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Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a movement to promote subjective pain (scale, 0 to 10) to the status of a "fifth vital sign" bolstered widespread prescribing for chronic, noncancer pain. This, coupled with rising misuse, initiated a surge in unintentional deaths, increased drug-associated acute coronary syndrome, and endocarditis. In response, the American College of Cardiology issued a call to action for cardiovascular care teams. Opioid toxicity is primarily mediated via potent μ-receptor agonism resulting in ventilatory depression. However, both overdose and opioid withdrawal can trigger major adverse cardiovascular events resulting from hemodynamic, vascular, and proarrhythmic/electrophysiological consequences. Although natural opioid analogues are devoid of repolarization effects, synthetic agents may be proarrhythmic. This perspective explores cardiovascular consequences of opioids, the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.

Opioids, both as prescription drugs and abuse substances, have been a hot topic and a focus of discussion in the media for the last few years. Although the literature published shows the occurrence of opioids and some of their metabolites in the aquatic environment, there are scarce data in the application of high resolution mass spectrometry (HRMS) for the analysis of these compounds in the environment. The use of HRMS allows increasing the number of opioids that can be studied as well as the detection of unknown opioids, their metabolites and potential transformation products. In this work, a retrospective analysis for the identification of opioids and their metabolites using a curated database was applied to surface water and wastewater samples taken in the state of Minnesota (U.S.) in 2009, which were previously analyzed by liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS) for antidepressants. The database comprised >200 opioids including natural opiates (e.g. morphine and codeine), their semi-synthetic derivatives (e.g. heroin, hydromorphone, hydrocodone, oxycodone, oxymorphone, meperidine and buprenorphine), fully synthetic opioids (e.g. fentanyl, methadone, tramadol, dextromethorphan and propoxyphene), as well as some of their metabolites (e.g. 6-monoacetylcodeine, dextrorphan, EDDP, normorphine and O-desmethyltramadol). Moreover, additional MS-MS experiments were performed to confirm their identification, as well as to recognize fragmentation patterns and diagnostic ions for several opioids. These data provide a better understanding of the historical occurrence of opioids and their metabolites in surface waters impacted by wastewater sources. The concentrations of individual opioids in surface water and wastewater effluent varied from 8.8 (EDDP) to 1640 (tramadol) ngL-1 and from 12 (dihydrocodeine) to 1288 (tramadol) ngL-1, respectively. The opioids with higher overall frequency detections were tramadol, dextromethorphan and its metabolite, dextrorphan.

Background This paper describes the performance of four Randox drug arrays, designed for whole blood, for the near-body analysis of drugs in a range of post-mortem body specimens. Methods Liver, psoas muscle, femoral blood, vitreous humor and urine from 261 post-mortem cases were screened in the mortuary and results were obtained within the time taken to complete a post-mortem. Specimens were screened for the presence of amfetamine, barbiturates, benzodiazepines, benzoylecgonine, buprenorphine, cannabinoids, dextropropoxyphene, fentanyl, ketamine, lysergide, methadone, metamfetamine, methaqualone, 3,4-methylenedioxymetamfetamine, opioids, paracetamol, phencyclidine, salicylate, salicylic acid, zaleplon, zopiclone and zolpidem using the DOA I, DOA I+, DOA II and Custom arrays. Results Liver and muscle specimens were obtained from each of the 261 post-mortem cases; femoral blood, vitreous humor and urine were available in 98%, 92% and 72% of the cases, respectively. As such, the equivalent of 12,978 individual drug-specific, or drug-group, immunoassay tests were undertaken. Overall >98% of the 12,978 screening tests undertaken agreed with laboratory confirmatory tests performed on femoral blood. Conclusions There is growing interest in the development of non-invasive procedures for determining the cause of death using MRI and CT scanning however these procedures are, in most cases, unable to determine whether death may have been associated with drug use. The Randox arrays can provide qualitative and semi-quantitative results in a mortuary environment enabling pathologists to decide whether to remove specimens from the body and submit them for laboratory analysis. Analysis can be undertaken on a range of autopsy specimens which is particularly useful when conventional specimens such as blood are unavailable.

