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Q methodological studies often incorporate post-Q sort interviews to facilitate and enrich the interpretation of identified factors. This article describes a novel approach in which Q methodology and interviews comprise separate strands which are analyzed separately then converged for further analysis. The new approach is exemplified in a study exploring over-the-counter codeine misuse in Australia. The Q methodology and interview results are summarized, integrated and then discussed, including methodological challenges. This article contributes to scholarly literature by introducing and illustrating the applicability of using mixed methods integration to combine Q methodology and interviews; providing new insights into over-the-counter codeine misuse; and proposing 'unique contribution' as an alternative descriptor to the integration fit of 'silence'. [ABSTRACT FROM AUTHOR]

In the present paper, a nanocomposite of rGO and TiO2 nanoparticles (TiO2/rGO) was prepared by a facile synthesis method with peroxo titanium complexes as TiO2 precursor. The morphology and structure of TiO2/rGO nanocomposite were investigated by X-ray diffraction (XRD), Raman spectroscopy, nitrogen adsorption/desorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive X-ray (EDX)-elementary mapping spectroscopy. It was found that TiO2/rGO nanocomposites with high surface area were formed involving strong coupling interaction between TiO2 and rGO. Based on the synergistic effect of rGO and TiO2 nanoparticles, an electrochemical sensor for paracetamol (PAR) and codeine (COD) was fabricated by modifying the glassy carbon electrode (GCE) with TiO2/rGO material. The cyclic voltammetry (CV) and differential pulse anodic stripping voltammetry (DP-ASV) were used to determine the electrochemical signals of these analytes. CVs of this sensor provided distinct and sharp oxidation peaks for PAR and COD. The DP-ASV parameters were optimized. It was found that the proposed electrode exhibits excellent electrochemical activity toward PAR and COD. Under the optimal conditions, the A low limit of detection of 0.28 µM for PAR and 0.25 µM for COD were achieved in the linear range from 0.4 to 2.0 µM for both PAR and COD. The proposed method was free from the interference effects of glucose, ascorbic acid, caffeine, and other inorganic salts. This electrode was also highly stable and sensitive making it applicable in the analysis of various real pharmaceutical samples. [ABSTRACT FROM AUTHOR]

The Papaveraceae family comprises more than 40 genera and 760 species. Papaver alkaloids have significant therapeutic importance in the treatment of various diseases and exhibit some antimicrobial properties. These alkaloids have been used in cancer medicine, cough, and hypertension. The main goal of this study is to determine the amounts of various alkaloids in samples collected from different regions of Iran. The findings of this research could provide valuable insights for the pharmaceutical industry. Two grams of dried and powdered plant material were extracted with 30 ml chloroform and 15 ml of 99% acetic acid for 30 minutes under sonication. The change in the pH of the sample was revealed by 10 through gradually adding ammonia. The mobile phases consisted of phosphoric acid and acetonitrile. The analysis of the Papaveraceae family in Iran was performed using high-performance liquid chromatography-ultraviolet detection. This paper focuses on the Papaver alkaloids (noscapine, morphine, thebaine, papaverine, and codeine) found in three species of Papaver and four species of Glaucium. The maximum contents of noscapine (21.02 mg/kg DW), morphine (34.51 mg/kg DW), thebaine (6.96 mg/kg DW), papaverine (103.76 mg/kg DW), and codeine (3.63 mg/kg DW) were reported in Papaver rhoeas L., Papaver fugax Poir and., Glaucium oxylobum Boiss. & Buhse, respectively. [ABSTRACT FROM AUTHOR]

Background: Paracetamol–codeine combination tablet is widely used in pain management after day surgery. For safety reasons, its use has decreased in recent years. Codeine is a prodrug metabolised in the liver by the cytochrome P450 2D6 (CYP2D6) enzyme to morphine that produces the analgesic effect of codeine. CYP2D6 is highly polymorphic, and based on genotypes, individuals can be divided into four categories: poor‐, intermediate‐, normal‐ and ultrarapid metabolisers. Differences in morphine and its metabolite concentrations have been described between different CYP2D6 genotypes following codeine administration. The aim of the study was to investigate the possible effect of CYP2D6 genotype on codeine efficacy and adverse effects in a large cohort of adult patients undergoing ambulatory surgery. Methods: A total of 987 patients scheduled for ambulatory surgery were included in the analyses. Operation types or anaesthesia methods were not limited in the study protocol. All study patients received a fixed dose of paracetamol (1000 mg) and codeine (60 mg) orally for premedication. A blood sample was drawn to identify the genotype of CYP2D6. At home, the first‐line analgesic was paracetamol–codeine combination of 1–2 tablets at 1–3 times per day. Data on the efficacy and side effects of codeine were collected on the day of surgery and the following two postoperative days. Results: Of the studied patients, 37 (3.7%) were poor CYP2D6 metabolisers, 264 (27%) were intermediate, 623 (63%) were normal and 63 (6.4%) were ultrarapid metabolisers. Activity scores ranged from 0 to 4. CYP2D6 genotype was not associated in a statistically significant manner with postoperative pain, opioid consumption or the adverse effects of codeine, except for constipation at home. Poor CYP2D6 metabolisers reported significantly less severe constipation compared with normal metabolisers (p =.009, OR 0.40, 95% Cl 0.20–0.80). Conclusion: CYP2D6 genotype appears to be of minor importance for the analgesic efficacy of oral paracetamol‐codeine combination therapy after ambulatory surgery in adult patients undergoing similar types of surgery as in the present study but it may affect the risk of constipation. [ABSTRACT FROM AUTHOR]

Aims: We aimed to determine the impact of codeine rescheduling on prescribing of codeine and other opioids, with a focus on demographic and diagnoses associated with codeine prescribing before and after rescheduling of codeine to prescription‐only in February 2018. Methods: We used interrupted time series analysis (February 2016‐February 2020) and probit regression to examine prescribing of codeine and other opioids according to primary care data from 464 general practice clinics in Victoria, Australia. Results: The rate of codeine prescribing increased in the month following rescheduling (additional 76 people/10000, 95% confidence interval [CI] 49‐103), then declined to baseline rates (slope −2.02, 95% CI 3.79, −0.25). Prescribing of other opioids did not change. Post rescheduling, females were more likely to receive codeine prescriptions compared to males (β = 0.094, 95% CI 0.08‐0.108) and those aged 70‐79 years were more likely to receive codeine compared to those aged <30 years. Those residing in the least disadvantaged areas had a greater probability of being prescribed codeine than those in more disadvantaged areas after rescheduling (β = 0.154, 95% CI 0.129‐0.179). A documented mental health diagnosis (β = 0.067, 95% CI 0.052‐0.082) or migraine diagnosis (β = 0.057, 95% CI 0.037‐0.078) was associated with increased likelihood of receiving a codeine prescription after rescheduling compared to before in contrast to those without such a diagnosis. Conclusion: Codeine rescheduling did not result in a sustained increase in codeine prescribing nor a change in the prescribing of other opioids. Patient factors associated with increased codeine prescribing after compared to before rescheduling included female sex, older age, migraine diagnosis and comorbid mental health conditions. Registration: EU PAS Register (EUPAS43218). [ABSTRACT FROM AUTHOR]

