

Short‐Term Clinical Exposure Evaluation of a Second‐Generation Electrically Heated Cigarette Smoking System

This randomized, controlled, forced‐switching, open‐label, parallel‐group study in 100 adult male and female smokers of conventional cigarettes evaluated 8 biomarkers of tobacco smoke exposure. After baseline exposure determinations, adult smokers were switched to a second‐generation electrically heated cigarette smoking system (EHCSS) for 8 days in a clinical setting. After 8 days of smoking the EHCSS biomarkers of exposure decreased by 43% to 85% compared to baseline. After correction for residual effects (carryover effects due to long elimination half‐life and non‐tobacco‐confounding sources of exposure), reductions in exposure ranged from 59% to 97%. Results from this short‐term clinical exposure study indicate that switching from a conventional cigarette to a second‐generation electrically heated cigarette smoking system substantially reduced the exposure to several measured potentially harmful constituents of tobacco smoke.

Buprenorphine compared with methadone to treat pregnant women with opioid use disorder: a systematic review and meta-analysis of safety in the mother, fetus and child.

Abstract Aims To assess the safety of buprenorphine compared with methadone to treat pregnant women with opioid use disorder. Methods We searched PubMed, Embase and the Cochrane Library from inception to February 2015 for randomized controlled trials (RCT) and observational cohort studies (OBS) that compared buprenorphine with methadone for treating opioid‐dependent pregnant women. Two reviewers assessed independently the titles and abstracts of all search results and full texts of potentially eligible studies reporting original data for maternal/fetal/infant death, preterm birth, fetal growth outcomes, fetal/congenital anomalies, fetal/child neurodevelopment and/or maternal adverse events. We ascertained each studys risk of bias using validated instruments and assessed the strength of evidence for each outcome using established methods. We computed effect sizes using random‐effects models for each outcome with two or more studies. Results Three RCTs (n = 223) and 15 cohort OBSs (n = 1923) met inclusion criteria. In meta‐analyses using unadjusted data and methadone as comparator, buprenorphine was associated with lower risk of preterm birth [RCT risk ratio (RR) = 0.40, 95% confidence interval (CI) = 0.18, 0.91; OBS RR = 0.67, 95% CI = 0.50, 0.90], greater birth weight [RCT weighted mean difference (WMD) = 277 g, 95% CI = 104, 450; OBS WMD = 265 g, 95% CI = 196, 335] and larger head circumference [RCT WMD = 0.90 cm, 95% CI = 0.14, 1.66; OBS WMD = 0.68 cm, 95% CI = 0.41, 0.94]. No treatment differences were observed for spontaneous fetal death, fetal/congenital anomalies and other fetal growth measures, although the power to detect such differences may be inadequate due to small sample sizes. Conclusions Moderately strong evidence indicates lower risk of preterm birth, greater birth weight and larger head circumference with buprenorphine treatment of maternal opioid use disorder during pregnancy compared with methadone treatment, and no greater harms.

A 12‐Month, Randomized, Controlled Study to Evaluate Exposure and Cardiovascular Risk Factors in Adult Smokers Switching From Conventional Cigarettes to a Second‐Generation Electrically Heated Cigarette Smoking System

This randomized, controlled, forced‐switching, open‐label, parallel‐group study in 97 adult male and female smokers of conventional cigarettes evaluated biomarkers of tobacco smoke exposure and cardiovascular risk factors. After baseline measurements, smokers were either switched to a second‐generation electrically heated cigarette smoking system (EHCSS) or continued smoking conventional cigarettes for 12 months. Biomarkers of exposure and cardiovascular risk factors were measured at 0.5, 1, 2, 3, 4, 5, 6, 9, and 12 months. There was a rapid and sustained reduction in all biomarkers of exposure after switching to the EHCSS, with statistically significant reductions from baseline in nicotine equivalents (−18%), plasma cotinine (−16%), total 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol (−73%), total 1‐hydroxypyrene (−53%), urine mutagenicity (−52%), 4‐aminobiphenyl hemoglobin adducts (−43%), carboxyhemoglobin AUC7–23 h (−80%), and 3‐hydroxypropylmercapturic acid (−35%). These reductions in exposure in the EHCSS group were associated with statistically significant and pathophysiologically favorable changes in several cardiovascular risk factors, including white blood cell count (−0.78 × 103/μL), hemoglobin (−0.16 g/dL), hematocrit (−0.44%), urine 11‐dehydrothromboxane B2 (−374 ng/24 h), and high‐density lipoprotein cholesterol (+5 mg/dL).