BackgroundPoint-of-care (POC) urine drug screening (UDS) assays provide immediate information for patient management. However, POC UDS assays can produce false positive results, which may not be recognized until confirmatory testing is completed several days later. To minimize the potential for patient harm, it is critical to identify sources of interference. Here we applied an approach based on statistical analysis of electronic health record (EHR) data to identify medications that may cause false positives on POC UDS assays.MethodsFrom our institution’s EHR data, we extracted 120,670 POC UDS and confirmation results, covering 12 classes of target drugs, along with each individual’s prior medication exposures. For a given assay and medication ingredient, we quantified potential interference as an odds ratio from logistic regression. We evaluated interference experimentally by spiking compounds into drug-free urine and testing the spiked samples on the POC device (Integrated E-Z Split Key Cup II, Alere).ResultsOur dataset included 446 false positive UDS results (presumptive positive screen followed by negative confirmation). We quantified potential interference for 528 assay-ingredient pairs. Of the six assay-ingredient pairs we evaluated experimentally, two showed interference capable of producing a presumptive positive: labetalol on the MDMA assay (at 200 μg/mL) and ranitidine on the methamphetamine assay (at 50 μg/mL). Ranitidine also produced a presumptive positive for opiates at 1600 μg/mL and for propoxyphene at 800 μg/mL.ConclusionsThese findings support the generalizability of our approach to use EHR data to identify medications that interfere with clinical immunoassays.

International audience; France is experiencing an increase in the number of opioid prescriptions and related fatalities. We carried out a retrospective observational study using data from the Paris PCC over a 10-year period. The main objective was to obtain an epidemiological description of the severe reported cases. The secondary objectives were to assess the evolution of the number of these cases and their severity defined by the use of fentanyl and its derivatives, the use of the opioid-poisoning treatment naloxone, and the number of fatalities. During 2008–2017, 268 511 cases were recorded, including 1 122 cases of opioid-related poisoning that required medical management. These poisonings involved tramadol (43%), codeine (25%), dextropropoxyphene (13%), and morphine (8%); most resulted from self-exposure (60%). During the 10-year study period, 130 opioid-related fatalities were recorded in the Paris area, mainly resulting from suicides (39%) in men and were attributed to morphine (27%), tramadol (24%), and methadone (21%). We did not identify an increase in the number of severe opioid-related poisonings or fatalities or in the use of fentanyl or its derivatives. Conversely, we observed an increase in the use of naloxone, suggesting an increase in the severity of opioid poisonings. Our findings show that, until 2017, the opioid overdose epidemiology in the Paris area is different to that in the USA. The systematic analysis of data from the PCCs could be a good tool for health monitoring. To assess trends in France, a national study over a longer period would also be useful.

Objective: To recognize comorbid medical and psychiatric illness of treatment-seeking prescription opioid abusers in Sikkim. Setting and Design: A cross-sectional descriptive study was conducted among 223 individuals who were seeking the treatment for prescription opioid and other substance abuse-related problems at different de-addiction centers of Sikkim. Subjects and Methods: Participants were interviewed by a single interviewer by administering pretested questionnaires. Those who gave informed consent were included in this study. Statistical Analysis Used: Database development and analysis were carried out using SPSS software version 20. Results: The mean age of prescription opioid abusers was 27 years. Prescription opioid abuse was found prevalent among unmarried, school dropout (40%) and those living in a nuclear family. A majority reported having serious employment problems in lifetimes. Dextropropoxyphene was reported as most used prescription opioid. About 52% reported getting hospitalized several times for chronic medical problems in lifetimes. Incidences of psychological distress, such as anxiety/tension (96.9% vs. 68.3%), were reported more than psychiatric problems such as severe depression in lifetimes. Conclusion: Increased incidences of prescription opioid abuse and need of treatment for substance abuse disorder and associated comorbid chronic health issues and psychiatric as well as the psychological illness was observed in Sikkim.

