Changes in misuse and abuse of prescription opioids following implementation of Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy.

PURPOSE: An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. METHODS: Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. RESULTS: RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. CONCLUSIONS: While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends.

Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration.

BACKGROUND: Prescription opioid abuse and misuse is a serious and growing public health issue. While the most common form of abuse is swallowing intact tablets/capsules, some abusers manipulate, or tamper with, these medications by altering the dosage form to allow for non-oral routes of administration (e.g., injection, inhalation) in order to achieve more rapid or enhanced psychoactive effects. Because administration of opioids via non-oral routes results in greater systemic availability and more rapid central nervous system penetration, we hypothesized that death and major medical outcomes occur more frequently with non-oral routes compared to oral route alone. METHODS: This retrospective cohort study analyzed data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Poison Center Program to investigate relative risk of prescription opioid abuse via oral and non-oral routes. RESULTS: While the oral route was the most commonly reported route of abuse (64.0%), non-oral routes were reported in 14.6% exposures and unknown routes in 21.4% exposures. The relative risk of an exposure resulting in death or major effect was 2.43 (95% CI 1.97, 2.99) if non-oral routes were reported compared to exposures involving oral route only. CONCLUSION: Analysis of acute health events recorded by poison centers indicates that death or major effects are twice as likely to occur with intentional abuse of prescription opioids via non-oral routes of administration than ingestion alone. Effective interventions to prevent abuse via non-oral routes of solid dosage forms of prescription opioids, such as abuse-deterrent formulations could have a significant public health impact.

Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing.

BACKGROUND: Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 µmol l(-1) have been suggested as a marker of paracetamol-induced hepatotoxicity. However, there is little information on the range of concentrations observed during prolonged therapeutic dosing. AIM: The aim of the present study was to describe the concentration of PPA in the serum of subjects taking therapeutic doses of paracetamol for at least 16 days. METHODS: Preplanned secondary aim of a prospective randomized controlled (placebo vs. 4g day(-1) paracetamol) trial. We measured subjects' serum PPA concentrations every 3 days for a minimum of 16 days. We also measured concentrations on study days 1-3 and 16-25 in subsets of patients. PPA were quantified as APAP-CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry. RESULTS: Ninety per cent of subjects had detectable PPA after five doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 µmol l(-1) on day 7, where they remained. The highest concentration measured was 1.1 µmol l(-1) and two subjects never had detectable PPA levels. PPA were detected in the serum of 78% of subjects 9 days after their final dose. CONCLUSIONS: PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 µmol l(-1) in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped.

Trends in opioid analgesic abuse and mortality in the United States.

BACKGROUND: The use of prescription opioid medications has increased greatly in the United States during the past two decades; in 2010, there were 16,651 opioid-related deaths. In response, hundreds of federal, state, and local interventions have been implemented. We describe trends in the diversion and abuse of prescription opioid analgesics using data through 2013. METHODS: We used five programs from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System to describe trends between 2002 and 2013 in the diversion and abuse of all products and formulations of six prescription opioid analgesics: oxycodone, hydrocodone, hydromorphone, fentanyl, morphine, and tramadol. The programs gather data from drug-diversion investigators, poison centers, substance-abuse treatment centers, and college students. RESULTS: Prescriptions for opioid analgesics increased substantially from 2002 through 2010 in the United States but then decreased slightly from 2011 through 2013. In general, RADARS System programs reported large increases in the rates of opioid diversion and abuse from 2002 to 2010, but then the rates flattened or decreased from 2011 through 2013. The rate of opioid-related deaths rose and fell in a similar pattern. Reported nonmedical use did not change significantly among college students. CONCLUSIONS: Postmarketing surveillance indicates that the diversion and abuse of prescription opioid medications increased between 2002 and 2010 and plateaued or decreased between 2011 and 2013. These findings suggest that the United States may be making progress in controlling the abuse of opioid analgesics. (Funded by the Denver Health and Hospital Authority.).

