Incident opioid drug use among older adults with chronic obstructive pulmonary disease: a population‐based cohort study

Aims

The purpose of the present study was to describe the scope, pattern and patient characteristics associated with incident opioid use among older adults with chronic obstructive pulmonary disease (COPD).

Methods

This was a retrospective population‐based cohort study using Ontario, Canada, healthcare administrative data. Study participants were individuals aged 66 years and older with physician‐diagnosed COPD, identified using a validated algorithm, who were not receiving palliative care. We examined the incidence of oral opioid receipt between 1 April 2003 and 31 March 2012, as well as several patterns of incident opioid drug use.

Results

Among 107 109 community‐dwelling and 16 207 long‐term care resident older adults with COPD, 72 962 (68.1%) and 8811 (54.4%), respectively, received an incident opioid drug during the observation period. Among long‐term care residents, multiple opioid dispensings (8.8%), dispensings for >30 days'' duration (up to 19.8%), second dispensings (35–43%) and early refills (24.2%) were observed. Incident opioid dispensing was also observed to occur during COPD exacerbations (6.9% among all long‐term care residents; 18.1% among long‐term care residents with frequent exacerbations). These same patterns of incident opioid use occurred among community‐dwelling individuals, but with relatively lower frequencies.

Conclusions

New opioid use was high among older adults with COPD. Potential safety concerns are raised by the degree and pattern of new opioid use, but further studies are needed to evaluate if adverse events are associated with opioid drug use in this older and respiratory‐vulnerable population.     

Awareness,knowledge and views of off‐label prescribing in children: a systematic review

AimThe aim of this review was to provide an updated overview of awareness, knowledge and views of off‐label prescribing in children.MethodA literature search using electronic databases including PubMed, Medline, Scopus, Science Direct, Springer Link, Proquest, Ebsco Host and Google Scholar was conducted. Additional articles were identified by reviewing the bibliography of retrieved articles. The articles were searched with any of the following medical subject headings (MeSH) terms in the title: attitude, awareness, knowledge, experience, view, off‐label, pediatric, paediatric and children. The inclusion criteria were full text articles published in English between January 2004 and February 2015 and reported outcome related to awareness, knowledge and views regarding off‐label prescribing in children. Editorials, reviews, notes, conference proceedings, letters and studies reporting prevalence of off‐label prescribing were excluded. The articles were scrutinized using thematic analysis.ResultsEleven studies conducted among doctors, community pharmacists, paediatric nurses, parents and children met the inclusion criteria. Nine themes were developed through document analysis which included main domains such as knowledge, awareness and views on off‐label drug use in children, choice of information sources, reasons and suggestions to reduce off‐label prescribing, concern regarding obtaining consent and participation in clinical trials.ConclusionThe studies reviewed reported that the majority of doctors and community pharmacists were familiar with the term off‐label prescribing but knowledge among parents was low. Awareness on off‐label prescribing in children remains low among all study participants. There is a mismatch between views on off‐label prescribing in children of study participants and the finding of previous studies.     

Metonitazene in the United States—Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry

Metonitazene is considered a new psychoactive substance (NPS) and emerging potent synthetic opioid, causing increased public health concern beginning in 2020. Metonitazene joins a growing list of new synthetic opioids (NSOs) contributing to deaths among people who use drugs in the United States and other parts of the world. Metonitazene (a 2-benzylbenzimidazole analogue) first appeared in mid-2020 in the recreational drug supply and subsequently began proliferating in death investigation casework towards the end of 2020. Screening and metabolite discovery were performed by liquid chromatography quadrupole time-of-flight mass spectrometry. Quantitative confirmation was performed by liquid chromatography tandem quadrupole mass spectrometry. Metonitazene was confirmed in 20 authentic forensic postmortem cases with an average concentration in blood at 6.3 ± 7.5 ng/ml (median: 3.8 ng/ml, range: 0.5–33 ng/ml, n = 18) and in urine at 15 ± 13 ng/ml (median: 11 ng/ml, range: 0.6–46 ng/ml, n = 14). Metonitazene was the only opioid identified in 30% of cases but was also found in combination with fentanyl (55%) and NPS benzodiazepines, opioids, and hallucinogens (45%). Medical examiners included metonitazene as a drug responsible for the cause of death, and the manner of death was always ruled to be an accident. The metabolism of metonitazene was found to be similar to that of isotonitazene, a closely related analogue. Toxicology laboratories and death investigators should ensure that metonitazene is included in forensic testing protocols, all while remaining vigilant for subsequent NSOs to emerge.     