Objective: To evaluate frequency and risk factors for dextropropoxyphene-induced QT-interval prolongation in the clinical setting. Design: Prospective, noninterventional, observational, longitudinal cohort approach. Electrocardiograms were blindly evaluated by independent professionals. Setting: General ward of a public hospital of metropolitan Buenos Aires. Patients, Participants: Ninety-two patients with indication of receiving dextropropoxyphene for analgesic purposes were included consecutively. All patients finished the study. Interventions: All patients were monitored with electrocardiographic controls (previous to drug administration and during steady state) to diagnose and quantify changes in the duration of the QTc interval. Main Outcome Measure: Frequency of drug-induced QTc interval prolongation, QTc interval correlation with plasma drug, and metabolite levels. Results: Ninety-two patients were studied (50 percent males). All patients received a (mean ± SD [range]) dextropropoxyphene dose of 125 ± 25[100-150] mg/d. Dextropropoxyphene and norpropoxyphene concentrations were 112 ± 38[45-199] and 65 ± 33[13-129] ng/mL, respectively. The intra-treatment QTc interval was >450 ms in only one patient (only with the Hodge correction). There were no cases of QTc > 500 ms, and there were no significant differences in the results considering different correction formulas (Bazzet, Fridericia, Framingham, Hodges). Dextropropoxyphene concentrations correlated with QTc (R > 0.45) interval and ΔQTc (R 0.52-0.87), whereas norpropoxyphene correlation was even greater for QTc (R > 0.40-0.64) and ΔQTc (R > 0.47-0.92). Depending on the QTc correction formula, eight patients presented ΔQTc > 30 ms and one patient with ΔQTc > 60 ms. No patient presented arrhythmia during the study. Conclusions: The authors did not observe a relationship between dextropropoxyphene and QTc interval prolongation at the therapeutic doses used in Argentina.

OBJECTIVE: Experts cautioned that patients affected by the November 2010 withdrawal of the opioid analgesic propoxyphene might receive riskier prescriptions. To explore this, we compared drug receipt and outcomes among propoxyphene users before and after market withdrawal. STUDY DESIGN: Using OptumLabs data, we studied three populations: commercial, Medicare Advantage aged (age 65+) and Medicare Advantage disabled (age

Objective: To describe opioid pharmacy claims patterns in the United States among an insured population.Design: Information was obtained from the US insurance claims database, IMS Lifelink™, between 1997 and 2002. Descriptive statistics of opioid claims patterns were described with stratification by gender, age, and year of use.Results: The prevalence of insured people with opioid claims increased from 17.1 percent in 1997 to 18.4 percent in 2002. Among people with an opioid claim, 24 percent had ≥30 days and 10 percent had ≥90 days of days supplied based on the insurance claims. Prevalence varied by type of opioid; 56 percent of people with a claim received propoxyphene, 43 percent received codeine, 23 percent received oxycodone, and 17 percent received hydrocodone. Sustained-release opioids were found among 6 percent of those with a claim. With respect to the dose of opioids in the pharmacy claims (expressed as morphine equivalent total daily dose), 71 percent had claims for

Objectives: To compare the efficacy of memantine with buprenorphine in the suppression of naloxone-precipitated acute withdrawal in heroin-dependent male subjects in an inpatient setting. Setting: Inpatient unit of tertiary level deaddiction facility. Participants: Forty-five treatment-seeking heroin-dependent males. Interventions: Subjects stabilized on 650 mg of dextropropoxyphene for 5 days were randomly divided into two groups on the sixth day: group A (n = 25) received 20 mg of memantine with buprenorphine placebo, and group B (n = 20) received 2 mg of buprenorphine with memantine placebo. Acute withdrawals were precipitated with naloxone (0.4 mg, intravenously) and were assessed using subjective and objective opioid withdrawal scales (SOWS and OOWS) and two separate visual analogue scales (VASs) for pain and dysphoria at baseline prior to test drug administration and again after the precipitation of acute withdrawal. Main outcome measures: Severity of precipitated opioid withdrawals. Results: Baseline opioid withdrawal symptoms in both groups did not differ significantly. After the precipitation of acute withdrawal, there were no significant differences between subjects in both groups on OOWS and both VASs but showed significant difference on SOWS. When changes in ratings from baseline (and after naloxone-precipitated acute withdrawal) were compared between the two groups, a significant difference in the change in SOWS scores was observed with greater decrease in withdrawal scores in the buprenorphine group. Conclusions: Memantine has comparable efficacy to buprenorphine in the suppression of objective signs of naloxone-precipitated acute opioid withdrawal; however, its role in the suppression of subjective symptoms is debatable.

