Validity and performance of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) among advanced urothelial cancer patients.

PURPOSE: The recent increase in emerging novel therapies in the bladder cancer therapeutic area has increased the need for fit-for-purpose patient-reported outcome (PRO) measures for these patients. This study evaluates the psychometric properties of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) in 182 patients with advanced urothelial cancer (UC) and fills an important gap by demonstrating its validity for use in clinical trials. METHODS: Data were collected as part of a multicentre, open-label study of durvalumab in patients with inoperable or metastatic solid tumours. Psychometric properties evaluated include item and subscale characteristics (including correlation analysis), reliability (estimated using Cronbach's α), validity (by independent sample t test), responsiveness (using mixed models with repeated measures), and clinically meaningful changes using both anchor-based and distribution-based methods. RESULTS: One hundred and seventy-two patients completed the FACT-Bl questionnaire at baseline. Many individual items had floor or ceiling effects indicative of minimal symptoms and high functioning. The psychometric properties of the existing established scales were assessed and found to range from acceptable to very good. Internal consistency (most Cronbach's α coefficients range 0.66-0.85) and stability (test-retest reliability) generally exceeded standards for good reliability (most estimated intraclass correlations [ICCs] exceeded 0.70, although ICCs for some items [e.g. emotional well-being, ICC 0.58; social well-being, ICC 0.66] were lower than 0.70). Evidence for known-group validity of relevant FACT-Bl subscales and total score was demonstrated by significant differences between groups defined by baseline tumour burden and quality of life scores (difference of FACT-Bl total between low/high tumour burden groups 11.72 (p = 0.001); difference between low/high QoL scores groups 30.51 (p < 0.0001)). The FACT-Bl subscale and total scores were responsive to changes in bladder cancer symptom severity. Clinically meaningful changes in FACT-Bl scores were estimated. CONCLUSIONS: Results support the use of the FACT-Bl within this patient population in future clinical research.

Psychometric Properties of the Problem Solving Inventory in Caregivers of Individuals With Memory Loss.

Limited research exists assessing problem-solving capabilities among caregivers of individuals with memory loss using a validated instrument. To address this gap, the current study evaluated the psychometric properties of the Problem Solving Inventory (PSI) using data at baseline and 8 weeks from a randomized controlled trial among caregivers (N = 78) of community-dwelling individuals with memory loss. Participants were mainly White (85.9%), female (71.8%), and on average age 66.5. Cronbach's alphas ranged from 0.84 to 0.92 for the subscales and overall PSI. Test-retest reliability over 8 weeks ranged from 0.44 to 0.56. Five factors were retained through exploratory factor analysis. Spearman's correlations showed convergent validity and discriminant validity between scores on the PSI and Beck Depression Inventory®-II (r = 0.32, p < 0.01), the Self-Efficacy for Managing Chronic Disease Scale (r = -0.44, p < 0.001), and the Newest Vital Sign questionnaire (r = -0.07, p > 0.05). Findings show that the PSI is reliable and valid in assessing problem-solving capabilities among caregivers of individuals with memory loss. [Journal of Gerontological Nursing, 44(6), 25-32.].

Predictors of medication adherence: fact or artifact.

Numerous studies have examined socio-demographic, psychosocial, and other factors as potential contributors to poor adherence. Variability exists in the strength and consistency of findings. We speculated that the method of measuring adherence might be a factor in the variability in identification of predictor variables. We examined the identification of predictors of adherence by method of measurement in two randomized, controlled trials of adherence interventions. Both studies used the Aardex Medication Event Monitor and the Morisky Self-Report Scale. Twenty-one days of baseline data from 698 subjects were examined in relation to measures of depression, functional status, perceived therapeutic efficacy, number of co-morbidities, and socio-demographic indices. Analysis included Spearman rho, Pearson r, and multiple logistic regression. Differences in the identification of predictors between adherence measurement methods were identified. These data support the hypothesis that different measurement methods yield different predictors of adherence.

An acetaminophen icon helps reduce medication decision errors in an experimental setting.