Concerns have been raised about how readily available over-the-counter (OTC) codeine formulations may be contributing to the expanding opioid epidemic. Focusing on the analytical methods used to find and measure codeine in various sample types, this systematic review provides a thorough analysis of OTC codeine abuse and misuse. It also includes case studies that highlight the seriousness of the problem by describing codeine-related deaths and intoxications. A wider view of the issue is provided by the crime statistics in this paper that relate to codeine and related drugs in India from 2017 to 2021. A thorough electronic search covering the years 2012–2022 was carried out from February 2023 to April 2023 to compile this review. Google Scholar, Science Direct, and PubMed were just a few of the search engines used. While crime statistics for India were sourced from the National Crime Records Bureau website, case reports were gathered from the Journal of Medical Case Reports and Wiley Online Library. Studies examining OTC codeine, its abuse, and the analytical methods used for its detection and quantification were all covered by our inclusion criteria. Case reports involving codeine seizures, fatalities, and intoxications were also included, along with review and research papers. On the other hand, studies with little connection to OTC codeine, books, documents, clinical trials, meta-analyses, non-English papers, and publications with only abstracts were disregarded. With the help of this systematic review, we located 531 studies in databases, 83 of which satisfied our inclusion requirements. Our research is organized into sections that cover crime data, case studies of codeine-related overdoses or deaths, and detection methods. For researchers, medical professionals, and policymakers actively engaged in the fight against codeine abuse and the societal harms it causes, this review is an invaluable resource.

Youngwoo Cho,1 Theodore Karrison,2 Matthew M Jack,3 Anish R Choksi,3,4 Randall W Knoebel,3,4 Kiang-Teck J Yeo,1,5 Samuel L Volchenboum,6 Russell Z Szmulewitz,1,7 Everett E Vokes,7 Mark J Ratain,1,3,7 Peter H O’Donnell1,3,7 1Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, USA; 2Biostatistics, Department of Health Service, University of Chicago, Chicago, IL, USA; 3Center for Personalized Therapeutics, University of Chicago, Chicago, IL, USA; 4Department of Pharmacy, University of Chicago Medicine, Chicago, IL, USA; 5Department of Pathology, University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA; 6Department of Pediatrics, University of Chicago, Chicago, IL, USA; 7Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center and Biological Sciences, Chicago, IL, USACorrespondence: Peter H O’Donnell, Email podonnel@bsd.uchicago.eduBackground: Cancer patients frequently suffer from pain, often managed with opioids. However, undertreated pain remains a significant concern. Opioid effectiveness varies due to genetic differences in how individuals metabolize some of these medications. While prior research suggests promise in tailoring opioid prescriptions based on CYP2D6 genetic makeup, its application in cancer pain management remains limited. This study investigates the potential benefits of preemptive CYP2D6 genotyping for cancer patients initiating opioid therapy, focusing on codeine, tramadol, and hydrocodone, whose efficacy is demonstrably impacted by CYP2D6 variations.Methods: This is a randomized, prospective study to evaluate the effects of preemptive pharmacogenomic (PGx) testing on opioid dosing decisions/selections and composite pain score in oncology patients. Patients with metastatic solid tumors for whom near-future opioid therapy is anticipated will be randomized to PGx and control arms, stratified by the presence or absence of bony metastases and history of opioid use. In the PGx arm, patients will be preemptively tested using a panel of pharmacogenomic genetic variants, and providers will receive opioid dosing guidance via an electronic medical record-embedded clinical decision support tool. In the control arm, pain prescribing will occur per standard of care without genotype information.Planned Outcome: The primary study outcome will be composite pain intensity during the first 45 days after an index opioid prescription for codeine, tramadol, or hydrocodone. Safety will be assessed by comparing opioid-related adverse event rates between the two study arms. Secondary outcomes will include rates of hospitalization/emergency room visits, cumulative morphine equivalents received, and type of first opioid prescribed.Keywords: pharmacogenomics, CYP2D6, codeine, tramadol, hydrocodone, genetic testing, pain score

Abstract Codeine is widely used to control coughs, although concerns about its overuse arise due to its side-effects. This study aimed to evaluate the status of codeine usage according to various medical conditions. The Korean National Health Insurance Service sample cohort was analyzed. Subjects with more than continuous sixty days of antitussive and codeine were defined as chronic users. It was evaluated according to age, smoking status, chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis (AR), bronchiectasis, chronic cough (CC), gastroesophageal reflux disease (GERD), and lung cancer. A total of 89,289 chronic antitussive users were identified, of whom 589 were chronic codeine users. The chronic codeine users were older, more likely to be smokers, and more likely to have multimorbidity (P

Abstract Background Today, the prescription of tramadol in patients with osteoarthritis (OA) has increased significantly, which can be associated with serious consequences. Contradictory results have been reported regarding the association of tramadol versus codeine with the risk of all-cause mortality (ACM) and cardiovascular diseases (CVD). Methods This systematic review and meta-analysis aimed to evaluate, for the first time, the association of tramadol versus codeine with the risk of ACM and CVD in OA patients for the first time. We searched PubMed, Scopus, Embase, Web of sciences, and Google Scholar with specific keywords and mesh terms to find relevant studies until January 2024. Two independent researchers did the process of searching and screening articles. Cochran’s Q and I2 tests evaluated the heterogeneity of the studies. Egger’s test was used to evaluate the existence of publication bias. Results Seven population-based cohort studies, matched by the propensity score method, including 1,939,293 participants, were reviewed. The study pooled results did not show a significant association between the prescriptions of tramadol versus codeine with increasing the risk of ACM in OA patients. (Hazard ratio (HR): 1.084, 95% confidence interval (95%) CI: 0.883, 1.286, P: 0.56) In addition, the prescription of tramadol versus codeine was not associated with an increased risk of CVD in OA. (HR: 1.025, 95% CI: 0.89, 1.16, P: 0.68, I2 = 37.8%) Conclusion Our systematic review showed that tramadol prescription compared to codeine in OA patients was not associated with an increased risk of ACM and CVD.