Although published literature provides a clear demonstration of widespread occurrence of opioid analgesics (OAs) in the aquatic environment, analytical methods suitable for a systematic study of this pharmaceutical class, which would include a broad spectrum of opioid analgesics and their metabolites, are still missing. In this work, a comprehensive multiresidue method for quantitative analysis of 27 opioid analgesics and their metabolites, including 2 morphine glucuronide conjugates, was developed and validated for three matrices: raw wastewater (RW), secondary effluent (SE) and river water. The method comprised different classes of opioid analgesics, including natural opiates (morphine and codeine), their semi- synthetic derivatives (hydrocodone, hydromorphone, oxycodone, oxymorphone and buprenorphine) as well as fully synthetic opioids such as methadone, fentanyl, sufentanil, propoxyphene and tramadol. The optimized enrichment procedure involved mixed- mode, strong cation-exchange sorbent in combination with a sequential elution procedure. The extracts were analyzed by reversed-phase liquid chromatography using a Synergy Polar column coupled to electrospray ionization tandem mass spectrometry (LC–MS/MS). Accurate quantification of target OAs was achieved using 19 deuterated analogues as surrogate standards. Method accuracies for RW, SE and river water varied in the range from 91 to 126%, 74 to 120% and 75 to 116%, respectively. Careful optimization of the procedure allowed reliable determination of OAs with method quantification limits in the low ng/L range (RW: 0.3-3.5 ng/L ; SE: 0.2-1.9 ng/L, river water: 0.1-0.8 ng/L. The developed method was applied for analysis of RW, SE and river water samples from Croatia. The concentrations of individual OAs in municipal wastewater varied in a wide range (from < QL to 859 ng/L) and the most prevalent representatives were tramadol, codeine, morphine and methadone and their derivatives. Elevated concentrations of morphine glucuronides (up to 370 ng/L) found in raw municipal wastewater indicated their importance in the overall morphine mass balance.

The consequences of the withdrawal of marketing authorisation of drugs have mostly been studied considering drug prescription patterns for the therapeutic alternatives of the withdrawn drugs. The potential concomitant changes in the reporting of adverse reactions concerning these alternatives have been studied less often. The objective of this study was to analyse the changes in the reporting of adverse events (AEs) for therapeutic alternatives after the withdrawal of three medicines (dextropropoxyphene, pioglitazone and tetrazepam) from the market for safety reasons. This study was performed using both the French pharmacovigilance database and the Echantillon Generaliste des Beneficiaires (a random sample of French health insurance affiliates). For dextropropoxyphene, pioglitazone and tetrazepam alternatives, the number and types of case reports were studied for both the year preceding the first official safety warning and the year following the withdrawal. Reporting rates expressed per 10,000 reimbursements (RRReimb) and per 10,000 treated patients (RRPat) were also compared for the two periods. After dextropropoxyphene withdrawal, case reports and reimbursements increased for tramadol (case reports: +23%, reimbursements: +13%) and codeine (case reports: +74%, reimbursements: +47%), RRPat being significantly increased for tramadol (0.92 vs. 1.06, p = 0.02). After pioglitazone withdrawal, case reports increased for dipeptidyl peptidase-4 (DPP-4) inhibitors, glinides, and glucagon-like peptide 1 (GLP-1) analogues (+84%, +22% and +5%, respectively) and reimbursements (+55, +11 and +50%, respectively); both decreased for sulfonylureas (case reports: −6%, reimbursements: −2%). RRPat increased for DPP-4 inhibitors (1.63 vs. 2.26, p = 0.008). After tetrazepam withdrawal, case reports increased for diazepam, methocarbamol and thiocolchicoside (+110, +86 and +157%, respectively), as lesser did reimbursements. RRPat increased for diazepam (1.78 vs. 2.41, p = 0.054) and thiocolchicoside (0.14 vs. 0.24, p = 0.013). For the three drug withdrawals investigated, the number of case reports involving alternatives increased to a larger extent than the numbers of prescriptions. This could relate to a higher occurrence of AEs in new users of alternatives who switched from the withdrawn medicines or to an increased awareness of possible AEs.

