[Source Apportionment of Morphine in Wastewater].

It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are complex, and distinguishing the contribution of different sources has become a key issue. A total of 262 influent samples from 61 representative wastewater treatment plants in a typical city were collected from October 2022 to March 2023. The concentrations of morphine, codeine, thebaine, papaverine, noscapine, and monoacetylmorphine were analyzed in wastewater and poppy straws. Combined with the proportion of alkaloids in poppy straws, the source analysis of alkaloids in wastewater was analyzed using the ratio method and positive matrix factorization model (PMF). Only five alkaloids were detected in wastewater, and monoacetylmorphine, a metabolite of heroin, was not detected. The concentrations of morphine and codeine were significantly higher than those of noscapine, papaverine, and thebaine. By constructing the ratios of codeine/(morphine + codeine) and noscapine/(noscapine + codeine), the source of poppy straw could be qualitatively distinguished. The PMF results showed that three sources of morphine for medical use, poppy straw, and codeine contributed 44.9%, 43.7%, and 9.4%, respectively. The different sources varied in these months due to the COVID-19 and influenza A outbreaks, in which the use of drugs containing poppy straws and codeine was the main source, whereas the use of morphine analgesics remained relatively stable. Inventory analysis further demonstrated the reliability of the source contributions from the PMF model, and morphine was not abused in this city.

Codeine and promethazine: Exploratory study on "lean" or "sizzurp" using national survey data and an online forum.

BACKGROUND: The concoction known as "lean" containing codeine and promethazine, holds a prominent cultural presence and is often referenced in mass media platforms (e.g., music and social media). Surprisingly, there's a scarcity of national data characterizing the use of lean. Therefore, the current study investigated the use of lean using national survey data and online forum participant input, and focused on identifying concurrent substance use, exploring co-administration with other substances (e.g., alcohol, cannabis), and determining lean-related experiences. METHODS: We analyzed data from the National Survey on Drug Use and Health (NSDUH) spanning 2007-2019, identifying persons who used lean (weighted N = 42,275). Additionally, we conducted a Reddit-based study to gather insights about lean consumtion (N = 192). RESULTS: The NSDUH data indicated that lean use was most prevalent among teenagers and young adults (ages 13-21), accounting for 66% of the sample. This trend was more pronounced in male respondents (75%) compared to females. Additionally, the use was predominantly observed among Black/African American (29%), Hispanic (28%), and White (33%) populations, with these groups also reporting higher levels of concurrent alcohol and cannabis use. Similarly, findings from Reddit showed that individuals who used lean were predominantly male (67%) and exhibited elevated concurrent rates of alcohol (83%) and cannabis (46%) use in the past 30 days. Moreover, approximately 66% of respondents met criteria for severe lean use disorder, and 37% acknowledged driving under its influence. CONCLUSION: The NSDUH data found that mostly young adult males reported consuming lean in the past twelve months, though the racial/ethnic breakdown of persons who used lean was diverse. The Reddit data found that most individuals in the sample met the criteria for a substance use disorder pertaining to their lean consumption. These findings underscore the clinical significance and necessity for further controlled research on lean.

Health Canada advisory impacts on the prevalence of oral codeine use in the Pediatric Canadian population: comparative study across provinces.

Health Canada (HC) has, since 2013, issued safety alerts restricting the use of codeine-containing drugs among breastfeeding women and children/adolescents under 18 years of age. These products are linked to breathing problems among ultra-rapid CYP2D6 metabolizers and early use of opioid can lead to future opioid misuse. Using a multi-province population-based cohort study, we estimate the impact of federal safety alerts on annual rates of codeine use in the Canadian pediatric population. We analyzed data from 8,156,948 children/adolescents in five Canadian provinces between 1996 and 2021, using a common protocol. Children/adolescents were categorized as: ≤ 12 years (children) or > 12 years (adolescents). We defined codeine exposure by ≥ 1 prescription filled for codeine alone or combined with other medications. For both age categories, we obtained province-specific codeine prescription filling rates per calendar year by dividing the number of children/adolescents with ≥ 1 codeine prescription filled by the number of person-time. Annual rates of codeine use per 1000 persons vary by province from 3.0 (Quebec) to 10.1 (Manitoba) in children, and from 5.5 to 51.3 in adolescents. After the 2013 HC advisory, exposure decreased in all provinces (adjusted level change from - 0.6 to - 18.4%) in children and from - 2.1 to - 17.9% in adolescents after the 2016 advisory. Annual rates declined over time in all provinces, following HC safety alerts specific to each of the two age categories.