Pharmacological pain treatment in older persons is presented by a multi-disciplinary group of European pain experts. Drugs recommended for acute or chronic nociceptive pain, also for neuropathic pain and the routes of administration of choice are the same as those prescribed for younger persons but comorbidities and polypharmacy in older persons increase the risk of adverse effects and drug interactions. Not all drugs are available or authorised in all European countries. For mild-to-moderate pain, non-opioids including paracetamol and non-steroidal anti-inflammatory drugs are first-line treatments, followed by nefopam and metamizole. Codeine, dihydrocodeine and tramadol are prescribed for moderate to severe pain and 'strong' opioids, including morphine, hydromorphone, oxycodone, fentanyl, buprenorphine, methadone and tapentadol, for severe pain. Chronic neuropathic pain treatment relies on coanalgesics, including anti-epileptics (gabapentinoids) and anti-depressants with additional option of topical lidocaine and capsaicine. The choice of analgesic(s) and the route of administration should be guided by the pain characteristics, as well as by the patient's comorbidities, organ function and medications. Several directions have been highlighted to optimise pharmacological pain management in older individuals: (1) before starting pain treatment adequately detect and assess pain and always perform a full geriatric assessment, (2) consider kidney function systematically to adjust the doses of analgesics and avoid the risks of overdose, (3) start with the lowest dose of an analgesic and increase it gradually under the control of the effect, (4) involve the older persons and family in their treatment, (5) reevaluate pain regularly during treatment and (6) combine pharmacological treatment with non-pharmacological approaches. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, family medication history is not routinely assessed as part of a patient's family health history (FHH). The information is self-reported and can depend on the individual's subjective perception. To illustrate how pharmacogenetic (PGx) testing results could be used to validate self-reported family medication history on drug-related problems (DRP), as well as to inform medication-related decisions, we herein present a case involving ten members of the same family. Case Presentation: Prior to a planned surgery, a preemptive PGx panel test was performed for a nine-year-old girl due to self-reported family medication history. The PGx panel test was also performed for her three siblings, parents, and grandparents. The focus was directed to the paternal grandmother, as she reported DRP from the hypnotic agent propofol, and to the maternal grandmother, as she described DRP after the administration of codeine and tramadol. A commercial PGx panel test of 100 variations in 30 different genes was conducted and analyzed focusing on genetic variants in cytochrome P450 enzyme 2B6 (CYP2B6), and CYP2D6 as they are involved in the biotransformation of propofol and the bioactivation of codeine and tramadol, respectively. The girl was identified as (1) CYP2B6 intermediate metabolizer (IM) with reduced enzyme activity and (2) CYP2D6 poor metabolizer (PM) with no enzyme activity. Regarding the planned surgery, it was recommended (1) to carefully titrate propofol dosage with increased monitoring of potential DRP and (2) to avoid opioids whose activation is mediated by CYP2D6 (e.g. codeine and tramadol). Further PGx testing revealed (1) the paternal grandmother as CYP2B6 normal metabolizer (NM) and (2) the maternal grandmother as CYP2D6 NM. Conclusion: The original trigger for PGx testing was the self-reported, conspicuous family medication history of DRP reported by the grandmothers. However, the girl's genotype predicted phenotypes of CYP2B6 IM and CYP2D6 PM, differed from the grandmothers'. With this exemplary case, we propose that hereditary concerns based on self-reported information on DRP should be verified by a PGx panel test, when the respective drug exhibits a PGx association. Also, the girl's PGx testing results provided important medication recommendations, which were considered perioperatively by the anesthetist suggesting to use PGx testing results preemptively to inform medication-related decisions. [ABSTRACT FROM AUTHOR]

Background and Objective: Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine. Methods: We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development. Results: Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers. Conclusions: Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine. [ABSTRACT FROM AUTHOR]

To describe analgesic-related deaths in France and report trends over a 10-year period. The DTA ("Décès Toxiques par Antalgiques") register is a French database of analgesic-related deaths among people without a history of drug abuse, reported by forensic toxicology experts. We included analgesic-related deaths occurring from January 2013 to December 2022 in France. Subject demographic characteristics and medical history, forensic autopsy findings, and toxicology reports were evaluated. Among the 1036 deceased individuals (mean [SD] age, 48.3 [15.6] years), there were slightly more women than men (M:F sex ratio, 0.89:1). Over the entire study period, tramadol was the leading cause of death, ahead of morphine. A relative increase in oxycodone-related mortality was observed (from 6.8% in 2013 to 21.1% in 2022) compared to a progressive decrease in tramadol, morphine, and codeine-related deaths (from 43.2%, 31.1% and 24.3% in 2013 to 37.5%, 26.6% and 20.3% in 2022, respectively). However, no statistically significant variations were found (Chi-squared tests of homogeneity). Other analgesics (buprenorphine, dihydrocodeine, fentanyl, gabapentin, ketamine, methadone, nefopam, and pregabalin) were also implicated in deaths, but with low and stable rates over the period studied. In France, no increase in fentanyl-related deaths and only a non-significant increase in oxycodone-related deaths were observed over the period 2013–2022. Tramadol was the leading cause of analgesic-related deaths throughout this period. Although close monitoring is still required, particularly for oxycodone, our data do not support the hypothesis of an opioid crisis in France. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the trends in post‐tonsillectomy analgesic utility and incidence of post‐tonsillectomy hemorrhage before and after the 2013 FDA Boxed Warning against codeine use after pediatric tonsillectomy. Methods: A retrospective study was conducted using TriNetX. A search for patients up to 18 years from 2008 to 2022 within the US Collaborative Network identified 15,648,542 subjects. CPT and ICD‐10 codes were used to identify children who experienced post‐tonsillectomy hemorrhage within 14 days of a tonsillectomy. Analgesics given within 14 days of tonsillectomy were tabulated annually from 2008 to 2022, including codeine, ibuprofen, acetaminophen, oxycodone, ketorolac, and hydrocodone. Bleeding percentage and analgesic utility were grouped into events before and after 2013. Results: Mean age at tonsillectomy was 5.6 years (SD = 3.0). Before 2013, the median percentage of children who experienced postoperative bleeding was 1.8% with 0.73% returning to the OR for bleeding control. After 2013, the median percentage of children who experienced postoperative bleeding was 2.4% (p = 0.029), and 0.99% returned to the OR (p = 0.008). Use of post‐tonsillectomy codeine fell from 10.4% to 0.5% (p = 0.003) whereas ibuprofen rose from 2.0% to 63.9% (p = <0.001), acetaminophen from 42.8% to 77.2% (p = <0.001), ketorolac from 1.2% to 9.2% (p = <0.001), and oxycodone from 2.0% to 30.9% (p = <0.001). No change was detected in use of hydrocodone. Conclusion: Analgesics used post‐tonsillectomy in children have changed since the FDA Boxed Warning against codeine. There has been a small but statistically significant increase in post‐tonsillectomy bleeding. Level of Evidence: 4 Laryngoscope, 134:4783–4788, 2024 [ABSTRACT FROM AUTHOR]

Introduction: The use of codeine in children aged < 12 years has been restricted in Japan since July 2017 due to safety concerns. Objective: We aimed to investigate the impacts of two labelling revisions restricting codeine use in children on the trends in its prescriptions in Japan. Methods: Children aged < 12 years (target group) and 12–17 years (control group) registered in the Japanese health insurance claims database between August 2015 and July 2021 were included. We analyzed the level and trend changes in monthly prescriptions of codeine and non-narcotic antitussives (reference) per 100,000 individuals using an interrupted time-series design across there period: the pre-intervention (before the first revision in July 2017), post-intervention (after the second revision in July 2019), and transitional (between the two revisions) periods. Results: There was a significant reduction in codeine prescriptions of 67.5% and 36.6% in the first labelling revision in the target and control groups, respectively. In the target group, a downward trend in the level of codeine prescriptions was observed until the end of the transitional period. After the second labelling revision, the level of codeine prescriptions decreased by approximately 95% compared with the last month of the pre-intervention period. For non-narcotic antitussives, there were no significant changes in the level and trend of prescriptions until the transitional period, but the trend significantly changed to negative after the second labelling revision. Conclusion: Restriction on codeine use in children by the labelling revisions could be effective for reducing codeine prescriptions in patients aged < 12 years. [ABSTRACT FROM AUTHOR]