Michael A Veronin,1 Robert P Schumaker,2 Rohit R Dixit,2 Harshini Elath21Social and Administrative Sciences, Department of Pharmaceutical Sciences, University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, Tyler, TX 75799, USA; 2Department of Computer Science, College of Business and Technology, University of Texas at Tyler, Tyler, TX 75799, USACorrespondence: Michael A VeroninSocial and Administrative Sciences, Department of Pharmaceutical Sciences, University of Texas at Tyler, Ben and Maytee Fisch College of Pharmacy, 3900 University Blvd., Tyler, Texas 75799, USATel +1 903 566 6148Fax +1 903 565 5598Email mveronin@uttyler.eduBackground: The U.S. Food and Drug Administration Adverse Event Reporting System(FAERS), contains information on adverse drug events and medication error reports submitted to the FDA through the MedWatch program. A significant number of adverse events reported in the FAERS database have been for opioid use. The objective of this study was to determine the frequency counts and associated deaths of opioid drug names in the FAERS database.Methods: Drug data were obtained from the DRUG and OUTCOME files in the database. Drugs identified included: morphine, fentanyl, oxycodone, hydrocodone, tramadol, hydromorphone, methadone, codeine, oxymorphone, meperidine, propoxyphene, diphenoxylate, and heroin. Frequency counts and concomitant deaths of opioid drug names were determined via the MySQL database management system.Results: Fifteen different opioid drugs identified in the FAERS database were associated with ADEs, including death, and 3 drugs (oxycodone, hydrocodone, fentanyl) accounted for more than half of the reports. The highest frequency count value was 158,181 for oxycodone, which represents approximately 20.2% of the frequency counts for the opioids. The lowest frequency count value was 2,161 for dextromethorphan, which represents approximately 0.3% of the total. The opioid with the highest proportion of deaths to drug count was heroin (71.8%), followed by dextromethorphan (55.6%), methadone (37.2%), morphine (26.8%), and propoxyphene (23.7%).Conclusion: The FAERS database represents an important source for detection and reporting of adverse drug events (ADEs), in particular the opioids and related drugs. It remains a challenge to estimate the true incidence of ADEs for this class of drugs in the general population.Keywords: adverse drug event, Food and Drug Administration, opioid, frequency count, FAERS database

Background Prescription drug suicide merits study to guide the development of strategies to reduce suicide risk. We examined prescription drug suicide specifically in non-abusers of prescription drugs; this is a relatively unexplored subject. Methods Six-year data on prescription drug suicide in non-abusers were extracted from the records of the Department of Forensic Medicine at the All India Institute of Medical Sciences, New Delhi. These records contained information obtained from the scene of the suicide, from interviews with relatives of the deceased, and from forensic toxicological analyses at two laboratories. Results There were 27 (8%) cases of prescription drug suicide in non-abusers out of 338 cases of suicidal poisoning. The mean age of this sample was 26 years. The sample was 74% male. Nearly half of the cases (44%) were students. A combination of dextropropoxyphene with dicyclomine, with or without paracetamol, was used by 41% of cases. Overdose was achieved through the ingestion of 10–40 (median, 30) tablets or by the injection of 2–3 (median, 2) vials of medication. In 52% of cases, it appeared that the drugs had been procured over the counter. Conclusions It is reassuring that the absolute number of prescription drug suicides in non-abusers was small; the findings, however, are important because they could serve as a baseline for assessing time trends in future studies. For the present, we suggest that prescription drugs of potential abuse, especially those containing opioids and antispasmodics, should be prescribed and dispensed judiciously, especially to youth.