A randomized, placebo-controlled trial to determine the course of aminotransferase elevation during prolonged acetaminophen administration.

BACKGROUND: Acetaminophen administration for more than 4 days causes aminotransferase elevation in some subjects. The objective of this randomized, placebo-controlled trial is to describe the course of alanine aminotransferase (ALT) elevation in subjects administered 4 g/day of acetaminophen for at least 16 days. METHODS: A randomized, placebo controlled trial of acetaminophen (4 g/day) vs placebo. Subjects were healthy volunteers with normal liver enzymes. The primary outcome was the course of ALT during acetaminophen administration. All subjects were treated for a minimum of 16 days. Subjects with ALT elevation at day 16 were continued on treatment until these elevations resolved up to a maximum of 40 days. Subjects were also evaluated for elevation of INR or serum bilirubin as evidence of hepatic dysfunction. RESULTS: 157/205 (77%) completed acetaminophen subjects had no ALT elevation or transient elevations that resolved by day 16. Of the 48 subjects who had ALT elevations at study day 16, 47 continued on acetaminophen and had resolution by study day 40. One acetaminophen subject did not have resolution by study day 40, and the course of aminotransferase elevation suggests an alternative cause. One placebo subject had an ALT elevation at day 16 that resolved by day 22. The highest observed ALT among all acetaminophen subjects was 191 IU/L. The mean ALT at day 16 was 4.4 IU/L higher for the acetaminophen than for the placebo group. No subject developed liver dysfunction. CONCLUSIONS: A minority of subjects treated with 4 g/day of acetaminophen for 16 days will have low-grade aminotransferase elevations that are not accompanied by liver dysfunction and resolve if administration is continued. TRIALS REGISTRATION: Clintrials.gov NCT00743093 registered August 26, 2008.

Assessment of prescription opioid intentional exposures across the rural-urban continuum in the United States using both population and drug availability rates.

PURPOSE: Prescription opioid abuse and misuse are a serious problem in the U.S. today. Several studies have shown that the epidemic disproportionately affects rural areas. This paper uses three different rates to gain a more complete picture of opioid abuse in rural areas. METHODS: This study examines prescription opioid intentional exposures using opioid classes tracked in the RADARS(®) System Poison Center Program. Intentional exposure rates were calculated adjusting for population and unique recipients of dispensed drug (URDD). These rates were analyzed using time (quarter) and the proportion of a three-digit zip code residing in a rural area as covariates. Additionally, the URDD per population rate was calculated to examine the proportion of the population filling prescriptions for opioids. RESULTS: After adjusting for population, intentional exposure cases significantly increased as the proportion of the population residing in a rural area increased. However, when adjusting for URDD, intentional exposure cases decreased with increasing rural population. The URDD per population increased as the proportion of people residing in a rural area increased. CONCLUSIONS: Using both population and URDD adjusted intentional exposure rates gives a more complete picture of opioid abuse in rural areas. Considering product availability can be used to develop opioid abuse prevention strategies and further the education of physicians serving rural areas about this epidemic.

Abuse and diversion of buprenorphine sublingual tablets and film.

Buprenorphine abuse is common worldwide. Rates of abuse and diversion of three sublingual buprenorphine formulations (single ingredient tablets; naloxone combination tablets and film) were compared. Data were obtained from the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System Poison Center, Drug Diversion, Opioid Treatment (OTP), Survey of Key Informants' Patients (SKIP), and College Survey Programs through December 2012. To control for drug availability, event ratios (rates) were calculated quarterly, based on the number of patients filling prescriptions for each formulation ("unique recipients of a dispensed drug," URDD) and averaged and compared using negative binomial regression. Abuse rates in the OTP, SKIP, and College Survey Programs were greatest for single ingredient tablets, and abuse rates in the Poison Center Program and illicit diversion rates were greatest for the combination tablets. Combination film rates were significantly less than rates for either tablet formulation in all programs. No geographic pattern could be discerned.