OBJECTIVES: To assess the effect of adding an acetaminophen ingredient icon to acetaminophen medication labels on consumer decision making about concomitant use of acetaminophen medications to avoid overdose, which is associated with liver injury. DESIGN: Parallel-group randomized study. SETTING: Consumer research facilities in Indianapolis, Baltimore, and Los Angeles. PARTICIPANTS: A total of 517 adults (30% with limited health literacy) recruited at 3 consumer research sites. INTERVENTION: Participants were randomized to a non-icon condition in which medications carried current labeling or an icon condition in which all acetaminophen medications were additionally marked with an icon. MAIN OUTCOME MEASURES: Participants were presented with a medicine cabinet containing 12 diverse prescription and non-prescription medications, one-half containing acetaminophen, and made decisions about which medications were appropriate to take after an acetaminophen medication had already been taken. Outcome measures were errors in medication decisions and response time. RESULTS: The icon reduced the odds of participants making medication-decision errors by 53% (CI 31%-68%), with effects evident across medication categories. The icon eliminated a trend for those with lower health literacy or less education to have a greater likelihood of making errors. The icon also reduced response times, indicating reduced cognitive load for decisions. CONCLUSION: An icon can improve decision making regarding acetaminophen-containing medications, particularly among individuals with limited health literacy or education.

Patterns of acetaminophen medication use associated with exceeding the recommended maximum daily dose.

BACKGROUND: Acetaminophen overuse has been linked to liver injury. PURPOSE: To identify patterns of medication use associated with exceeding the recommended daily maximum dose of 4 g acetaminophen. METHODS: Respondents from a national panel completed a detailed daily medication diary online for 7 days (n = 5649), identifying medications taken from a comprehensive list of over-the-counter (OTC) and prescription (Rx) acetaminophen medications. Respondents were not told the study concerned acetaminophen. Total daily intake was calculated from diary data. Generalized estimating equations assessed the association of medication patterns with exceeding 4 g per day among 3618 respondents who used acetaminophen medications (on 13,852 days) during the diary period. RESULTS: Acetaminophen intake exceeded 4 g on 3.1% of usage days; median intake on those days was 5.5 g. As expected, days when intake exceeded 4 g were almost always (92%) marked by deviations from label directions-exceeding the one-time dose, re-dosing too soon, and concomitant use of multiple acetaminophen medications. Re-dosing too soon was the most frequent deviation, and concomitant use was most strongly tied to exceeding the daily limit. Use of both an Rx and an OTC medication on the same day also increased the odds of exceeding 4 g on days when concomitant use occurred. CONCLUSIONS: Excess dosing of acetaminophen is associated with deviations from label directions and by use of both OTC and Rx medications containing acetaminophen within a single concomitant use day.

Assigning dose of nicotine gum by time to first cigarette.

INTRODUCTION: Nicotine gum, a proven effective aid to cessation, comes in two doses: 2-mg and 4-mg. Assignment to the higher dose has traditionally been based on daily cigarette consumption. This paper evaluates efficacy of the gum when the 4-mg dose is assigned based on time to first cigarette (TTFC) being ≤ 30 min. METHODS: In a secondary analysis of a randomized, double-blind, placebo-controlled trial that allocated smokers randomly to placebo, 2-mg, or 4-mg gum (Garvey, A. J., Kinnunen, T., Nordstrom, B. L., Utman, C. H., Doherty, K., Rosner, B., et al. (2000). Effects of nicotine gum dose by level of nicotine dependence. Nicotine & Tobacco Research, 2, 53-63. doi:10.1080/14622200050011303), we evaluated outcomes when 4-mg gum was given to subjects with TTFC ≤ 30 (n = 158, placebo n = 159). RESULTS: Active treatment doubled or tripled abstinence rates versus placebo. This also held among smokers with a history of treatment failure. The effect of 4-mg gum was significant among light smokers (<25 CPD) with TTFC ≤ 30; 2-mg gum was not. CONCLUSION: This analysis suggests that assigning dose of nicotine gum based on TTFC is an effective and appropriate means of dose allocation.

Prevalence and correlates of exceeding the labeled maximum dose of acetaminophen among adults in a U.S.-based internet survey.