Agreement between self‐reported antihypertensive drug use and pharmacy records in a population‐based study in The Netherlands

From 1987 to 1991, over 36,000 men and women aged 2059 years have been examined in the Monitoring Project on Cardiovascular Disease Risk Factors in The Netherlands. Classification of the treatment status of hypertensives in this populationbased study was based on selfadministered questionnaires. In order to assess the accuracy of selfreported antihypertensive drug use we compared the questionnaire information with computerized pharmacy records from a sample of 372 hypertensive subjects. Most antihypertensive drugs that were mentioned in the questionnaire were present in the pharmacy medication history (93%). However, this percentage was less (76%) when a comparison was made with the calculated duration of use based on the number of units prescribed and the directions for use in the pharmacy records. About 94% of the hypertensive subjects who were using an antihypertensive drug according to the pharmacy records, also mentioned at least one antihypertensive drug in the questionnaire. Agreement between selfreported antihypertensive drug use and pharmacy records was consistently high for all classes of antihypertensive drugs. Among 321 (86%) subjects, the number and types of selfreported antihypertensive drugs were exactly the same as in the pharmacy records. In conclusion, the agreement between selfreported antihypertensive drug use and pharmacy records was high, and the selfreported questionnaire information on antihypertensive drug use can be reliably used for the classification of treatment status of hypertensive subjects in this populationbased study.     

Risk factors for clinically relevant deviations in patients’ medication lists reported by patients in personal health records: a prospective cohort study in a hospital setting

International Journal of Clinical Pharmacy - Background Personal health records have the potential to identify medication discrepancies. Although they facilitate patient empowerment and broad...     

Dose-effect relationships of intravenous enoxaparin in patients undergoing percutaneous coronary intervention：a population and bayesian approach based study

AIM: Recent studies have suggested that intravenous enoxaparin can be used as an alternative therapy in patients percutaneous coronary intervention (PCI); yet the optimal regimen is to be defined. METHODS: Anti-Xa activities were measured in 556 patients who received a single 0.5 mg/kg dose of enoxaparin intravenously immediately before PCI. A population pharmacoki-     

Stage of change as a predictor of abstinence among alcohol‐dependent subjects in pharmacotherapy trials

Abstract

Although tobacco use is reported by the majority of substance use disordered (SUD) youth, little work has examined tobacco focused interventions with this population. The present study is an initial investigation of the effect of a tobacco use intervention on adolescent SUD treatment outcomes. Participants were adolescents in SUD treatment taking part in a cigarette smoking intervention efficacy study, assessed at baseline and followed up at 3- and 6-months post-intervention. Analyses compared treatment and control groups on days using alcohol and drugs and proportion abstinent from substance use at follow up assessments. Adolescents in the treatment condition reported significantly fewer days of substance use and were somewhat more likely to be abstinent at 3-month follow up. These findings suggest that tobacco focused intervention may enhance SUD treatment outcome. The present study provides further evidence for the value of addressing tobacco use in the context of treatment for adolescent SUD's.     

Risk of chemotherapy-induced febrile neutropenia with same-day versus next-day pegfilgrastim prophylaxis among patients aged ≥65 years: a retrospective evaluation using Medicare claims

Background: Two recent evaluations reported that risk of febrile neutropenia (FN) may be higher when pegfilgrastim prophylaxis (PP) is administered on same day as chemotherapy rather than per recommendation (1–3 days following chemotherapy). Such evidence is based largely on the experience of younger privately insured adults and may not be generalizable to older patients in US clinical practice.

Methods: A retrospective cohort design and data from Medicare Claims Research Identifiable Files (January 2008–September 2015) were employed. Patients were aged ≥65 years, had breast cancer or non-Hodgkin’s lymphoma, received chemotherapy with intermediate/high risk for FN, and received PP in ≥1 cycle; cycles with PP were stratified based on administration day (same-day [“Day 0”] vs. 1–3 days following chemotherapy [“Days 1–3”]) and were pooled for analyses. Adjusted odds ratios (ORs) for FN during the cycle were estimated for patients who received PP on Day 0 versus Days 1–3.

Results: Study population included 65,003 patients who received PP in 261,184 cycles; in 5% of cycles, patients received PP on Day 0. Incidence proportion for FN in cycle 1 was 11.4% for Day 0 versus 8.4% for Days 1–3; adjusted OR was 1.4 (p?p?p?p?Conclusions: Among Medicare patients receiving chemotherapy and PP in US clinical practice, PP was administered before the recommended timing in 5% of cycles and FN incidence was significantly higher in these cycles. Along with prior research, study findings support recently updated US practice guidelines indicating that PP should be administered the day after chemotherapy.     