Concerns have been raised about how readily available over-the-counter (OTC) codeine formulations may be contributing to the expanding opioid epidemic. Focusing on the analytical methods used to find and measure codeine in various sample types, this systematic review provides a thorough analysis of OTC codeine abuse and misuse. It also includes case studies that highlight the seriousness of the problem by describing codeine-related deaths and intoxications. A wider view of the issue is provided by the crime statistics in this paper that relate to codeine and related drugs in India from 2017 to 2021. A thorough electronic search covering the years 2012–2022 was carried out from February 2023 to April 2023 to compile this review. Google Scholar, Science Direct, and PubMed were just a few of the search engines used. While crime statistics for India were sourced from the National Crime Records Bureau website, case reports were gathered from the Journal of Medical Case Reports and Wiley Online Library. Studies examining OTC codeine, its abuse, and the analytical methods used for its detection and quantification were all covered by our inclusion criteria. Case reports involving codeine seizures, fatalities, and intoxications were also included, along with review and research papers. On the other hand, studies with little connection to OTC codeine, books, documents, clinical trials, meta-analyses, non-English papers, and publications with only abstracts were disregarded. With the help of this systematic review, we located 531 studies in databases, 83 of which satisfied our inclusion requirements. Our research is organized into sections that cover crime data, case studies of codeine-related overdoses or deaths, and detection methods. For researchers, medical professionals, and policymakers actively engaged in the fight against codeine abuse and the societal harms it causes, this review is an invaluable resource. [ABSTRACT FROM AUTHOR]

Background: Codeine was rescheduled in Australia to prescription only in February 2018. Initial studies reported an increase in population level paracetamol and ibuprofen sales following codeine upscheduling. However, to date no study has been able to investigate changes in non-opioid analgesic use at the individual patient level to determine if sales data reflect actual consumption patterns. Aim: To address this gap, we aimed to determine the impact of codeine rescheduling on non-opioid analgesic use in people who regularly used over-the-counter codeine, primarily for pain, prior to the rescheduling change. Method: We conducted a prospective cohort study with 260 participants who reported regular over-the-counter codeine consumption at cohort entry. Surveys were completed at baseline (November 2017, 3 months before rescheduling) and at 1 month (February 2018), 4 months (June 2018), and 12 months (February 2019), following rescheduling. The primary outcomes were mean daily doses of non-opioid analgesics, captured through a 7 day medication diary. Results: The mean daily paracetamol dose decreased from 1754.4 mg (95% CI 1300.5–2208.3) at baseline to 1023.8 mg (95% CI 808.5–1239.1) at the final time-point (+ 12 months) (p =.009). The mean daily ibuprofen dose decreased from 305.1mg (95% CI 217.9–392.4) at baseline to 161.2 mg (95% CI 98.5–224.0) 12 months after rescheduling (p =.03). No significant change in doses of other medications remained was found. Conclusion: In people who regularly consumed over-the-counter codeine, doses of non-opioid analgesics either reduced or remained stable following codeine rescheduling, suggesting concerns of medication substitution or overuse following the change were not realised. [ABSTRACT FROM AUTHOR]

Opioids are still being prescribed to manage acute postsurgical pain. Unnecessary opioid prescriptions can lead to addiction and death, as unused tablets are easily diverted. To determine whether combination nonopioid analgesics are at least as good as opioid analgesics, a multisite, double-blind, randomized, stratified, noninferiority comparative effectiveness trial was conducted, which examined patient-centered outcomes after impacted mandibular third-molar extraction surgery. Participants were randomized to receive 5 mg of hydrocodone with 300 mg of acetaminophen (opioid) or 400 mg of ibuprofen and 500 mg of acetaminophen (nonopioid). After an initial dose, analgesic was taken every 4 through 6 hours as needed for pain. In this randomized multisite clinical trial (n = 1,815 adults), those not taking opioids experienced significantly less pain (numeric rating scale ranging from 0 [no pain] through 10 [worst pain imaginable]) for first day and night (mean difference, –0.70; 95% CI, –0.94 to –0.45; P <.001) and second day and night (mean difference, –0.28; 95% CI, –0.52 to –0.04; P =.015), and experienced no more pain than participants taking opioids over the entire postoperative period (mean difference, –0.20; 98.75% CI, –0.45 to 0.05; P =.172). Participants not taking opioids had higher overall satisfaction at the postoperative visit (85.3% extremely satisfied or satisfied vs 78.9%; 95% CI, 1.21 to 1.98; P =.006). The ibuprofen and acetaminophen combination managed pain better for the first 2 days and led to greater satisfaction over the entire postoperative period than hydrocodone with acetaminophen. At no time did hydrocodone outperform the nonopioid. Routine opioid prescribing after dental surgery is not supported. The results of this study confirmed the American Dental Association's recommendations that ibuprofen and acetaminophen in combination should be the first-line therapy for acute pain management. This clinical trial was registered at ClinicalTrials.gov. The registration number is NCT04452344. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate pain management practices and perspectives among emergency department's (ED) discharged patients. Methods: A prospective observational study using an electronic questionnaire was conducted at King Fahad Hospital of the University between November 2023 and February 2024. Patients discharged from the ED who received pain medications were included. Pain presentations were categorized into headache, chest pain, abdominal pain, back pain, musculoskeletal pain, renal colic, or other unspecified conditions. Results: A total of 331 patients were included, with 56.8% males, 84.9% Saudi nationals, and 29.0% completed high school. The mean age was 35.7 ±11.0 years, and the most common presentation was musculoskeletal pain (48.6%). Regarding acetaminophen use, 65.6% of patients knew the recommended dose (1 g), while only 42.0% were aware of the 6-hour interval between doses. A minority (15.3%) correctly identified the maximum daily dose (4 g). Additionally, 43.8% of patients were discharged on acetaminophen. Fevadol had the highest level of dose-reduction awareness (56.8%), while 73.4% were unsure about dose reductions for Solpadeine. Non-steroidal anti-inflammatory drugs were prescribed to all chest pain cases and the majority of headache cases (88.9%). Conclusion: Suboptimal escalation of pain medications was seen in more than half of the patients. Also, the use of other pain medications after discharge and unawareness about acetaminophen content in common pain medications was greatly noted. [ABSTRACT FROM AUTHOR]