PURPOSE: Acetaminophen is a commonly used analgesic; excessive doses can lead to liver damage. We sought to determine the proportion of acetaminophen users exceeding the recommended maximum daily dose of 4 g and identify correlates of such behavior. METHODS: U.S. adults were recruited from an internet panel in summer 2010, oversampling past 30-day acetaminophen users. Among 47 738 starting the study, 5649 completed all phases; individuals with low education were underrepresented. Subjects completed a 7-day daily diary online, reporting intake of acetaminophen products selected from a comprehensive list; total daily dose was computed from product names. An exit survey elicited: attitudes/knowledge related to product ingredients, label reading, dosing behavior; demographics, medical history, general physical, and mental health status. Unconditional logistic regression identified variables independently associated with use exceeding 4 g. RESULTS: Among 3618 acetaminophen users, 163 took >4 g on ≥1 day (4.5%); the median dose was 5.5 g; 26 took >8 g (0.7%). >4-g users were characterized by chronic pain, poor physical status, and heavy use of medical care. Knowledge of ingredients and recommended OTC doses for all products taken was inversely associated with >4-g use (multivariable odds ratios [ORs] = 0.5-0.6), as was the attitude to start with the lowest dose (OR = 0.6). The attitude that users could choose their own dose was positively associated (OR = 1.3). CONCLUSIONS: The results estimate the proportion of acetaminophen users exceeding 4 g in a group of U.S. adults, identify potentially modifiable attitudes and knowledge associated with such use, and characterize subpopulations at higher risk.

Consumer understanding of prescription drug information: an illustration using an antidepressant medication.

BACKGROUND: Patient education and warnings have emerged as prominent interventions for improving drug safety. As part of the provision of information and guidance on safe use of drugs, patients often receive multiple pieces of written information when they obtain a prescription medication, including a Food and Drug Administration (FDA)-mandated medication guide (MG), consumer medication information (CMI), and patient package insert (PPI). OBJECTIVE: To determine whether patients understand the materials providing drug information and whether the materials convey the intended information. METHODS: Fifty-two adults with a high school education or less were shown an actual (blinded) MG, CMI, and PPI for a marketed antidepressant medication. Comprehension was tested with methods used by the FDA to assess label comprehension for nonprescription products. RESULTS: The majority of participants (88.2%) looked at all 3 pieces of information provided. The mean (SD) time spent reviewing the CMI was 5.2 (4.8) minutes (range 0-21.9), 16.5 (13.3) minutes for the PPI (range 0-43.0), and 2.5 (1.6) minutes for the MG (range 0-7.6). Less than 20% of participants were able to identify the symptoms of a rare but potentially life-threatening situation that can occur with this medication and only 61.5% recalled the risk of teen suicide, which is the sole focus of the MG. Respondents with lower literacy scores performed more poorly than those with higher literacy scores. CONCLUSIONS: Information provided with at least some prescription drugs is not adequately understood by less-educated consumers and does not effectively communicate critical safety messages or directions.

Self-reported weight loss practices among African American and Hispanic adults in the United States.

OBJECTIVE: To describe weight loss methods used and interactions with health care professionals on the issue of weight among African Americans and Hispanics. METHODS: Five hundred thirty-seven African American and 526 Hispanic adults who self-described as being overweight participated in a telephone interview. RESULTS: Exercise and healthy eating were the 2 most commonly used weight loss methods among both groups; prescription medications were the least-utilized weight loss aid. Forty-one percent of African Americans and 35% of Hispanics reported having been advised to lose weight by a health care professional. CONCLUSIONS: Do-it-yourself approaches to weight loss predominate among African Americans and Hispanics; formal assistance is rarely used. Physician advice on weight loss is suboptimal.

Psychometric Properties of the Patient Assessment of Own Functioning Inventory Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the psychometric properties of the Patient Assessment of Own Functioning Inventory (PAOFI) following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The PAOFI was completed by 182 participants 3 months after verified aSAH. Exploratory factor analysis was used to evaluate the underlying factor structure of the PAOFI and reliability and concurrent validity were evaluated for each subscale. RESULTS: A three-factor structure accounted for 58.9% of the extracted variance. Cronbach's alpha coefficients for extracted factors ranged from .867 to .924. The PAOFI subscales demonstrated concurrent validity with neuropsychological tests measuring similar constructs. CONCLUSION: There is evidence of reliability and validity of the PAOFI following aSAH. Further studies are needed to confirm these results.

Rapid absorption of nicotine from new nicotine gum formulations.