Development of a Potential-Modulated Electrochemiluminescence Measurement System for Selective and Sensitive Determination of the Controlled Drug Codeine.

Codeine is a common analgesic drug that is a pro-drug of morphine. It also has a high risk of abuse as a recreational drug because of its extensive distribution as an OTC drug. Therefore, sensitive and selective screening methods for codeine are crucial in forensic analytical chemistry. To date, a commercial analytical kit has not been developed for dedicated codeine determination, and there is a need for an analytical method to quantify codeine in the field. In the present work, potential modulation was combined with electrochemiluminescence (ECL) for sensitive determination of codeine. The potential modulated technique involved applying a signal to electrodes by superimposing an AC potential on the DC potential. When tris(2,2'-bipyridine)ruthenium(II) ([Ru(bpy)3]2+) was used as an ECL emitter, ECL activity was confirmed for codeine. A detailed investigation of the electrochemical reaction mechanism suggested a characteristic ECL reaction mechanism involving electrochemical oxidation of the opioid framework. Besides the usual ECL reaction derived from the amine framework, selective detection of codeine was possible under the measurement conditions, with clear luminescence observed in an acidic solution. The sensitivity of codeine detection by potential modulated-ECL was one order of magnitude higher than that obtained with the conventional potential sweep method. The proposed method was applied to codeine determination in actual prescription medications and OTC drug samples. Codeine was selectively determined from other compounds in medications and showed good linearity with a low detection limit (150 ng mL-1).

Characterization of Codeine Treatment Responders Among Patients with Refractory or Unexplained Chronic Cough: A Prospective Real-World Cohort Study.

PURPOSE: Codeine is a narcotic antitussive often considered for managing patients with refractory or unexplained chronic cough. This study aimed to evaluate the proportion and characteristics of patients who responded to codeine treatment in real-world practice. METHODS: Data from the Korean Chronic Cough Registry, a multicenter prospective cohort study, were analyzed. Physicians assessed the response to codeine based on the timing and degree of improvement after treatment initiation. Follow-up assessments included the Leicester Cough Questionnaire and cough severity visual analog scale at six months. In a subset of subjects, objective cough frequency was evaluated following the initiation of codeine treatment. RESULTS: Of 305 patients, 124 (40.7%) responded to treatments based on anatomic diagnostic protocols, while 181 (59.3%) remained unexplained or refractory to etiological treatments. Fifty-one subjects (16.7%) were classified as codeine treatment responders (those showing a rapid and clear response), 57 (18.7%) as partial responders, and 62 (20.3%) as non-responders. Codeine responders showed rapid improvement in objective cough frequency and severity scores within a week of the treatment. At 6 months, responders showed significantly improved scores in cough scores, compared to non-responders. Several baseline parameters were associated with a more favorable treatment response, including older age, non-productive cough, and the absence of heartburn. CONCLUSIONS: Approximately 60% of chronic cough patients in specialist clinics may require antitussive drugs. While codeine benefits some, only a limited proportion (about 20%) of patients may experience rapid and significant improvement. This underscores the urgent need for new antitussive drugs to address these unmet clinical needs.

Advanced chemometric methods for simultaneous quantitation of caffeine, codeine, paracetamol, and p-aminophenol in their quaternary mixture.

Two different multivariate techniques have been applied for the quantitative analysis of caffeine, codeine, paracetamol and p-aminophenol (PAP) in quaternary mixture, namely, Partial Least Squares (PLS-1) and Artificial Neural Networks (ANN). For suitable analysis, a calibration set of 25 mixtures with various ratios of the drugs and PAP impurity were established using a 4-factor 5-level experimental design. The most meaningful wavelengths for the chemometric models were chosen using Genetic Algorithm (GA) as a variable selection technique. By using an independent validation set, the validity of the proposed methods was evaluated. A comparative study was established between the three multivariate models (PLS-1, GA-PLS and GA-ANN). The comparison between the various models revealed that the GA-ANN model was superior at resolving the highly overlapped spectra of this quaternary combination. The drugs were successfully quantified in their pharmaceutical dosage form utilizing the GA-ANN models.