In this work, a UPLC-MS/MS assay was established for the determination of morphine, codeine, thebaine, papaverine and noscapine in rat plasma. ACQUITY UPLC BEH C18 column was employed for chromatographic separation with the mobile phase comprised acetonitrile-10 mmol L−1 ammonium acetate aqueous solution (0.05% aqueous ammonia) using gradient elution. Midazolam was used as internal standard (IS). Electrospray ionization (ESI) in positive-ion mode with reaction monitoring (MRM) was used for quantitative analysis. The calibration curves for morphine, codeine, thebaine, papaverine and noscapine demonstrated good linearity (r > 0.995) in the range of 5–500 ng mL−1 for morphine and codeine, and 1–100 ng mL−1 for thebaine, papaverine and noscapine. The intra-day and inter-day precisions of morphine, codeine, thebaine, papaverine and noscapine were within 15%, the intra-day and inter-day accuracies were 89–114%, the recovery was better than 65%, and the matrix effects were 96–112%. The developed UPLC-MS/MS assay was successfully applied in the pharmacokinetics of papaverine and noscapine. [ABSTRACT FROM AUTHOR]

Opium poppy is a plant used in both the pharmaceutical and food industries. Substances found on the surface of dry poppy seeds belong to the group of opium alkaloids. However, the presence of these substances in food products poses a risk to consumer health, which is why new permissible levels for both substances in poppy seeds and derivative products have been introduced in Regulation (EU) 2023/915. This research aimed to analyze the content of all six opium alkaloids in poppy seeds provided directly by producers as well as those available on the local market in Poland. The research confirmed the presence of morphine in all examined poppy seed samples. The alkaloid content ranged from 12.46 to 102.86 mg/kg for seeds purchased in local markets and from 1.1 to 110.1 mg/kg for seeds obtained directly from producers. Both groups showed similar levels of morphine content as well as other OAs, which significantly exceeded the permissible limit of 20 mg/kg set by the European Commission (EU) 2023/915. These results indicate that the presence of morphine and other opium alkaloids in poppy seeds exceeds permissible levels, posing a serious health issue and necessitating further research and improvement in processing methods. [ABSTRACT FROM AUTHOR]

Purpose Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US. Summary Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19 -clopidogrel, CYP2D6 -codeine, CYP2D6 -tramadol, CYP2B6 -efavirenz, TPMT -thiopurines, and NUDT15 -thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization. Conclusion A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing. [ABSTRACT FROM AUTHOR]

In this study, continuous-flow membrane microextraction was connected online with a high-performance liquid chromatography-UV detector for the pre-concentration and high clean-up of papaverine and codeine in biological samples. The extraction cell was designed with donor and acceptor chambers separated by a sheet membrane. By adjusting the pH of the donor phase (10 mL, pH 11), the analyte molecules were extracted into the supported liquid membrane (SLM) (15 µL of 1-octanol). The donor solution was circulated through the donor chamber using a peristaltic pump and magnetically agitated by a bar stirrer placed near the membrane, enhancing the diffusion and convection flow of the targeted drugs from the donor solution to the SLM. Subsequently, by adjusting the acceptor solution to an acidic pH of 2 (100 µL), the drugs in ionic form were reversely extracted into the acceptor phase. The procedure exhibited desirable relative standard deviation of less than 3.70%, linear ranges of 7–600 ng mL−1 for codeine and 2.0–600 ng mL−1 for papaverine, and limits of detection of 2.0 ng mL−1 for codeine and 0.6 ng mL−1 for papaverine. The design of the extraction cell significantly improved the performance for determining targeted drugs in complex matrices such as plasma and urine. [ABSTRACT FROM AUTHOR]

Opioid dependence has become a public health problem in several countries. A cohort study was used to assess first-time dispensed opioids, in 2012–2015, by drug type, doses, oral morphine equivalents, and diagnoses, in Sweden. First-time opioid users aged 18–64 years, previously cancer-free and opioid-naïve for at least 6.5 years, were studied. Time trends in opioid use in Sweden 2006–2021 were also studied. During the study, 617,568 patients were dispensed opioids for the first time. The crude proportion of first-time opioid users in the population was 2.7% in 2012 and 2.6% in 2015. The combination product of codeine and paracetamol was the most frequent dispensed opioid with 322,818 patients (52.3%), followed by tramadol (120,271, 19.6%) and oxycodone (104,418, 16.9%). From 2012 to 2015, tramadol as first dispensed opioid dropped from 26.5% to 13.7% and oxycodone increased from 10.0% to 24.4%. For the four most commonly dispensed opioids, the median initial dispensal ranged from 250 to 400 oral morphine equivalents. The most common indication was fracture of the lower leg during inpatient care and back pain for specialized outpatient care. Trends in dispensed opioids in Sweden show a shift from tramadol to oxycodone, but do not show an increase in total opioid use. [ABSTRACT FROM AUTHOR]

The primary objective of the present study is to systematically investigate the solubility data and thermodynamic properties associated with codeine phosphate within mixtures comprising ethylene glycol (EG) and N-methyl-2-pyrrolidone (NMP) under atmospheric pressure conditions within the temperature range of 293.2–313.2 K. The analysis reveals a discernible positive correlation with both temperature and the ratio of EG. Mathematical models are employed for the purpose of correlating the obtained data, and the reliability of these models is rigorously assessed through the computation of mean relative deviations for back-calculated values. Additionally, the density values of codeine phosphate saturated mixtures are meticulously measured and subsequently correlated utilising the Jouyban-Acree model. Furthermore, the apparent thermodynamic properties governing the solubilisation process of codeine phosphate, including standard enthalpy, entropy and Gibbs free energy, are computed through the application of Gibbs and van’t Hoff equations, and the obtained results are comprehensively documented. [ABSTRACT FROM AUTHOR]

This is a case of a 21-year-old male, African American Division I basketball player with a fibula stress fracture. The athlete initially reported pain, without distinct injury and was diagnosed with a stress fracture. After a short period of immobilization in a walking boot, this individual opted to undergo surgical intervention consisting of an intramedullary screw inserted in his left fibula. This was in consultation with the orthopedic team physician and orthopedic trauma surgeon. After a brief period of rest and continued immobilization in a walking boot, weight bearing as tolerated, the patient was able to start rehabilitation. He continued rehabilitation and progressive return to activity and was able to return to limited practice approximately 4 weeks. He played 13 min of a game in under 5 weeks (31 days). Stress fractures are not uncommon in basketball players, but a fibula stress fracture is one not often seen, and there is a paucity of data in the literature regarding this injury. A nonoperative approach to treatment of a fibula stress fracture typically yields good results but may lead to longer return than a surgical intervention. Providing athletes options for treatment may result in a quicker recovery. This case demonstrates a novel treatment option resulting in a quicker return to play. [ABSTRACT FROM AUTHOR]