RATIONALE: A clinically limiting feature of currently-available nicotine gum is its slow rate of nicotine delivery and consequently slow onset of therapeutic effects. Previous research suggested that a nicotine hydrogen tartrate gum (NHTG1) that delivered nicotine more rapidly provided more effective craving relief. A subsequent gum formulation (NTHG2) was developed to further increase speed of delivery. OBJECTIVE: Compare the plasma nicotine absorption and clinical tolerability of NHTG2 to NHTG1 and Nicorette FreshMint. METHODS: A single-dose, randomized, crossover study evaluated the early kinetics of nicotine absorption and tolerability of 4 mg NHTG2 compared to NHTG1 and Nicorette. RESULTS: NHTG2 gum reached higher Cmax (p=0.059 versus Nicorette; p=0.006 versus NHTG1) and delivered significantly more nicotine than Nicorette or NHTG1 within the first 10-30 min of chewing (AUCs0-10, 0-30) and overall (AUC0-180). NHT gums and Nicorette were well tolerated, with little difference in their AE profiles. CONCLUSIONS: Study results indicate that NHTG2 gum provided more rapid uptake of nicotine in blood without notable decreases in tolerability. To the extent that rate of delivery and onset of therapeutic effects are related, these gums would be expected to provide more rapid therapeutic effects.

Psychometric Evaluation of the Barriers to Healthy Eating Scale: Results from Four Independent Weight Loss Studies.

OBJECTIVE: The purpose of this study was to evaluate the psychometric properties of the 22-item Barriers to Healthy Eating (BHE) scale in four independent weight loss studies conducted over 13 years. METHODS: Principal axis factoring with promax rotation was performed to reveal the underlying factor structure. Internal consistency was assessed using Cronbach α, and convergent validity was assessed by correlating the baseline BHE with the Weight Efficacy Lifestyle questionnaire total and subscale scores. Predictive validity was examined by the association of BHE change with weight loss over 6 months. RESULTS: The four studies had similar gender (82.9%-89.9% female) and race (70.5%-81.4% white) distributions. Factor analyses suggested removal of two items and a three-factor structure: self-control and motivation (10 items), daily mechanics (7 items), and social support (3 items). The Cronbach α for the 20-item BHE ranged from 0.849 to 0.881 across the four studies. The BHE and Weight Efficacy Lifestyle questionnaire total and subscale scores were all negatively correlated with each other, showing good convergent validity (r = 0.120-0.544, P < 0.05). BHE change was associated with weight loss from 0 to 6 months (r = 0.282-0.450, P < 0.05). CONCLUSIONS: The BHE scale showed very good psychometric properties over time, supporting its use in measuring barriers to one's ability to adopt or maintain a healthy eating plan.

Use of nicotine replacement therapy among never smokers in the 1999-2006 National Health and Nutrition Examination Surveys.

Nicotine replacement therapies (NRT) have been available without a prescription in the United States since 1996. Given that nicotine, at least as it is delivered through tobacco products, is addictive, we examined whether NRT was being used by individuals who have never smoked cigarettes. Adults (n=18,986) and adolescents (n=9187) who participated in the in-home survey and physical examination components of the 1999-2006 National Health and Nutrition Examination Surveys were assessed for cigarette smoking status, other tobacco use or exposure, and use of NRT. Among the 8415 adults (ages 20 and older) who reported never having smoked 100 cigarettes and who provided a blood sample during their physical exam, 3 (0.08%; 95% CI=0.02-0.28%) reported using NRT within the 5 days prior to being examined. Among the 5510 adolescents (aged 12-19 years) who reported never smoking and who provided a blood sample, 5 (0.12%; 95% CI=0.04%-0.36%) reported using NRT. Analyses of cotinine (a metabolite of nicotine) from their blood samples, along with analysis of their other survey responses regarding additional nicotine exposures suggest that it is unlikely that any of the adults were never smokers using NRT and perhaps 2 adolescents may have been never smokers who used NRT. Based on these assessments, the re-estimated prevalence of NRT use by never smokers would be 0% among adults and 0.05% (95% CI=0.01-0.27%) among adolescents.

Psychometric Properties of the Simons Simplex Collection Sleep Interview.

BACKGROUND AND PURPOSE: An estimated 40%-80% of children with autism spectrum disorders (ASD) have sleep problems. The Simons Simplex Collection Sleep Interview (SSCSI) is a parent-report questionnaire assessing bedtime and nighttime sleep problems and daytime function. The present study evaluated the factorial model of the SSCSI that best characterizes children aged 4-18 years with ASD. METHODS: Exploratory factor analysis was performed using principal component analysis and promax rotation, beginning with 16 items and ending with 10 items. RESULTS: Exploratory factor analysis concluded with ten dichotomous items, plus ageand regular sleep duration, in three factors: nighttime problems, daytime problems, andsleep duration problems. The analysis was performed on the full sample, and onprepubertal (4-8-years), pubertal (9-13-years), and postpubertal (14-18-years) subgroups. CONCLUSION: Further refinement, including confirmatory factor analysis, test-retest reliability, and convergent validity testing, is needed.