Opt-in versus universal codeine provision for medical abortion up to 10 weeks of gestation at British Pregnancy Advisory Service: a cross-sectional evaluation.

OBJECTIVE: To assess patient experiences of pain management during medical abortion up to 10 weeks' gestation with opt-in versus universal codeine provision. METHODS: We invited patients who underwent medical abortion up to 10 weeks of gestation to participate in an online, anonymous, English-language survey from November 2021 to March 2022. We performed ordinal regression analyses to compare satisfaction with pain management (5-point Likert scale) and maximum abortion pain score (11-point numerical rating scale) in the opt-in versus universal codeine provision groups. RESULTS: Of 11 906 patients invited to participate, 1625 (13.6%) completed the survey. Participants reported a mean maximum pain score of 6.8±2.2. A total of 1149 participants (70.7%) reported using codeine for pain management during their abortion. Participants in the opt-in codeine provision group were significantly more likely to be satisfied with their pain management than those in the universal group (aOR 1.48, 95% CI 1.12 to 1.96, p<0.01). Maximum abortion pain scores were lower on average among the opt-in codeine provision group (OR 0.80, 95% CI 0.66 to 0.96, p=0.02); however, this association was not statistically significant in the model adjusted for covariates (aOR 0.85, 95% CI 0.70 to 1.03, p=0.09). CONCLUSION: Our findings suggest that patients have a better experience with pain management during medical abortion when able to opt-in to codeine provision following counselling versus receiving this medication routinely.

Fast concurrent determination of guaifenesin and pholcodine in formulations and spiked plasma using first derivative synchronous spectrofluorimetric approach.

Guaifenesin and pholcodine are frequently co-formulated in certain dosage forms. A new fast first derivative synchronous spectrofluorometric method has been used for their simultaneous analysis in mixtures. Here, first derivative synchronous spectrofluorometry enabled the successful simultaneous estimation of guaifenesin at 283 nm and pholcodine at 275 nm using a wavelength difference (Δλ) of 40 nm. The method was fully validated following International Council of Harmonization guidelines. For guaifenesin and pholcodine, linearity was determined within the corresponding ranges of 0.05-0.30 and 0.10-6.0 µg/ml. The two drugs were effectively analyzed using the developed approach in their respective formulations, and the results showed good agreement with those attained using reference methods. The method demonstrated excellent sensitivity, with detection limits down to 0.007 and 0.030 µg/ml and quantitation limits of 0.020 and 0.010 µg/ml for guaifenesin and pholcodine, respectively. Therefore, the procedure was successful in determining these drugs simultaneously in vitro in spiked plasma samples and syrup dosage form. The developed methodology also offered an environmentally friendly advantage by utilizing water as the optimal diluting solvent throughout the whole work. Different greenness approaches were investigated to ensure the method's ecofriendly properties.

Urine and hair drug test results associated with daily consumption of codeine-predominant poppy seed food products.

This study examined the urine and hair opiate profiles associated with the daily consumption of presumptive codeine-predominant poppy seed food products. Ten participants consumed one of five food products at breakfast for 10 consecutive days. Baseline urine and hair samples were collected on Day 1. The urine samples were collected 4, 8 and 12 h following poppy seed consumption on Days 1 and 10, and the first morning void urine samples were collected on Days 2-10. A second hair specimen was collected on Day 20 ± 2. Urine drug test results: Three of the food products were associated with opiate-negative urine drug test results at all time points at a 300 ng/mL cut-off. Two of the food products were associated with opiate-positive drug test results at all non-baseline time points at a 300 ng/mL cut-off. Of these, all samples (n = 60) were codeine-positive, and 27 (45%) were morphine-positive. Codeine concentrations exceeded morphine concentrations in every sample and always by multiples. Thirty-nine of the 60 samples (65%) were codeine-positive at a 2,000 ng/mL cut-off, while none of these samples were morphine-positive at this cut-off. None of the 60 samples reached an opiate threshold of 15,000 ng/mL, although one participant produced a maximum codeine concentration of 13,161 ng/mL (13,854 ng/mg creatinine). There was no clear trend toward increasing urinary opiate concentrations over the course of the study. Hair drug test results: The hair samples of two participants produced quantifiable codeine (41 pg/mg and 51 pg/mg), but no sample reached a common reporting threshold of 200 pg/mg for codeine or morphine.

Defining opioid naïve and implications for monitoring opioid use: A population-based study in Alberta, Canada.