Background Analgesics are used most frequently in fatal and non-fatal medicinal self-poisonings. Knowledge about their relative toxicity in overdose is important for clinicians and regulatory agencies. Methods Using data for 2005–2012 we investigated case fatality (number of suicides relative to number of non-fatal self-poisonings) of paracetamol, aspirin, codeine, dihydrocodeine, tramadol, paracetamol with codeine (co-codamol), paracetamol with dihydrocodeine (co-dydramol), ibuprofen and co-proxamol (paracetamol plus dextropropoxyphene; withdrawn in the UK in 2008 due to high toxicity). Data on suicides obtained from the Office for National Statistics and on non-fatal self-poisonings from the Multicentre Study of Self-harm in England. Case fatality was estimated for each drug, using paracetamol as the reference category. Results Compared to paracetamol and based on single drug deaths the case fatality index of dihydrocodeine was considerably elevated (odds ratio (OR) 12.81, 95% Confidence Interval (CI) 10.19–16.12). Case fatality indices for tramadol (OR 4.05, 95% CI 3.38–4.85) and codeine (OR 2.21, 95% CI 1.81–2.70) were also significantly higher than for paracetamol. The results when multiple drug deaths were included produced similar results. The relative toxicity of co-proxamol far exceeded that of the other analgesics. Limitations Data on fatal self-poisonings were based on national data, whereas those for non-fatal poisonings were based on local data. Conclusions Dihydrocodeine and tramadol are particularly toxic in overdose and codeine is also relatively toxic. They should be prescribed with caution, particularly to individuals at risk of self-harm.

In general 9–10 drugs are routinely tested in most hospital laboratories and as a result many designer drugs escape detection. Moreover, compliance with benzodiazepine may not be monitored using routine benzodiazepine screen in urine using immunoassays due to poor cross-reactivity of many benzodiazepines with assay antibody as well as very poor cross-reactivity of glucuronide metabolite of lorazepam, temazepam, and other benzodiazepines. Moreover, compliance of patients with oxycodone therapy cannot be monitored by using opiate immunoassays because oxycodone has very poor cross-reactivity with opiate immunoassays although hydromorphone and hydrocodone may have some cross-reactivity. In general, other opioids such as propoxyphene, methadone, tramadol, fentanyl, etc. cannot be detected by opiate immunoassays, although specific immunoassays are available for some opioids. Therefore, if routine toxicology screen is negative in a suspected overdosed patient, then specimens should be sent to a reference laboratory capable of screening many drugs using liquid chromatography combined with tandem mass spectrometry.

Sys Stybe Johansen,1 Christina Jacobsen,2 Kristian Linnet1 1Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Purpose: We present a retrospective analysis of fatal intoxications among non-drug addicts medicolegally autopsied in Eastern Denmark (DK) over a 5-year period (2008–2012) and compare our results with three older similar studies covering periods from 1992 to 2007. Material and methods: Retrospective results showed that among 3,535 medicolegal autopsies performed in Eastern DK within the 5-year study period, 312 were fatal intoxications among non-drug addicts. Results: A total of 67% of the intoxications were caused by pharmaceuticals, most often by strong opioids, 23% by carbon monoxide in connection with fires and 9% by acute ethanol intoxication. The number of fatal intoxications varied within the 5-year period from 52 to 75 per year. A total of 54% of the intoxications involved men, and the dominant age groups were 40–49 years for men and 50–59 years for women. In 57% of the fatal intoxications, the manner of death was accidental; 24% were suicides; 0.6% were homicides; and 16% were unknown. A total of 75% of the intoxications involved one substance, 11% involved multiple substances (all at lethal post-mortem blood concentrations), and 13.5% were combination intoxications. Although the total number of intoxications had decreased by 25% from the previous 5-year period, carbon monoxide, ethanol, and the strong opioids morphine and methadone were again the most common fatal substances. Tramadol, another opioid, was the fifth most fatal intoxicating substance, and its prevalence increased within the last two study periods, as also seen in the amount of defined daily doses of tramadol sold in DK. Clozapine, an antipsychotic drug, was new among the ten most fatal intoxicating substances in this study. Conclusion: In general, the findings are comparable with the last 20 years’ observations in DK, although the number of intoxications was reduced by 25%. Small changes among the most frequent fatal substances were observed compared with the previous periods. Keywords: fatal poisonings, cause of manner and death, medicine users, ethanol, pharmaceuticals, DDDs