Dose‐dependent plasma clearance of MK‐826, a carbapenem antibiotic,arising from concentration‐dependent plasma protein binding in rats and monkeys

After intravenous administration of MK‐826, a new carbapenem antibiotic, the compound exhibited nonlinear pharmaco‐kinetics in rats and monkeys. In both species, time‐averaged plasma clearance (based on total concentrations) increased about 5‐fold over the 10‐ to 180‐mg/kg dose range. MK‐826 was extensively plasma protein bound in rat and monkey plasma, and the extent of binding was concentration dependent at plasma concentrations achieved after administration of these doses. Rosenthal analysis of the plasma protein binding indicated that there were two classes of binding sites. The binding capacity of the primary site was comparable to the plasma albumin concentration, which suggested that this primary site consisted of a single site on albumin. The extent of binding of MK‐826 to rat albumin was similar to that in whole plasma. Clearance values based on unbound concentrations appeared independent of dose from 10 to 180 mg/kg, which is consistent with saturation of protein binding as the primary cause of the nonlinear pharmacokinetic behavior.     

Pharmacokinetic modelling of cefotaxime and desacetylcefotaxime—a population study in 25 elderly patients

Objective To develop a pharmacostatistical model to simultaneously characterise the pharmacokinetics of cefotaxime and its main metabolite, desacetylcefotaxime, in elderly patients.Methods Cefotaxime, 1 g, was infused three times daily to 25 elderly patients, 66–93 years old. Cefotaxime and desacetylcefotaxime plasma concentrations (289 and 304 samples, respectively), along with demographic and physiological characteristics, were analysed using a population approach.Results Cefotaxime pharmacokinetics was best described by a two-compartment open model in which desacetylcefotaxime was produced from the central compartment. The final parameter estimates were derived from simultaneous fit of parent/metabolite data. Cefotaxime clearance, mean 5.5 l/h, was positively influenced by body weight and serum protein concentration and negatively influenced by serum creatinine and age. In contrast, desacetylcefotaxime elimination was only decreased by age. The mean terminal half-lives of cefotaxime and desacetylcefotaxime were 1.7 h and 2.6 h, respectively. The stability and predictive performance of the final population pharmacokinetic model was assessed using 200 bootstrap samples of the original data.Conclusion Cefotaxime and desacetylcefotaxime elimination decreased with increasing age above 60 years. This decreased elimination was related to individual characteristics that are typically related to renal function.     

Comparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar,and rituximab

AimsTo evaluate potential differences between PF‐05280586 and rituximab sourced from the European Union (rituximab‐EU) and USA (rituximab‐US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF‐05280586.MethodsA randomised, double‐blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti‐tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab‐EU and rituximab‐US responses using longitudinal nonlinear mixed effects models.ResultsThe analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group‐to‐group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF‐05280586 vs. rituximab‐EU or rituximab‐US lie outside the reference ranges were low.ConclusionsNo clinically meaningful differences were detected in DAS28 or ACR response between PF‐05280586 and rituximab‐EU or rituximab‐US as the differences were within the pre‐specified reference ranges. TRIAL REGISTRATION Number: {"type":"clinical-trial","attrs":{"text":"NCT01526057","term_id":"NCT01526057"}}NCT01526057.     

Risk–benefit assessment of the combined oral contraceptive pill in women with a family history of female cancer

Introduction: Oral contraceptive pills (OCPs) are the most frequently used form of effective, reversible contraception among women of childbearing potential. In the average risk population, OCPs may offer a protective benefit against ovarian, endometrial and colorectal malignancies. In women at high risk for breast, ovarian, endometrial or colorectal malignancies, the risk–benefit profile is less well studied.

Areas covered: In this article, we review pertinent literature on the use of OCPs in patients with genetic susceptibilities due to mutations in BRCA1, BRCA2 or mismatch repair genes implicated in hereditary nonpolyposis colorectal cancer as well as those with a strong family history of malignancies associated with these syndromes.

Expert opinion: For women at high risk for ovarian, endometrial and/or colorectal malignancies due to genetic susceptibilities or a strong family history, the possibility of chemoprevention with OCPs may be an attractive option; however, the potential increase in breast cancer, although small, must be considered in clinical decision-making. The ultimate decision to use OCPs in a high-risk woman should be based on a consideration of her specific genetic risk, her age, her reproductive plans and her willingness to consider surgical prophylaxis options.     

Understanding mixed environmental exposures using metabolomics via a hierarchical community network model in a cohort of California women in 1960’s

Even though the majority of population studies in environmental health focus on a single factor, environmental exposure in the real world is a mixture of many chemicals. The concept of “exposome” leads to an intellectual framework of measuring many exposures in humans, and the emerging metabolomics technology offers a means to read out both the biological activity and environmental impact in the same dataset. How to integrate exposome and metabolome in data analysis is still challenging. Here, we employ a hierarchical community network to investigate the global associations between the metabolome and mixed exposures including DDTs, PFASs and PCBs, in a women cohort with sera collected in California in the 1960s. Strikingly, this analysis revealed that the metabolite communities associated with the exposures were non-specific and shared among exposures. This suggests that a small number of metabolic phenotypes may account for the response to a large class of environmental chemicals.     