PURPOSE: Reducing initial exposure of "opioid naïve" patients to opioids is a public health priority. Identifying opioid naïve patients is difficult, as numerous definitions are used. The objective is to summarize current definitions and evaluate their impact on opioid naïve measures in Alberta. METHODS: An exploratory data analysis of the literature was conducted over the last 10 years to identify definitions commonly used in the literature to define opioid naïve. Then, using these definitions as a guide, we descriptively report the proportion of patients in Alberta between 2017 and 2021 who would be considered as opioid naïve using these definitions and all opioid dispensing data. RESULTS: Three categories of definitions were broadly identified: (1) no opioid use within the previous 30 days/6 months/1 year, based on dispensation date; (2) no opioid use based on dispensation date plus days of supply; and, (3) exclusion of codeine from Definitions 1 and 2. Applying these definitions to the Alberta population showed a very wide range in the proportion who would be considered as opioid naïve. Overall, 36.4% of Albertans (n = 1 551 075) had an opioid dispensation in 2017-2021. The average age was 46.6 ± 18.8 and 52.8% were female. The proportion of opioid naïve were most affected by the "opioid free" period, with 97.4%, 83.2%, and 65.6% being classified as opioid naïve using time windows from Definition 1 (30 days, 6 months, 1 year of no prior opioid use). Definitions 2 and 3 did not materially change the results. Further extending the "opioid free" period to 2 years showed only 35% were opioid naïve. CONCLUSIONS: The most convenient definition for "opioid naïve" was the use of an "opioid free" period. The choice of window would depend on how the information may be used to assistant in clinical decisions with longer windows more likely to reflect true opioid naïve patients. Irrespective of definition used, a large proportion of opioid users would be considered opioid naïve in Alberta.

Older Adult-Onset of Inflammatory Bowel Diseases Is Associated With Higher Utilization of Analgesics: A Nationwide Cohort Study.

INTRODUCTION: Patients with inflammatory bowel diseases (IBD) commonly require analgesic medications to treat pain, which may be associated with complications. We examined trends of analgesic use according to age at IBD onset. METHODS: This nationwide cohort study included adults diagnosed with IBD between 1996 and 2021 in Denmark. Patients were stratified according to their age at IBD onset: 18-39 years (young adult), 40-59 years (adult), and older than 60 years (older adult). We examined the proportion of patients who received prescriptions for analgesic medications within 1 year after IBD diagnosis: strong opioids, tramadol, codeine, nonsteroidal anti-inflammatory drugs, and paracetamol. Multivariable logistic regression analysis was performed to examine the association between age at IBD onset and strong opioid prescriptions and the composite of strong opioid/tramadol/codeine prescriptions. RESULTS: We identified 54,216 adults with IBD. Among them, 25,184 (46.5%) were young adults, 16,106 (29.7%) were adults, and 12,926 (23.8%) were older adults at IBD onset. Older adults most commonly received analgesic prescriptions of every class. Between 1996 and 2021, strong opioid, tramadol, and codeine prescriptions were stable, while paracetamol prescriptions increased and nonsteroidal anti-inflammatory drug prescriptions decreased. After multivariable logistic regression analysis, older adults had higher adjusted odds of receiving strong opioid prescriptions (adjusted odds ratio 1.95, 95% confidence interval 1.77-2.15) and the composite of strong opioid/tramadol/codeine prescriptions (adjusted odds ratio 1.93, 95% confidence interval 1.81-2.06) within 1 year after IBD diagnosis compared with adults. DISCUSSION: In this nationwide cohort, older adults most commonly received analgesic prescriptions within 1 year after IBD diagnosis. Additional research is needed to examine the etiology and sequelae of increased analgesic prescribing to this demographic.

Development and validation of a brief screening tool for over-the-counter codeine dependence.