Development of a Risk Index for Serious Prescription Opioid‐Induced Respiratory Depression or Overdose in Veterans’ Health Administration Patients

Abstract Objective Develop a risk index to estimate the likelihood of life‐threatening respiratory depression or overdose among medical users of prescription opioids. Subjects, Design, and Methods A case‐control analysis of administrative health care data from the Veterans’ Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid‐induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. Results Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The models C‐statistic was 0.88 and Hosmer–Lemeshow goodness‐of‐fit statistic 10.8 (P > 0.05). Conclusion RIOSORD performed well in identifying medical users of prescription opioids within the Veterans’ Health Administration at elevated risk of overdose or life‐threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated.

A pharmacoepidemiologic analysis of the impact of calendar packaging on adherence to self-administered medications for long-term use.

BACKGROUND Calendar blister packaging (CBP) that incorporates a day or date feature is a simple medication packaging technology that is designed to improve medication adherence and persistence. OBJECTIVE This study was conducted to assess the effect of a new calendar packaging technology on prescription refill adherence and persistence for daily, self-administered, long-term medication use. METHODS Anonymized pharmacy dispensing data from a large US mass merchandiser were analyzed. This retrospective cohort study included people aged 18 to 75 years who filled prescriptions for oral lisinopril or enalapril (control group) at a study pharmacy during 1 year before and after the switch of lisinopril packaging from vials to CBP. Cohorts were stratified into new and prevalent medication users. We used linear and logistic regression modeling and propensity score matching to assess the impact of CBP on refill adherence, using medication possession ratio (MPR) and proportion of days covered (PDC), and persistence using length of therapy (LOT). RESULTS Our sample comprised 76,321 new users and 249,040 prevalent users. Across all user, medication, and packaging groups, the mean unadjusted LOT decreased in the follow-up year, possibly due to economic recession. The LOT decline was attenuated in the CBP cohort. After adjustment for covariates, CBP use in new and prevalent medication users was associated with significantly higher LOT and PDC but not MPR. The odds of achieving PDC ≥80% were higher by 15% in new users (odds ratio [OR] = 1.15; 95% CI, 1.09-1.21) and 12% in prevalent users (OR = 1.12; 95% CI, 1.09-1.15) who switched to CBP, compared with continued vial use. CONCLUSIONS CBP of medication prescribed for daily, self-administered, long-term use was associated with modest improvement in prescription refill adherence and persistence. An adherence strategy of even small effect size that is broadly implemented on a population level could significantly leverage therapeutic effect and provide substantial cumulative public health benefit. Clinical benefit, or harm, associated with use of CBP should be investigated. Usability assessments of CBP in patient subgroups may provide insight about differential impact on adherence and persistence.

Environmental tobacco smoke (ETS) evaluation of a third-generation electrically heated cigarette smoking system (EHCSS)

This sub-study of a randomized, controlled, forced-switching, open-label, parallel-group, clinical study compared environmental tobacco smoke (ETS) produced when 60 male and female adult smokers switched to a third-generation electrically heated cigarette smoking system (EHCSS), continued to smoke a conventional cigarette (CC), or stopped smoking (No-smoking). Concentrations of air constituents including respirable suspended particulate (RSP), carbon monoxide (CO), ammonia and total volatile organic compounds (TVOCs) and ETS markers including solanesol-related particulate matter (Sol-PM), ultraviolet absorbing particulate matter (UVPM), fluorescent particulate matter (FPM), nicotine and 3-ethenyl pyridine (3-EP) were measured in a ventilated, furnished conference room over a 2-h period on separate occasions for each smoking condition. When the EHCSS was used, concentrations of CO and most ETS markers were in the same range as during no-smoking. Concentrations of ammonia were reduced by 41% and concentrations of other selected constituents of ETS were reduced by 87-99% in the air of a room in which EHCSS cigarettes were smoked as compared to concentrations in the same room when conventional cigarettes were smoked. Switching from conventional cigarette smoking to the EHCSS resulted in substantial reductions in concentrations of several markers of environmental tobacco smoke.