Seasonal variation in suicidal behavior with prescription opioid medication.

BACKGROUND: Suicide attempts by self-poisoning utilizing prescription opioids account for more than half of prescription drug abuse and misuse emergency calls received by poison centers. Additionally seasonal suicidal behavior using other means is a commonly replicated finding. We hypothesized seasonal behavior would exist in individuals using opioid medication as a suicide means, and that this pattern would change at different latitudes in the United States. METHODS: We used a harmonic regression strategy to investigate sinusoidal seasonal variations of suicidal behavior utilizing prescription opioids, and to contrast changes in seasonal behavior by latitude within the United States. Further, we investigated associations between suicide frequency utilizing opioid medication and frequency of dispensed opioid prescriptions. RESULTS: Seasonal patterns were identified; overall, all harmonic terms were significant (p<0.05). Interaction terms of harmonic by latitude and harmonic by gender also were significant (p<0.05). After stratification, females had significant harmonic terms at all latitudes. A changing peak time period with latitude also was observed, such that the peak appeared later at more southern latitudes. Additionally, increased dispensed prescriptions rates per population were associated with increased suicidal behavior utilizing prescription opioids. LIMITATIONS: This study has limitations due to its ecological nature and to missing data that may inform our understanding of suicide risk factors, such as marital status and socio-economic status. CONCLUSION: Suicidal behavior with prescription opioids follows a seasonal pattern that changes with latitude within the United States. Further, increased accessibility may contribute to increased suicidal attempt rates utilizing prescription opioids.

Association of unintentional pediatric exposures with decriminalization of marijuana in the United States.

STUDY OBJECTIVE: We compare state trends in unintentional pediatric marijuana exposures, as measured by call volume to US poison centers, by state marijuana legislation status. METHODS: A retrospective review of the American Association of Poison Control Centers National Poison Data System was performed from January 1, 2005, to December 31, 2011. States were classified as nonlegal if they have not passed legislation, transitional if they enacted legislation between 2005 and 2011, and decriminalized if laws passed before 2005. Our hypotheses were that decriminalized and transitional states would experience a significant increase in call volume, with more symptomatic exposures and more health care admissions than nonlegal states. RESULTS: There were 985 unintentional marijuana exposures reported from 2005 through 2011 in children aged 9 years and younger: 496 in nonlegal states, 93 in transitional states, and 396 in decriminalized states. There was a slight male predominance, and the median age ranged from 1.5 to 2.0 years. Clinical effects varied, with neurologic effects the most frequent. More exposures in decriminalized states required health care evaluation and had moderate to major clinical effects and critical care admissions compared with exposures from nonlegal states. The call rate in nonlegal states to poison centers did not change from 2005 to 2011. The call rate in decriminalized states increased by 30.3% calls per year, and transitional states had a trend toward an increase of 11.5% per year. CONCLUSION: Although the number of pediatric exposures to marijuana reported to the National Poison Data System was low, the rate of exposure increased from 2005 to 2011 in states that had passed marijuana legislation.

Medically significant late bleeding after treated crotaline envenomation: a systematic review.

STUDY OBJECTIVE: We estimate the proportion of patients with crotaline snake envenomation who are treated with Crotalidae polyvalent immune Fab (ovine) antivenom and who develop medically significant late bleeding. METHODS: We performed a systematic review of all published cohort studies of North American crotaline snake envenomation patients treated with Fab antivenom. We searched PubMed, Ovid MEDLINE, and EMBASE from January 1, 1997, to April 30, 2012. Data were extracted by 2 trained researchers. Late bleeding was defined as bleeding that began or recurred after initial control of the envenomation syndrome. Medically significant late bleeding was defined a priori as late bleeding treated with RBC transfusion, vasoactive drug infusion, surgery, or rehospitalization or associated with a hemoglobin decrease of greater than or equal to 3 g/dL, hematocrit decrease of greater than or equal to 8%, disability, or death. Summary incidence and 95% confidence intervals (CIs) were calculated with a random-effects Poisson regression model. RESULTS: Nineteen unique cohort studies were identified. Four studies collected data prospectively, and in 9 studies, patients were followed actively after hospital discharge. A total of 1,017 subjects were enrolled in these cohort studies. Late bleeding was reported in 9 subjects (0.9%; 95% CI 0.4% to 2.2%), of whom 5 subjects (0.5%; 95% CI 0.1% to 1.7%) had medically significant late bleeding. Three patients received RBC transfusion; no deaths or permanent sequelae were reported. Estimates of risk may be affected by underreporting. CONCLUSION: Medically significant late bleeding appears to be uncommon in snakebite victims treated with Fab antivenom.