BACKGROUND: Low-dose codeine is sold without a prescription in countries like the UK, Ireland, and South Africa. Due to misuse concerns, exploring pharmacy screening tools to identify those at risk and needing additional support is vital. OBJECTIVES: The study aims to develop and validate a brief screening tool that assesses the risk of codeine dependence with language appropriate for routine use in community pharmacies. METHOD: Scale development and validation occurred over two studies. In Study 1, scale item generation was based on structured analyses of psychosocial and pharmacy variables from frequent over-the-counter codeine consumers (N = 795). CFA was used to assess the cohesiveness of the resultant four-item Codeine Dependence Scale (CDS). ROC analyses were used to assess the performance of the CDS against risk cases identified by the Severity of Dependence Scale; identifying an optimal cut-off value of ≥2 as representing individuals at risk of codeine dependence. In Study 2, this CDS threshold was assessed against positive DSM-5 Opioid Use Disorder (OUD) cases related to codeine use assessed using the AUDADIS-IV. RESULTS: With a cut-off score of ≥2, the CDS has sensitivity and specificity of 76% and 48%, respectively, against a DSM-5 codeine-related OUD diagnosis using the AUDADIS-IV. For identification of any codeine-related OUD (as measured by the AUDADIS-IV) 15 months after baseline, the CDS achieved an overall correct classification rate of 52%; 72% for positive cases. CONCLUSIONS: The CDS exhibits reasonable cross-sectional and longitudinal sensitivity but low specificity, partly due to its brevity. However, the inclusive nature of the CDS is not a negative for application as a screening tool in a pharmacy setting as individual CDS items represent critical conversation points with a pharmacist, regardless of the screening outcome. The non-confronting nature of CDS items make the scale a viable option for pharmacy-based SBI in countries where codeine remains OTC.

Pholcodine and allergy to neuromuscular blocking agents: where are we and how did we get here?

Despite the purported link between pholcodine and neuromuscular blocking agent allergy, screening for prior pholcodine use offers no practical benefit to patients, and anaesthetists should continue to use a neuromuscular blocking agent where this is clinically indicated.

Association of tramadol use with risk of hip fractures in patients with osteoarthritis: A systematic review and meta-analysis of observational studies.

OBJECTIVE: Many studies have reported conflicting results for the use of tramadol with the risk of fractures, especially hip fractures. This systematic review and meta-analysis study aimed to evaluate the association of tramadol use versus codeine use with the risk of hip fracture for the first time. METHODS: PubMed, Scopus, Google Scholar, and Web of Science databases were searched with specific keywords to find studies that examined the association of tramadol use with hip fracture risk in patients with osteoarthritis up to May 2023. The risk of hip fracture secondary to tramadol versus codeine use was estimated based on age and sex. This systematic review was conducted based on the PRISMA checklist. Heterogeneity between studies was evaluated using Cochran's Q and I2 tests. Egger's test was used to check publication bias. The Newcastle-Ottawa Checklist (NOS) was used to assess the quality of the studies. FINDINGS: Ten studies with 1,939,293 participants were reviewed. The majority of participants were female. Based on the study evaluation checklist, most studies were of good quality. Tramadol use significantly increases the overall risk of hip fracture. (HR: 1.32, 95% CI: 1.14, 1.51, P: 0.001, I2:19.3%) Tramadol use significantly increases the risk of hip fracture in men (HR: 1.48, 95% CI: 1.24, 1.73, P: 0.001 I2:35%) and age ≤65 years (HR: 1.63, 95% CI: 1.45, 1.80, P: 0.001, I2:0%). CONCLUSION: The use of tramadol significantly increases the risk of hip fracture. This increased risk of hip fracture was greater in males younger than 65 years.

In silico affinity between analgesic/anti-inflammatory drugs and the transient receptor potential A1 to predict potential pharmacological managing approaches for bleaching sensitivity.

Reducing in-office tooth bleaching sensitivity represents a challenge for professionals. Researchers have associated the block of the pain receptor TRPA1 with reducing bleaching sensitivity. However, the chemical affinity of analgesic/anti-inflammatory drugs to the TRPA1 needs to be verified. To perform a virtual screening of multiple drugs (analgesic and anti-inflammatory drugs) to verify chemical affinity for the TRPA1 receptor. The crystal structure of the TRPA1 receptor proteins was retrieved from the Protein Data Bank. The SMILES codes of the ligands were extracted from PubChem. The binding energy of the complex was obtained in ∆G - kcal/mol by AutoDock Vina© and replicated in the webservers SwissDock©, Dockthor©, and CbDock©. LigPlus© confirmed the binding sites. Codeine and dexamethasone showed regularity among all servers, even showing binding energy values of -7.9 kcal/mol for codeine and -8.1 kcal/mol for dexamethasone. Codeine and dexamethasone may be potential drugs to manage tooth bleaching sensitivity if they reach the dental pulp TRPA1 receptor.