Validation of a Screening Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in a US Commercial Health Plan Claims Database

Abstract Objective To validate a risk index that estimates the likelihood of overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids. Subjects and Methods A case-control analysis of 18,365,497 patients with an opioid prescription from 2009 to 2013 in the IMS PharMetrics Plus commercially insured health plan claims database (CIP). An OIRD event occurred in 7,234 cases. Four controls were selected per case. Validity of the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD), developed previously using Veterans Health Administration (VHA) patient data, was assessed. Multivariable logistic regression was used within the CIP study population to develop a slightly refined RIOSORD. The composition and performance of the CIP-based RIOSORD was evaluated and compared with VHA-based RIOSORD. Results VHA-RIOSORD performed well in discriminating OIRD events in CIP (C-statistic = 0.85). Additionally, re-estimation of logistic model coefficients in CIP yielded a 0.90 C-statistic. The resulting comorbidity and pharmacotherapy variables most highly associated with OIRD and retained in the CIP-RIOSORD were largely concordant with VHA-RIOSORD. These variables included neuropsychiatric and cardiopulmonary disorders, impaired drug excretion, opioid characteristics, and concurrent psychoactive medications. The average predicted probability of OIRD ranged from 2% to 83%, with excellent agreement between predicted and observed incidence across risk classes. Conclusions RIOSORD had excellent predictive accuracy in a large population of US medical users of prescription opioids, similar to its performance in VHA. This practical risk index is designed to support clinical decision-making for safer opioid prescribing, and its clinical utility should be evaluated prospectively.

A Swedish Population-based Study of Adverse Birth Outcomes among Pregnant Women Treated with Buprenorphine or Methadone: Preliminary Findings

Background Untreated opioid dependence in pregnant women is associated with adverse birth outcomes. Buprenorphine and methadone are options for opioid agonist medication-assisted treatment during pregnancy. Objective The aim of this study was to describe adverse birth outcomes observed with buprenorphine or methadone treatment compared to the general population in Sweden. Methods Pregnant women and their corresponding births during 2005–2011 were identified in the Swedish Medical Birth Register. Data on stillbirth, neonatal/infant death, mode of delivery, gestational age at birth, Apgar score, growth outcomes, neonatal abstinence syndrome, and congenital malformations were examined. Frequencies were compared using two-sided Fishers exact tests. Unadjusted estimates of birth outcomes for women treated with buprenorphine or methadone were compared to the registered general population. Results A total of 746,257 pregnancies among 538,178 unique women resulted in 746,485 live births. Among the 194 women treated with buprenorphine (N = 176) or methadone (N = 52), no stillbirths or neonatal/infant deaths occurred. Neonatal abstinence syndrome developed in 23.3% and 38.5% of infants born to mothers treated with buprenorphine and methadone, respectively. The frequency of the selected adverse birth outcomes assessed in women treated with buprenorphine as compared to the general population was not significantly different. However, a significantly higher frequency of preterm birth and congenital malformations was observed in women treated with methadone as compared to the general population. Compared with the general population, methadone-treated women were significantly older than buprenorphine-treated women, and both treatment groups began prenatal care later, were more likely to smoke cigarettes, and did not cohabitate with the babys father. Conclusions An increased frequency of the selected adverse birth outcomes was not observed with buprenorphine treatment during pregnancy. Twofold increased frequency of preterm birth [2.21 (1.11, 4,41)] and congenital malformations [2.05 (1.08, 3.87)] was observed in the methadone group, which may be partly explained by older average maternal age and differences in other measured and unmeasured confounders.