Using poison center exposure calls to predict prescription opioid abuse and misuse-related emergency department visits.

BACKGROUND: Prescription drug abuse is a critical problem in the USA and has been linked to more deaths than automobile accidents. Despite this growing epidemic, the USA lacks a timely early warning system. Poison centers (PCs) have the potential to act as sentinel reporting entities for prescription drug abuse and misuse due to near-real-time data reporting and abundant coverage in the USA. METHODS: Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System PC program were compared with data from the Drug Abuse Warning Network (DAWN) from 2004 through 2010. Population rates of PC call mentions regarding abuse and misuse of prescription opioids were compared with population rates of emergency department visit mentions of the same using linear regression. Products included in the analysis were the following: buprenorphine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, and oxycodone. RESULTS: The strength of association between RADARS System PC data and DAWN emergency department visits regarding all opioids in aggregate was strong (R² = 0.81, p < 0.001). The correlations between the two programs at the drug class level also were strong for buprenorphine, hydrocodone, hydromorphone, methadone, and oxycodone (all R² > 0.70, all p < 0.01), significant for fentanyl (p = 0.05), and moderate for morphine (p = 0.09). CONCLUSIONS: Data on prescription opioid drug abuse from the RADARS System PC program correlates well with emergency room data from DAWN. Due to timeliness of data, geographic coverage and strong associations with other warning systems, PC data can be used for sentinel reporting on prescription drug abuse and misuse in the USA.

Root causes, clinical effects, and outcomes of unintentional exposures to buprenorphine by young children.

OBJECTIVE: To characterize the rates, root causes, and clinical effects of unintentional exposures to buprenorphine sublingual formulations among young children and to determine whether exposure characteristics differ between formulations. STUDY DESIGN: Unintentional exposures to buprenorphine-containing products among children 28 days to less than 6 years old were collected from the Researched Abuse, Diversion, and Addiction-Related Surveillance System Poison Center Program and Reckitt Benckiser Pharmaceuticals' pharmacovigilance system from October 2009-March 2012. After adjustment for drug availability, negative binomial regression was used to estimate average exposure rates. Root cause assessment was conducted, and an expert clinician panel adjudicated causality and severity of moderate to severe adverse events (AEs). RESULTS: A total of 2380 cases were reviewed, including 4 deaths. Exposures to buprenorphine-naloxone combination film were significantly less frequent than exposures to buprenorphine tablets (rate ratio 3.5 [95% CI, 2.7-4.5]) and buprenorphine-naloxone combination tablets (rate ratio 8.8 [7.2-10.6]). The most commonly identified root causes were medication stored in sight, accessed from a bag or purse, and not stored in the original packaging. Among 536 panel review cases, the most common AEs reported for all formulations were lethargy, respiratory depression, miosis, and vomiting. The highest level AE severity did not differ significantly by formulation. CONCLUSIONS: Unintentional exposure to buprenorphine can cause central nervous system depression, respiratory depression, and death in young children. Exposure rates to film formulations are significantly less than to tablet formulations. Package and storage deficiencies contribute to unintentional exposures in young children.

QTc interval screening in an opioid treatment program.