Risk factors for treatment failure in patients receiving β-lactam/β-lactamase inhibitor combinations for Enterobacteriaceae bloodstream infection: A retrospective,single-centre,cohort study

The aim of this study was to investigate risk factors for treatment failure in patients receiving in vitro-active therapy with β-lactam/β-lactamase inhibitor (BL/BLI) for Enterobacteriaceae bloodstream infection (E-BSI). This was a retrospective, single-centre study of patients diagnosed with E-BSI at an Italian centre over a 4-year period. Exclusion criteria were age <18 years, clinical data unavailable, polymicrobial BSI, failure to receive in vitro-active therapy and death within 72 h from drawing the index blood culture. Patients who received BL/BLI as appropriate empirical and/or definitive therapy for ≥50% of the total treatment duration were selected. The primary endpoint was all-cause 30-day mortality. The secondary endpoint was 90-day relapse. Of 1319 eligible patients, 835 were selected. A total of 714 received BL/BLI as appropriate empirical therapy, of whom 522 remained on BL/BLI as definitive therapy and 192 shifted to another antibiotic for <50% of the treatment duration; 121 received BL/BLI as definitive therapy only. Non-susceptibility to extended-spectrum cephalosporins (NS-ESCs) was detected in 207 episodes (24.8%). All-cause 30-day mortality was 6.8%. In multivariate analysis adjusted for NS-ESC, independent predictors of mortality were Charlson comorbidity index, septic shock, Proteus spp. and CVC-related BSI, whilst urinary source was a protective factor. The 90-day relapse rate was 4.2%. Immunosuppression was the main independent predictor for relapse. BL/BLI was the most common antibiotic administered to patients with E-BSI in this cohort. Among patients appropriately treated with BL/BLI, failure rates were low and were primarily associated with underlying diseases, clinical severity at BSI onset and infection source.     

The validity of a symptom diary in ratings of dyspepsia measured against a detailed interview: do patients and clinicians agree in their assessment of symptoms?

BACKGROUND: Patients' self-assessment of symptoms is central in drug treatment trials of functional dyspepsia. The validity of such ratings is important. AIM: To validate a diary for monitoring severity and duration of dyspepsia. METHOD: We compared the diary-cards with two clinicians' ratings of the patient's open-ended responses to the same questions administered by interview. Agreements were evaluated by estimation of the overall agreement and weighted kappa values (Kw). RESULTS: Forty-six patients were evaluated. The Kw between the two clinicians rating severity and duration of symptoms were 0.59 and 0.86, respectively. Overall agreement between patients' diary rating and clinicians' consensus rating of severity were 52%, and a moderate agreement with Kw of 0.49 was found. For duration of symptoms the overall agreement and Kw were 67% and 0.59, respectively. Qualitative data revealed useful insight in the possible causes of suboptimal agreement between patients and clinicians. CONCLUSIONS: We found a moderate to good agreement between patient and observer ratings, indicating that patients to a reasonable extent interpret severity and duration of dyspeptic symptoms in the same way as do investigators. A ceiling effect of the duration scale indicates suboptimal response categories, which should be adjusted before further use.     

Risk assessment of thujone in foods and medicines containing sage and wormwood – Evidence for a need of regulatory changes?

Thujone is a natural substance found in plants commonly used in foods and beverages, such as wormwood and sage, as well as in herbal medicines. The current limits for thujone in food products are based on short-term animal studies from the 1960s, which provided evidence for a threshold-based mechanism, yet only allowed for the derivation of preliminary values for acceptable daily intakes (ADI) based on the no-observed effect level (NOEL). While the 2008 European Union Regulation on flavourings deregulated the food use of thujone, the European Medicines Agency introduced limits for the substance in 2009. The present study re-evaluates the available evidence using the benchmark dose (BMD) approach instead of NOEL, and for the first time includes data from a long-term chronic toxicity study of the National Toxicology Program (NTP). The NTP data provide similar results to the previous short-term studies. Using dose–response modelling, a BMD lower confidence limit for a benchmark response of 10% (BMDL10) was calculated as being 11 mg/kg bw/day for clonic seizures in male rats. Based on this, we propose an ADI of 0.11 mg/kg bw/day, which would not be reachable even for consumers of high-levels of thujone-containing foods (including absinthe). While fewer data are available concerning thujone exposure from medicines, we estimate that between 2 and 20 cups of wormwood or sage tea would be required to reach this ADI, and view that the short-term medicinal use of these herbs can also be regarded as safe. In conclusion, the evidence does not point to any need for changes in regulations but confirms the current limits as sufficiently protective for consumers.