Heroin use is responsible for many drug-related deaths, so the determination of its biomarkers, except for 6-acetylmorphine, in biological samples, is of particular concern in toxicological laboratories worldwide, for a better investigation of these cases. Th use of 6-acetylmorphine as a heroin biomarker has some limitations due to its rapid bioconversion to morphine within a few hours, especially in blood samples. The need for new indirect biomarkers, like the ones that come from the processing of opium during the clandestine production of heroin, becomes imperative. A GC/MS method was developed and validated for the determination of meconin, thebaine, papaverine, acetylcodeine and noscapine, along with morphine, codeine and 6-acetylmorphine, in different biological samples of heroin users. For all analytes and all individual biological samples, the LOD and LOQ were 2.00 and 5.00 ng/mL, respectively, the calibration curves were linear (R2≥0.991) from 5.00 to 500.0 ng/mL, and absolute recoveries were higher than 91.9 %. The method was applied during the toxicological investigation of 34 forensic cases after positive immunoassay screening for opiates. The results indicate that meconin is the most frequently detected indirect biomarker of heroin use, as it was found in 91.2 % of all cases, whilst in 23.5 % of them no 6-acetylmorphine was detected. Papaverine was found in 67.6 % of all cases and is considered to be the second most important indirect biomarker of heroin use. The establishment of detecting meconin and papaverine in biological materials in parallel with the detection of morphine, codeine and 6-acetylmorphine can contribute to more conclusive results concerning heroin use in forensic cases.

Abstract Aim To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over‐the‐counter (OTC) drugs before and after COVID‐19 based on the 2018 and 2022 data of the “Nationwide Psychiatric Hospital (NPH) Survey on Drug‐related Psychiatric Disorders.” Method A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022. Result A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD‐10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years. Conclusion By comparing NPH Surveys before and after the COVID‐19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor‐made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan‐containing OTC drugs has increased alarmingly.

The article presents a case study of a 61-year-old female with chronic focal abdominal pain successfully treated with botulinum toxin A (BoNT-A) in a celiac plexus block. Topics discussed include the mechanism of BoNT-A in pain management, the effectiveness of celiac plexus blocks for abdominal pain, and the significant reduction in pain and medication use experienced by the patient.

Bile leakage is a serious early postoperative complication of cholecystectomy. A leak in the duct of Luschka, though rare, can cause significant patient morbidity after a cholecystectomy. Early recognition of this uncommon complication allows for early therapeutic intervention. [ABSTRACT FROM AUTHOR]

Systemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats. The animals were tracheotomized and electromyogram (EMG) electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra-nodose ganglion vagotomy (SNGx). A dose response to intravenous codeine was performed in each animal. Swallowing was elicited by injection of 3 mL of water into the oropharynx. The number of swallows after vehicle was significantly higher in the VI group than in SNGx. Codeine had no significant effect on the number of swallows induced by water in any of the groups. However, the magnitudes of water swallow-related EMGs of the thyropharyngeus muscle were significantly increased in the VI and CVx groups by 2-4 fold in a dose-related manner. In the CVx group, the geniohyoid muscle EMG during water swallows was significantly increased. There was a significant dose-related increase in spontaneous swallowing in each group from codeine. The spontaneous swallow number at the 10 mg/kg dose of codeine was significantly larger in the CVx group than that in the SNGx group. During water-evoked swallows, intravenous codeine increased upper airway motor drive in a dose-related manner, consistent with dysregulation. The data support the existence of both central and peripheral actions of codeine on spontaneous swallowing. At the highest dose of codeine, the reduced spontaneous swallow number in the SNGx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself. The higher number of swallows in the CVx group than the VI group supports disinhibition of this behavior by elimination of inhibitory vagal sensory afferents. [ABSTRACT FROM AUTHOR]

Aim: To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over‐the‐counter (OTC) drugs before and after COVID‐19 based on the 2018 and 2022 data of the "Nationwide Psychiatric Hospital (NPH) Survey on Drug‐related Psychiatric Disorders." Method: A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022. Result: A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD‐10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years. Conclusion: By comparing NPH Surveys before and after the COVID‐19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor‐made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan‐containing OTC drugs has increased alarmingly. [ABSTRACT FROM AUTHOR]

The evolving landscape of opioid prescription practices necessitates a comprehensive understanding of emerging patterns, particularly among new opioid users discharged from emergency departments. This study delves into the intricate realm of opioid utilization by elucidating the prevalence of their prescriptions. A retrospective analysis of electronic health records was conducted, including a cohort of 71 patients who received opioid prescriptions upon discharge from emergency departments from 1 January 2022 to 30 June 2022. Demographic characteristics and prescription details were systematically examined. This study illuminates tramadol's prominence, with 84% of prescriptions and a Defined Daily Dose (DDD) morphine equivalent of 60 mg, as the primary choice as a new opioid, a finding that draws attention due to the closely aligned dosages with morphine equivalents. This discovery prompts a critical reassessment of tramadol's therapeutic role, considering its multifaceted nature encompassing serotonergic effects and heightened fall risks. This study advocates for a nuanced and vigilant approach to tramadol prescription, cognizant of its potential risks and therapeutic implications, and highlights the imperative of optimizing data quality and traceability within electronic health records to enhance patient care and facilitate future research endeavors. [ABSTRACT FROM AUTHOR]

Background: The Opioid Analgesic Reduction Study is a double-blind, prospective, clinical trial investigating analgesic effectiveness in the management of acute post-surgical pain after impacted third molar extraction across five clinical sites. Specifically, Opioid Analgesic Reduction Study examines a commonly prescribed opioid combination (hydrocodone/acetaminophen) against a non-opioid combination (ibuprofen/acetaminophen). The Opioid Analgesic Reduction Study employs a novel, electronic infrastructure, leveraging the functionality of its data management system, Research Electronic Data Capture, to not only serve as its data reservoir but also provide the framework for its quality management program. Methods: Within the Opioid Analgesic Reduction Study, Research Electronic Data Capture is expanded into a multi-function management tool, serving as the hub for its clinical data management, project management and credentialing, materials management, and quality management. Research Electronic Data Capture effectively captures data, displays/tracks study progress, triggers follow-up, and supports quality management processes. Results: At 72% study completion, over 12,000 subject data forms have been executed in Research Electronic Data Capture with minimal missing (0.15%) or incomplete or erroneous forms (0.06%). Five hundred, twenty-three queries were initiated to request clarifications and/or address missing data and data discrepancies. Conclusion: Research Electronic Data Capture is an effective digital health technology that can be maximized to contribute to the success of a clinical trial. The Research Electronic Data Capture infrastructure and enhanced functionality used in Opioid Analgesic Reduction Study provides the framework and the logic that ensures complete, accurate, data while guiding an effective, efficient workflow that can be followed by team members across sites. This enhanced data reliability and comprehensive quality management processes allow for better preparedness and readiness for clinical monitoring and regulatory reporting. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). Methods: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time‐series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. Results: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post‐rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre‐period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre‐period and 2090 visits occurred in the post‐period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. Conclusions: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre‐rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine‐involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts. [ABSTRACT FROM AUTHOR]