Methadone is highly effective for opioid dependency, but it is associated with Torsade de pointes. Although electrocardiography (ECG) has been proposed, its utility is uncertain, because an ECG-based intervention has not been described. An ECG-based cardiac safety program in methadone maintenance patients was evaluated in a single opioid treatment program from September 1, 2009, to August 31, 2011, in the United States. Time from pretreatment to repeat ECG in new entrants was assessed. The proportion with marked rate-corrected QT (QTc) interval prolongation (>500 ms) and the effect of the intervention on the QTc interval in this group were evaluated. Multivariate predictors of QTc interval change were assessed using a mixed-effects model. Of 531 new entrants, 436 (82%) underwent ≥1 electrocardiographic assessment, and 186 (35%) underwent pretreatment ECG. Median time to follow-up ECG was 43 days but decreased over time (p <0.0001). In 21 patients with QTc intervals >500 ms, the mean QTc interval from peak to final ECG decreased significantly (-55.5 ms, 95% confidence interval -77.0 to -33.9, p = 0.001), and 12 of 21 (57.1%) decreased to lower than the 500-ms threshold. In new entrants with serial ECG, only methadone dose (p = 0.009) and pretreatment QTc interval (p <0.0001) were associated with the magnitude of QTc interval change. In conclusion, this study suggests that the implementation of an ECG-based intervention in methadone maintenance can decrease the QTc interval in high-risk patients; clinical characteristics alone were inadequate to identify patients in need of electrocardiographic screening.

Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data.

BACKGROUND: Long-acting opioids are a leading cause of accidental death in the United States, and methadone is associated with greater mortality rates. Whether this increase is related to the proarrhythmic properties of methadone is unclear. OBJECTIVE: To describe methadone-associated arrhythmia events reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). DESIGN: Description of national adverse event registry data before and after publication of a 2002 report describing an association between methadone and arrhythmia. SETTING: FAERS, November 1997 and June 2011. PATIENTS: Adults with QTc prolongation or torsade de pointes and ventricular arrhythmia or cardiac arrest. MEASUREMENTS: FAERS reports before and after the 2002 report. RESULTS: 1646 cases of ventricular arrhythmia or cardiac arrest and 379 cases of QTc prolongation or torsade de pointes were associated with methadone. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1 to 0.5) before the 2002 publication to a mean of 3.5 (CI, 2.5 to 4.8) after it. After 2000, methadone was the second-most common primary suspect in cases of QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associated with disproportionate reporting similar to that of antiarrhythmic agents known to promote torsade de pointes. Antiretroviral drugs for HIV were the most common coadministered drugs. LIMITATION: Reports to FAERs are voluntary and selective, and incidence rates cannot be determined from spontaneously reported data. CONCLUSION: Since 2002, reports to FAERS of methadone-associated arrhythmia have increased substantially and are disproportionately represented relative to other events with the drug. Coadministration of methadone with antiretrovirals in patients with HIV may pose particular risk. PRIMARY FUNDING SOURCE: Colorado Clinical and Translational Sciences Institute, National Institutes of Health, and Agency for Healthcare Research and Quality.

A randomized, double-blind, placebo-controlled trial of a highly purified equine F(ab)2 antibody black widow spider antivenom.