Psychometric Evaluation of the Relapse Situation Efficacy Questionnaire in a Weight Loss Treatment Study.

Objectives We assessed the psychometric properties of the Relapse Situation Efficacy Questionnaire - Weight (RSEQ-W) including internal consistency reliability, criterion-related validity (concurrent and predictive validity) and construct validity (convergent validity and factor analysis). Methods We administered the RSEQ-W at baseline, and at 6 and 12 months in a 12-month prospective behavioral weight loss study. Spearman correlations were used to examine the convergent and concurrent validity; multivariate linear regression was used to assess the predictive validity; exploratory factor analysis was conducted using principal component analysis. Results The sample (N = 148) was 90.5% women and 81.1% white with a mean body mass index of 34.1 ± 4.6 kg/m2. The RSEQ-W showed good internal consistency (Cronbach's α = .95) and convergent validity (r = .69). PCA results revealed that the 31 items can be factored into 6 components negative affect, positive affect, social occasions, low focus, activity andlack of energy. Conclusion These results provide preliminary support for the reliability and validity of the RSEQ-W. Future work needs to apply RSEQ-W in studies with larger and more diverse samples and also consider adding more items to the factor lack of energy.

Smokers' preferences for medicinal nicotine vs smokeless tobacco.

OBJECTIVE: To assess and compare smokers' interest in medicinal nicotine (MN) and smokeless tobacco (SLT) and preference between them. METHODS: Two studies presented US smokers verbally with MN and SLT concepts and assessed their appeal as smoking substitutes. Both studies evaluated interest and preference between products, with attention to the hypothesis that SLT is preferred over MN. RESULTS: Study 1 described well-known MN and SLT products. Fifty-nine percent preferred MN and 22% SLT. Study 2 presented less familiar MN and SLT products. Forty-four percent preferred MN and 35% SLT. CONCLUSIONS: The data show that MN products, as presented to smokers in this study, are perceived to be more appealing to smokers.

Tobacco cessation and weight loss: trends in media coverage.

OBJECTIVE: To examine time trends in amount of media coverage on tobacco cessation versus weight loss and test whether the 2 topics compete for limited media attention. METHODS: Monthly print and broadcast media coverage from 1995 to 2003 was estimated. RESULTS: Tobacco and weight coverage were uncorrelated. Tobacco coverage peaked in 1997-98, whereas coverage of weight increased linearly between 1995 and 2003. CONCLUSION: Tobacco and weight topics do not appear to compete for media coverage. Interest in weight topics is rising, consistent with its growing public health importance. Coverage of tobacco is declining, suggesting a need to keep tobacco and cessation in the public eye.

Successful treatment with a nicotine lozenge of smokers with prior failure in pharmacological therapy.

AIMS: To assess the influence of unsuccessful past quit attempts using pharmacological treatment on smoking cessation when using a new nicotine lozenge. DESIGN: A double-blind, randomized, placebo-controlled trial. SETTING: Fifteen sites in the United Kingdom and the United States. PARTICIPANTS: A total of 1818 smokers seeking smoking cessation treatment; 1145 had had previous pharmacological treatment for smoking cessation. INTERVENTION: Lozenge, 2 mg or 4 mg (or matched placebo); a higher dose was assigned to smokers who smoked their first cigarette of the day within 30 minutes, a sign of dependence. Smokers received minimal instruction and counseling. MEASUREMENT: Outcome was 28-day, CO-verified continuous abstinence at 6 weeks. Past use of medications was ascertained by self-report. FINDINGS: Lozenge was efficacious among smokers with prior pharmacotherapy as well as among those without such history. The effect of lozenge (versus placebo) was significantly greater among those with previous treatment experience, because previous treatment was associated with significantly poorer outcome on placebo, and active lozenge treatment corrected this imbalance. Lozenge efficacy was similar whether smokers had previously tried patch or acute forms of nicotine replacement therapy (gum, inhaler and spray), and also similar for past use of Zyban (bupriopion). CONCLUSIONS: Smokers with a history of past failure of pharmacological treatment have lower success rates without pharmacological treatment, but equally good outcomes with active lozenge treatment. Smokers who previously tried pharmacological treatments but resumed smoking should be encouraged to try quitting again with the new nicotine lozenge.

Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions.

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) Tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple-drug-induced deaths compared to single (OXC only)-drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple-drug-induced deaths, OxyContin identified, 0.93 microg/mL (N = 167); multiple-drug-induced deaths, OxyContin not identified, 0.73 microg/mL (N = 579); single (OXC)-drug-induced deaths, OxyContin identified, 1.55 microg/mL (N = 12); and single (OXC)-drug-induced deaths, OxyContin not identified, 1.70 microg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC)-drug-induced, drug-abuse deaths > multiple-drug-induced drug-abuse deaths > drug-related drug-abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple-drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple-drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 microg/mL (N = 90) as compared to 1.64 microg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple-drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple-drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.

Oxycodone involvement in drug abuse deaths. II. Evidence for toxic multiple drug-drug interactions.

Recent surveys suggest that the abuse of drugs, often in combination, is pervasive throughout society. Adverse consequences of drug abuse tend to be attributed to the single drug "most likely" to be responsible. This is frequently seen in fatality cases, particularly those involving opioids. However, it is difficult to determine the specific cause of death when multiple drugs are involved. Although enhanced toxicity of alcohol and other centrally acting drugs with opioids has been well established in animal studies, there is a paucity of data in well-controlled human studies. We evaluated 1014 fatality cases involving oxycodone (OXC) for evidence of enhanced toxicity associated with multiple drug-drug interactions. We previously reported on these cases, and we classified them by a standardized method into groups that distinguished cases unrelated to drug abuse from those related to drug abuse, cases that involved only OXC from cases involving multiple drugs, drug-induced fatalities from drug-related fatalities, and cases in which the specific drug product OxyContin (oxycodone HCl controlled-release) tablets were identified from cases where OxyContin was not identified. Our working hypothesis was that OXC in combination with other centrally acting drugs is more toxic than OXC alone, evidenced by the finding of lower mean blood concentrations of OXC in multiple drug-induced deaths compared to single (OXC only) drug-induced deaths. Assessment of blood levels determined by specific assay methodology (primarily gas chromatography-mass spectrometry) in these cases provided the following mean postmortem concentrations of OXC: multiple drug-induced deaths, OxyContin identified, 0.93 mg/mL (N = 167); multiple drug-induced deaths, OxyContin not identified, 0.73 mg/mL (N = 579); single (OXC) drug-induced deaths, OxyContin identified, 1.55 mg/mL (N = 12); and single (OXC) drug-induced deaths, OxyContin not identified, 1.70 mg/mL (N = 15). Overall, mean OXC concentration trends were as follows: single (OXC), drug-induced, drug abuse deaths > multiple, drug-induced drug abuse deaths > drug-related drug abuse deaths approximately deaths unrelated to drug abuse; and deaths in which OxyContin was identified approximately deaths in which OxyContin was not identified, whether the deaths involved oxycodone alone or multiple drugs. Drug abuse patterns in the multiple drug-induced cases were complex. Over 135 drugs that were considered to be plausibly contributory to enhanced toxicity were identified in body fluids and tissues. Evaluation of mean OXC blood concentrations in cases that contained one, two, three, four, five, and six or more contributory drugs in combination demonstrated consistently lower mean OXC concentrations than those cases in which OXC was the only drug identified. A smaller number of cases were evaluated in the multiple drug-induced groups in which OXC was paired with a single other contributory drug. The overall mean OXC concentration for these cases was 0.71 mg/mL (N = 90) as compared to 1.64 mg/mL (N = 27) for the cases in the single drug-induced groups. The consistent finding of lower mean OXC blood levels associated with multiple drug-induced fatalities supports the stated hypothesis that OXC in combination with other centrally active drugs is more toxic than when OXC was the only drug involved. It was concluded that in cases of multiple drug fatalities, cause of death (COD) should not be attributed to any single drug. Rather, the unique combination of drugs, the pattern of drug use/abuse, and individual factors, such as tolerance to the respiratory depressant effects of opioids, must be taken into account in arriving at a valid COD statement.