Objectives: Opioid use has increased globally, dramatically increasing opioid overdose, dependence, abuse and mortality. Limited research is available on opioid use patterns in older adults in New Zealand and internationally. This study aims to address this gap by determining the incidence and prevalence of opioid use among older adults (age ≥65 years) in New Zealand from 2007 to 2018. Methods: This was a population‐based retrospective cohort study conducted using New Zealand national administrative healthcare databases. The annual opioid use incidence (2008–2018) and prevalence (2007–2018) in older adults were determined and stratified by sex, age, and opioid type and strength. We used descriptive statistics to summarise the patterns of opioid dispensing. Data analysis was conducted using MS Excel, and data linking was performed using SQL software. Results: A total of 820,349 older adults were initiated on opioids during the study period. The overall incidence of opioid use in older adults showed a steady increase from 2008 to 2015; similarly, the prevalence steadily increased from 2007 to 2015, and thereafter, both rates fluctuated. A slight decrease in both prevalence and incidence rates was observed in 2018. Codeine and tramadol were the most commonly dispensed opioids during the study period. Females had a higher incidence and prevalence of all opioids than males. Conclusions: The incidence and prevalence of opioid dispensing increased in New Zealand older adults over time. Monitoring the trends of opioid use in older adults is critical to enable clinicians and policymakers to deliver early interventions to prevent future opioid‐related adverse events. [ABSTRACT FROM AUTHOR]

Objectives: Codeine, a prodrug used as an opioid agonist, is metabolized to the active product morphine by CYP2D6. This study aimed to establish physiologically based pharmacokinetic (PBPK) models of codeine and morphine and explore the influence of CYP2D6 genetic polymorphisms on the pharmacokinetics of codeine and morphine. Methods: An initial PBPK modeling of codeine in healthy adults was established using PK-Sim® software and subsequently extrapolated to CYP2D6 phenotyperelated PBPK modeling based on the turnover frequency (Kcat) of CYP2D6 for different phenotype populations (UM, EM, IM, and PM). The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between the predicted and observed values of the pharmacokinetic parameters to evaluate the accuracy of PBPK modeling. The validated models were then used to support dose safety for different CYP2D6 phenotypes. Results: The developed and validated CYP2D6 phenotype-related PBPK model successfully predicted codeine and morphine dispositions in different CYP2D6 phenotypes. Compared with EMs, the predicted AUC0-8 value of morphine was 98.6% lower in PMs, 60.84% lower in IMs, and 73.43% higher in UMs. Morphine plasma exposure in IMs administered 80 mg of codeine was roughly comparable to that in EMs administered 30 mg of codeine. CYP2D6 UMs may start dose titration to achieve an optimal individual regimen and avoid a single dose of over 20 mg. Codeine should not be used in PMs for pain relief, considering its insufficient efficacy. Conclusion: PBPK modeling can be applied to explore the dosing safety of codeine and can be helpful in predicting the effect of CYP2D6 genetic polymorphisms on drug-drug interactions (DDIs) with codeine in the future. [ABSTRACT FROM AUTHOR]

Purpose: To investigate opioid prescription fills following pediatric/adolescent dental procedures in central/southeastern Ohio. Methods: This population-based, retrospective cohort study utilized health insurance claims from a pediatric public accountable care organization ('Medicaid') in central/ southeastern Ohio. Patients aged 18 years and younger who had a dental procedure between January 2012 and February 2019 were identified, and claims were searched for opioid prescription fills within 14 days post-procedure. Trends in prescription fill percentages, types of opioid, procedure classification and patient characteristics were examined. Results: A total of 512,922 encounters among 212,813 patients were included. The overall opioid prescription fill was 4.9 percent. Percentages decreased throughout the study period from 6.1 percent (95 percent confidence interval [95% CI]=5.9 to 6.3) in 2012 to 3.4 percent (95% CI=3.1 to 3.8) in early 2019. When limited to extractions and endodontic procedures, the overall prescription fill percentage fell from 15.7 percent (95% CI=15.2 to 16.1) in 2012 to 9.5 percent (95% CI=8.5 to 10.4) in early 2019. The most common opioids were hydrocodone (68.6 percent) and codeine (24.7 percent), with marked annual reductions in codeine prescription fills among children younger than 14 years. From 2017 to 2018, surgical extractions compared to endodontics-only procedures (risk difference [RD]=40.7; 95% CI=38.6 to 42.9) and older patient age (RD for 18-year-olds versus 13-year-olds=21.9; 95% CI=19.8 to 24.0) were strong risk factors for filling an opioid prescription. Conclusion: Post-procedure opioid prescription fill percentages have decreased since 2012 among pediatric/adolescent Medicaid enrollees undergoing dental procedures in central/southeastern Ohio. Substantial differences in the likelihood of filling a prescription remained by procedural and demographic variables. There were marked trends in the types of opioid for which prescriptions were filled, which varied by patient age. [ABSTRACT FROM AUTHOR]

Background: Although several studies have noted that patients are routinely overprescribed opioids, few have reported usage after arthroscopic surgery. Purpose: To determine opioid consumption and allocation for unused opioids after common arthroscopic surgeries. Study Design: Case series; Level of evidence, 4. Methods: Patients between the ages of 15 and 40 years who were scheduled to undergo anterior cruciate ligament reconstruction (ACLR), labral repair of the hip or shoulder, meniscectomy, or meniscal repair were prospectively enrolled. Patients were prescribed either 5 mg hydrocodone-325 mg acetaminophen or 5 mg oxycodone-325 mg acetaminophen based on surgeon preference. Patients completed a daily opioid usage survey during the 2-week postoperative period. In addition, patients completed a survey on postoperative day 21 inquiring about continued opioid use and medication disposal, if applicable. Opioid medication consumption was converted to morphine milligram equivalents (MMEs). Results: Of the 200 patients who were enrolled in the study, 176 patients had sufficient follow-up after undergoing 85 (48%) ACLR, 26 (14.8%) hip labral repair, 34 (19.3%) shoulder labral repair, 18 (10.2%) meniscectomy, and 13 (7.4%) meniscal repair procedures. Mean age was 26.1 years (SD, 7.38); surgeons prescribed a mean of 26.6 pills whereas patients reported consuming a mean of 15.5 pills. The mean MME consumption in the 14 days after each procedure was calculated: ACLR (95.7; 44% of prescription), hip labral repair (84.8; 37%), shoulder labral repair (57.2; 35%), meniscectomy (18.4; 27%), and meniscal repair (32.1; 42%). This corresponded to approximately 39% of the total opioid prescription being utilized across all procedures. Mean MME consumption was greatest on postoperative day 1 in hip, shoulder, and meniscal procedures and on postoperative day 2 in ACLR. Only 7.04% of patients reported continued opioid use in the third postoperative week. Patients had a mean of 11 unused pills or 77.7 MMEs remaining. Of the patients with remaining medication, 24.7% intended to keep their medication for future use. Conclusion: The results of our study indicate that patients who undergo the aforementioned arthroscopic procedures consume <75 MMEs in the 2-week postoperative period, translating into a mean of 10 to 15 pills consumed. Approximately 60% of total opioids prescribed went unused, and one-fourth of patients intended to keep their remaining medication for future usage. We have provided general prescribing guidelines and recommend that surgeons carefully consider customizing their opioid prescriptions on the basis of procedure site to balance optimal postoperative analgesia with avoidance of dissemination of excess opioids. [ABSTRACT FROM AUTHOR]