STUDY OBJECTIVE: Black widow spider antivenom has never been tested in a randomized clinical trial, to our knowledge. We explore various efficacy measures for a novel F(ab)2 antivenom in patients with moderate to severe pain caused by black widow spider envenomation. METHODS: A randomized, placebo-controlled, double-blind, clinical trial was conducted in 12 academic emergency departments. We included patients at least 10 years old with moderate to severe latrodectism. Subjects received either a single intravenous infusion of antivenom or placebo. Pain was assessed with the visual analog scale. The primary efficacy outcome was the difference in pre- and posttreatment visual analog scale score. Prospectively defined secondary outcomes included treatment failures and time to clinically important decrease in pain. RESULTS: Twenty-four subjects were enrolled between October 2005 and October 2006; 13 were randomized to antivenom and 11 to placebo. The median change in visual analog scale at 150 minutes posttreatment was -50.0 mm (Interquartile Range [IQR] -67, -41 mm) in the antivenom treatment group and -46.0 mm (IQR -51, 0 mm) in the placebo treatment group (P=.14). There were 7 treatment failures (64%; 95% confidence interval 35% to 92%) in the placebo group and 3 (23%; 95% confidence interval 0.2% to 46%) in the antivenom group (P=.06). The median time to a clinically important decrease in pain after treatment was shorter in the antivenom group compared with the placebo group (30 minutes [IQR 30, 60 minutes] versus 90 minutes [IQR 30, 90 minutes]; P=.03). No serious adverse events or deaths were reported. CONCLUSION: Although the overall reduction in pain was similar for antivenom- and placebo-treated subjects, antivenom reduced pain more rapidly than placebo. No significant adverse events occurred in either group.

Effect of therapeutic doses of acetaminophen (up to 4 g/day) on serum alanine aminotransferase levels in subjects consuming ethanol: systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVE: To quantify the effect of therapeutic doses of acetaminophen on serum alanine aminotransferase (ALT) levels in subjects who consumed ethanol. DESIGN: Systematic review of six randomized placebo-controlled trials, of which five were included in a meta-analysis. SUBJECTS: Subjects included in the meta-analysis were those who consumed ethanol and received acetaminophen in doses up to 4 g/day (551 subjects) or placebo (350 subjects). MEASUREMENTS AND MAIN RESULTS: A comprehensive literature search of the MEDLINE, EMBASE, and International Pharmaceutical Abstracts databases and the Cochrane Central Register of Controlled Trials was performed to identify randomized, placebo-controlled trials that enrolled subjects who consumed ethanol, received acetaminophen in therapeutic doses up to 4 g/day, and had serum ALT level measurements. A total of 184 articles were identified; six articles met all criteria. Five of the six articles reported ALT levels on study day 4 for both groups of subjects who received acetaminophen or placebo. Thus, for the meta-analysis, we used the primary outcome of mean change in serum ALT level from baseline to day 4 in the acetaminophen groups compared with the placebo groups. We found that the difference in mean change from baseline ALT levels between the acetaminophen and placebo groups on day 4 was 0.0 U/L (95% confidence interval -0.2-0.1 U/L). There were no reports of liver dysfunction, liver failure, or death in any of the trials. CONCLUSION: In randomized, placebo-controlled trials of subjects who consumed ethanol, no elevation of ALT level on study day 4 was noted when subjects ingested up to 4 g/day of acetaminophen.

Do prescription monitoring programs impact state trends in opioid abuse/misuse?

OBJECTIVE: Prescription monitoring programs (PMPs) are statewide databases containing prescriber and patient-level prescription data on select drugs of abuse. These databases are used by medical professionals or law enforcement officials to identify patients with prescription drug use patterns indicative of abuse or providers engaging in illegal activities. Most states have implemented PMPs in an attempt to curb prescription drug abuse and diversion. However, assessment of their impact on drug abuse is only beginning. This study aimed to evaluate the relationship between PMPs and opioid misuse over time in two drug abuse surveillance data sources. METHODS: Data from the RADARS® System Poison Center and Opioid Treatment surveillance databases were used to obtain measures of abuse and misuse of opioids. Repeated measures negative binomial regression was applied to quarterly surveillance data (from 2003 to mid-2009) to estimate and compare opioid abuse and misuse trends. PMP presence was modeled as a time varying covariate for each state. RESULTS: Results support an association between PMPs and mitigated opioid abuse and misuse trends. Without a PMP in place, Poison Center intentional exposures increased, on average, 1.9% per quarter, whereas opioid intentional exposures increase 0.2% (P = 0.036) per quarter with a PMP in place. Opioid treatment admissions increase, on average, 4.9% per quarter in states without a PMP vs 2.6% (P = 0.058) in states with a PMP. In addition to the time trend, population and a measure of drug availability were also significant predictors. A secondary analysis that classified PMP based upon ideal characteristic showed consistent though not significant results. CONCLUSIONS: Two observational data sources offer preliminary support that PMPs are effective. Future efforts should evaluate what PMP characteristics are most effective and which opioids are most impacted.