Purpose The study aimed to test whether directives on opioid prescribing released by the Veterans Health Administration (VHA) or the Food and Drug Administration (FDA) had an impact on prescribing among VHA providers. Methods We used the VHA's linked pharmacy and patient medical records database to identify new prescriptions written for propoxyphene, fentanyl, and controlled release (CR) oxycodone between 1/1/2000 and 12/31/2009. We plotted the monthly proportion of these prescriptions that complied with components of four specific safety alerts or directives for these substances issued by the VHA or FDA between 1/1/2001 and 12/31/2008. We modeled compliance using interrupted time series analysis and a generalized additive model with the addition of an indicator variable to flag prescriptions that followed the directive's release date. Results A total of 32.2 million new prescriptions for fentanyl, oxycodone CR, and propoxyphene were written for VHA patients meeting inclusion criteria. Compliance with guidelines in the directives increased steadily throughout the entire study period, with no clinically meaningful inflection point near the date of each directive's release. Generalized additive modeling and interrupted time series analysis found that the indicator flag slightly improved the fit of the data, but visual inspection of the plots revealed no change at a level of practical significance. Conclusions While prescribing compliance increased throughout the period, release of FDA and VHA alerts and guidelines did not appear to contribute to this change. Given the fivefold increase in the rate of drug-related overdose deaths since 1990, identifying effective methods to communicate safety messages and change prescriber behavior remains a priority for future work. Copyright © 2016 John Wiley & Sons, Ltd.

Objective Animal studies and in vitro human studies suggest that certain opioid analgesics impair crucial immune functions. This study was undertaken to determine whether opioid use is associated with increased risk of serious infection in patients with rheumatoid arthritis (RA). Methods We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid in 1995–2009. Within-person comparisons of the risk of hospitalization for serious infection during periods of opioid use versus non-use were performed using conditional Poisson regression. Fixed confounders were accounted for by design; time-varying confounders included age and use of disease-modifying antirheumatic drugs, glucocorticoids, and proton-pump inhibitors. In additional analyses, risks associated with new opioid use, use of opioids known to have immunosuppressive properties, use of long-acting opioids, and different opioid dosages were assessed. Sensitivity analyses were performed to account for potential protopathic bias and confounding by indication. Results Among 1,790 patients with RA who had at least 1 hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared to non-use, with an incidence rate ratio (IRR) of 1.39 (95% confidence interval [95% CI] 1.19–1.62). The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared to non-use (IRR 2.01 [95% CI 1.52–2.66], IRR 1.72 [95% CI 1.33–2.23], and IRR 2.38 [95% CI 1.65–3.42], respectively). Results of sensitivity analyses were consistent with the main findings. Conclusion In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalization for serious infection.

Purpose There has been concern regarding the increasing use of opioids and related harm. We present data on opioid utilisation across Australia and consider sociodemographic factors that may affect utilisation rates. Methods IMS Health national sales data for over-the-counter (codeine) and prescription opioids (buprenorphine, codeine, dextropropoxyphene, fentanyl, hydromorphone, methadone, morphine, oxycodone, tapentadol and tramadol) were used to estimate total utilisation rates in the community during 2013, mapped to Statistical Local Areas (SLAs) and Remoteness Areas. All opioid amounts were measured in pack sales and milligrammes then converted to oral morphine equivalent milligrammes (OME mg) for comparison across opioids. Data on the demographic characteristics of SLAs were obtained from the ABS (sex and age distribution, income and levels of physical labour) and other sources (number of pharmacies in SLAs) and were included in linear regression analyses. Results In 2013, an estimated 10 747 kg (OME) of opioids were sold across Australia, equating to 481 OME mg per person. There was considerable geographic variation in opioid utilisation, with higher rates of use in rural and regional areas. Geographic areas that were less populated, had more men and older people, proportionally more low-income earning households and greater proportions in jobs requiring physical labour had higher utilisation rates. Conclusions Substantial geographic variation in opioid utilisation was identified, with areas outside of major cities having higher rates of utilisation of all types of opioids. Prescription monitoring and best practice interventions aimed at improving opioid use need to have a particular focus on areas outside of major cities. Copyright © 2016 John Wiley & Sons, Ltd.