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo‐controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate‐certainty to low‐certainty evidence). Nonsteroidal anti‐inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate‐to‐severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals. [ABSTRACT FROM AUTHOR]

The purpose of the current study is the investigation of the solubility data and thermodynamic properties of codeine phosphate in mixtures of N-methyl-2-pyrrolidone and 1-propanol under atmospheric pressure at 293.2–313.2 K. Positive correlations of the solubility with temperature and N-methyl-2-pyrrolidone ratio were observed. The measured data were correlated using some mathematical models, and their reliability was studied by computing the mean relative deviations of the back-calculated values. The density values of codeine phosphate saturated solutions were also measured and correlated using the Jouyban–Acree model. Furthermore, the apparent thermodynamic properties of the codeine phosphate solubilisation (e.g. standard enthalpy, entropy, and Gibbs free energy) are also computed based on Gibbs and van't Hoff equations and reported. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Using Entman's framing theory, we explored primary news frames in Nigerian newspaper coverage of national opioid abuse. Results yielded 12 news frames: 5 causal frames (Poor governance, Trauma coping mechanism, The perfect trafficking hub, Corrosive culture, Performance boosters), 3 consequential frames (Nigeria as a failing state, Thriving Black Market demand, Uptick in criminal kinsmen: fraudsters and terrorists) and 4 solution frames (Hawkeyed pharmacovigilance, Policy power plays, Drug rehab health services, All hands on deck: strengthening societal values). These research insights represent one of few communication studies on African opioid abuse and offer cultural context for future health intervention strategies. [ABSTRACT FROM AUTHOR]

Background There has been increasing concern over opioid-related harms across the world. In Australia in 2018, codeine-containing products were up-scheduled from over-the-counter access at pharmacies, to requiring a prescription. The drug regulator’s decision to up-schedule was contentious and widely debated, due to the potentially large impact on consumers and healthcare professionals. This study aimed to analyse influences on the codeine up-scheduling policy. Methods This retrospective policy analysis used the Advocacy Coalition Framework (ACF) to understand how policy actors with shared beliefs formed adversarial coalitions to shape policy. Data were drawn from documents (regulator policy documents, public submissions, news reports, organisational media releases and position statements) and semistructured interviews with 15 key policy actors. Codes were generated relating to policy processes and actor beliefs; broad themes included the role of health professionals, perceptions of opioids, impact on consumers, and the role of government in healthcare. Results Two coalitions in this policy subsystem were identified: (1) supportive [with respect to the up-scheduling], and (2) opposing. The key evident beliefs of the supportive coalition were that the harms of codeine outweighed the benefits, and that government regulation was the best pathway for protecting consumers. The opposing coalition believed that the benefits of codeine accessible through pharmacists outweighed any harms, and consumers should manage their health without any more intervention than necessary. The policy decision reflected the influence of the supportive coalition, and this analysis highlighted the importance of their public health framing of the issue, the acceptability of their experts and supporting evidence, and the perceived legitimacy of the up-scheduling process. Conclusion Understanding these coalitions, their beliefs, and how they are translated through existing policy processes and institutions provides insight for those interested in influencing future health policy. Specific lessons include the importance of strategic frames and advocacy, and engagement with formal policy processes.

Systemic administration of opioids has been associated with aspiration and swallow dysfunction in humans. We speculated that systemic administration of codeine would induce dysfunctional swallowing and that this effect would have a peripheral component. Experiments were conducted in spontaneously breathing, anesthetized cats. The animals were tracheotomized and electromyogram (EMG) electrodes were placed in upper airway and chest wall respiratory muscles for recording swallow related motor activity. The animals were allocated into three groups: vagal intact (VI), cervical vagotomy (CVx), and supra-nodose ganglion vagotomy (SNGx). A dose response to intravenous codeine was performed in each animal. Swallowing was elicited by injection of 3 mL of water into the oropharynx. The number of swallows after vehicle was significantly higher in the VI group than in SNGx. Codeine had no significant effect on the number of swallows induced by water in any of the groups. However, the magnitudes of water swallow-related EMGs of the thyropharyngeus muscle were significantly increased in the VI and CVx groups by 2–4 fold in a dose-related manner. In the CVx group, the geniohyoid muscle EMG during water swallows was significantly increased. There was a significant dose-related increase in spontaneous swallowing in each group from codeine. The spontaneous swallow number at the 10 mg/kg dose of codeine was significantly larger in the CVx group than that in the SNGx group. During water-evoked swallows, intravenous codeine increased upper airway motor drive in a dose-related manner, consistent with dysregulation. The data support the existence of both central and peripheral actions of codeine on spontaneous swallowing. At the highest dose of codeine, the reduced spontaneous swallow number in the SNGx group relative to CVx is consistent with a peripheral excitatory action of codeine either on pharyngeal/laryngeal receptors or in the nodose ganglion itself. The higher number of swallows in the CVx group than the VI group supports disinhibition of this behavior by elimination of inhibitory vagal sensory afferents.

Background: Pharmacy professionals working in community pharmacies frequently provide pharmacist-initiated therapy, including codeine-containing medicines. Codeine is an opioid with great potential for misuse, adding to the global opioid epidemic burden. Professional pharmacy personnel are the first intervention point in relation to management of codeine use. This study highlights the importance of pharmacy professionals’ perceptions and behaviours in combatting the opioid epidemic. Methods: A descriptive cross-sectional study was conducted. Simple random sampling included pharmacy professionals in the metropolitan city of Johannesburg. An electronic questionnaire was distributed via e-mail and data analysed descriptively. Results: Findings indicate that pharmacy personnel routinely ask patients about codeine use (n = 48; 53.9%), avoid dispensing over-the-counter (OTC) codeine as an initial treatment (n = 61; 69%) and express confidence to identify and manage codeine misuse (n = 69; 77.5%). Despite this, increased patient demands for OTC codeine (n = 69; 77.5%) were concerning, highlighting the ease of availability from internet sources (n = 76; 85.4%) and multiple pharmacies (n = 84; 94.4%). Apprehension about the lack of patient awareness on adverse health consequences (n = 66; 74.2%) and the risk of codeine dependence (n = 79; 88.8%) was expressed. Conclusion: Growing concern regarding availability and accessibility of codeine-containing medicines within the community pharmacy sector is highlighted. Adverse health consequences of codeine misuse and dependence are not understood by customers and the ineffective information provided by pharmacy personnel was highlighted as a concern. Contribution: The results of this study give insight to the influence of dispensing personnel’s attitude towards the growing challenges with respect to codeine containing medication abuse.