Impact of cardiovascular disease guideline dissemination on provider knowledge.

INTRODUCTION: Provider characteristics associated with higher cardiovascular disease (CVD) knowledge and learning through clinical practice guidelines (CPG) dissemination are not well understood. METHODS: A baseline knowledge survey was distributed to licensed primary care practitioners. A CPG was then distributed following 6-weeks later by a repeat survey to assess proportion reading the CPG and changes in an aggregate knowledge score. The authors examined provider characteristics as predictors of CPG review and knowledge. Changes in CVD knowledge and specific CVD knowledge deficits were assessed. RESULTS: Of 1415 providers, 59% (830) completed the initial survey, 46% (651) completed the survey after CPG dissemination and 37% (523) completed both. The weighted percentage of CPG review was 51% (95% CI: 47%-55%) and was higher among midlevel providers (63% versus 44%, P < 0.001) and those in practice >5 years (53% versus 40%, P=0.017). Overall, baseline knowledge score was 71.2% and improved to 72.2% (P=0.038). Improvement in knowledge score was greater among midlevel providers (mean increase 2.4%, 95% CI: 1.0%-4.0%). Paradoxically, those in practice >5 years exhibited a trend toward lower improvements (2.2% versus 1.1%, P=0.08). CONCLUSIONS: Direct dissemination of a CPG resulted in a moderate rate of review, yet only small improvements in knowledge. This suggests that CPG dissemination alone is inadequate to substantively improve provider knowledge, although midlevel providers were more likely to read the CPG and increase their knowledge score. Multicomponent education strategies tailored to provider characteristics may be more effective improving knowledge.

A US perspective of symptomatic Latrodectus spp. envenomation and treatment: a National Poison Data System review.

BACKGROUND: Black widow spider (Latrodectus spp.) envenomation remains the most clinically significant spider envenomation in the US. The syndrome is characterized by painful muscle rigidity and autonomic disturbances. Treatment has ranged from symptomatic care to administration of specific antivenom. Declining antivenom availability and, possibly, the fear of hypersensitivity allergic reactions, has limited antivenom use in the US. OBJECTIVE: To describe Latrodectus spp. exposures and the subsequent treatment reported to US poison centers; the secondary objective was to identify factors associated with shorter duration of symptoms (<24 hours). METHODS: All Latrodectus spp. exposures reported to the National Poison Data System (NPDS) between January 1, 2000, and December 31, 2008, were reviewed. Cases with at least minor clinical effects due to Latrodectus spp. exposure were extracted. Descriptive statistics were generated. The probability that symptom duration was less than 24 hours was modeled, using logistic regression. RESULTS: From 2000 through 2008, a total of 23,409 Latrodectus spp. exposures were reported in 47 states; 9872 cases had at least minor clinical effects and were included in the subsequent analysis. Exposures peaked in September and fell to a nadir in January and February. Fifty-eight percent of the cases involved males, and the mean (SD) age was 31.5 (17.4) years. Sixty-five percent of the patients had minor clinical effects, 33.5% had moderate effects, 1.4% had major effects, and there were no deaths. Antivenom use was associated with symptom duration of less than 24 hours in moderate and major outcome groups. There was no evidence of shorter symptom duration in patients who received benzodiazepines or calcium. Adverse drug reactions were more common in patients receiving benzodiazepines and antivenom. CONCLUSIONS: In the US, most symptomatic Latrodectus spp. exposures reported to the NPDS are minor. Few patients receive antivenom, although antivenom is associated with shorter symptom duration among moderate and major outcomes.