Urine drug screens are commonly performed to identify drug use or monitor adherence to drug therapy. The purpose of this retrospective study was to evaluate the true positive and false positive rates of one of our in-house urine drug screen panels. The urine drugs of abuse panel studied consists of screening by immunoassay then positive immunoassay results were confirmed by mass spectrometry. Reagents from Syva and Microgenics were used for the immunoassay screen. The screen was performed on a Beckman AU5810 random access automated clinical analyzer. The percent of true positives for each immunoassay was determined. Agreement with previously validated GC-MS or LC-MS-MS confirmatory methods was also evaluated. There were 8,825 de-identified screening results for each of the drugs in the panel, except for alcohol (N = 2,296). The percent of samples that screened positive were: 10.0% for amphetamine/methamphetamine/3,4-methylenedioxy-methamphetamine (MDMA), 12.8% for benzodiazepines, 43.7% for opiates (including oxycodone) and 20.3% for tetrahydrocannabinol (THC). The false positive rate for amphetamine/methamphetamine was ∼14%, ∼34% for opiates (excluding oxycodone), 25% for propoxyphene and 100% for phencyclidine and MDMA immunoassays. Based on the results from this retrospective study, the true positive rate for THC drug use among adults were similar to the rate of illicit drug use in young adults from the 2013 National Survey; however, our positivity rate for cocaine was higher than the National Survey.

Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone, buprenorphine…). When these products are misused, they are often addictive. Thus, we aimed to develop an analytical method able to rapidly quantify several opiates and opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, ethylmorphine, heroin, methadone, morphine, nalbuphine, naloxone, norbuprenorphine, norcodeine, norpropoxyphene, oxycodone and propoxyphene) in whole blood by ultra-high performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The validated assay requires only 100 µL of the blood sample. The sample is prepared by a rapid liquid–liquid extraction using 5% zinc sulfate (W/V), methanol and acetonitrile. Calibration curves range from 0.98 to 1000 µg/L, except for buprenorphine (0.39–100 µg/L) and norbuprenorphine (0.20–100 µg/L). Inter- and intra-analytical accuracy was less than 15%. Therefore, we describe the development and full validation of an accurate, sensitive and precise assay using UHPLC-HRMS for the analysis of opioids in whole blood. After validation, this new assay is successfully applied on a routine laboratory application basis.

Background and Objectives: Some opioid-dependent injecting buprenorphine (BPN) users can continue to inject BPN even while using dextropropoxyphene as a treatment or as a drug of abuse. With this rationale, this study was aimed to assess the effect of injection BPN on psychomotor and cognitive functioning in opioid-dependent patients receiving oral dextropropoxyphene. Methods: This was a randomized, placebo-controlled, double-blind, crossover study, carried out in the inpatient unit of the tertiary level de-addiction facility. Twenty opioid-dependent male, current injecting drug users were given a single dose of injection of BPN (1.2 mg) or placebo, in a crossover design, 2 h after the routine morning dose of oral dextropropoxyphene at day 4 and day 6 of admission. Psychomotor and cognitive functioning was assessed with the help of standard tools (trail making – Parts A and B, digit symbol substitution test, delayed recall test, and digit span) at baseline and after 10 min, 3 h, and 6 h of injection BPN/placebo. Results: There was no significant difference in the scores on any of the tests for psychomotor and cognitive functioning at any time period after receiving either injection BPN or placebo. Conclusions: A single dose of intravenous BPN in opioid-dependent patients on oral dextropropoxyphene did not produce any significant change in psychomotor and cognitive functioning as compared to placebo.