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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 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]

Objective This study compared opioid utilization trajectories of persons initiating tramadol, short-acting hydrocodone, or short-acting oxycodone, and it characterized opioid dose trajectories and type of opioid in persistent opioid therapy subsamples. Methods A retrospective cohort study of adults with chronic non-cancer pain who were initiating opioid therapy was conducted with the IQVIA PharMetrics® Plus for Academics data (2008–2018). Continuous enrollment was required for 6 months before ("baseline") and 12 months after ("follow-up") the first opioid prescription ("index date"). Opioid therapy measures were assessed every 7 days over follow-up. Group-based trajectory modeling (GBTM) was used to identify trajectories for any opioid and total morphine milligram equivalent measures, and longitudinal latent class analysis was used for opioid therapy type. Results A total of 40 276 tramadol, 141 023 hydrocodone, and 45 221 oxycodone initiators were included. GBTM on any opioid therapy identified 3 latent trajectories: early discontinuers (tramadol 39.0%, hydrocodone 54.1%, oxycodone 61.4%), late discontinuers (tramadol 37.9%, hydrocodone 39.4%, oxycodone 33.3%), and persistent therapy (tramadol 6.7%, hydrocodone 6.5%, oxycodone 5.3%). An additional fourth trajectory, intermittent therapy (tramadol 16.4%), was identified for tramadol initiators. Of those on persistent therapy, 2687 individuals were on persistent therapy with tramadol, 9169 with hydrocodone, and 2377 with oxycodone. GBTM on opioid dose resulted in 6 similar trajectory groups in each persistent therapy group. Longitudinal latent class analysis on opioid therapy type identified 6 latent classes for tramadol and oxycodone and 7 classes for hydrocodone. Conclusion Opioid therapy patterns meaningfully differed by the initial opioid prescribed, notably the presence of intermittent therapy among tramadol initiators and higher morphine milligram equivalents and prescribing of long-acting opioids among oxycodone initiators. [ABSTRACT FROM AUTHOR]

Easy access to over-the-counter (OTC) drugs makes it possible to procure active substances that normally used in therapeutic doses do not raise health problems. The use of high doses of OTC drugs containing codeine, loperamide, pseudoephedrine, diphenhydramine or dimenhydrinate, as well as the use of benzidamine systemically raises concerns regarding the increase in units sold. These drugs are used for recreational or euphorizing purposes, including by young women of childbearing age, psychoactive substance users representing a risk group in terms of the possibility of an unplanned pregnancy. Abusive consumption of OTC products during pregnancy is harmful, with consequences for both fetal and late development that can occur in the infant. This literature review presents the risks (teratogenicity, fetal toxicity, neonatal abstinence syndrome, etc.) associated with the use of potentially psychoactive OTC drugs to emphasize the importance of re-evaluating OTC classification and dispensing. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and by Avicenna (980–1037). Reference to opium like products is made by Paracelsus and by Shakespeare. Charles Louis Derosne and Fredrich Wilhelm Adam Serturner isolated morphine from raw opium in 1802 and 1806 respectively, and it was Sertürner who named the substance morphine, after Morpheus, the Greek God of dreams. By the middle 1800s, Opium and related opioid derived products were the source of a major addiction in USA, and to some extent in the United Kingdom. Opioid products are of major therapeutic value in the treatment of pain from injury, post surgery, intractable pain conditions, and some forms of terminal cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/Aims This study aims to evaluate the effects of acute codeine administration on primary and secondary esophageal peristalsis in patients with ineffective esophageal motility (IEM). Methods Eighteen IEM patients (8 women; mean age 37.8 years, range 23-64 years) were enrolled in the study. The patients underwent highresolution manometry exams, consisting of 10 single wet swallows, multiple rapid swallows, and ten 20 mL rapid air injections to trigger secondary peristalsis. All participants completed 2 separate sessions, including acute administration of codeine (60 mg) and placebo, in a randomized order. Results Codeine significantly increased the distal contractile integral (566 ± 81 mmHg·s·cm vs 247 ± 36 mmHg·s·cm, P = 0.001) and shortened distal latency (5.7 ± 0.2 seconds vs 6.5 ± 0.1 seconds, P < 0.001) for primary peristalsis compared with these parameters after placebo treatment. The mean total break length decreased significantly after codeine treatment compared with the length after placebo (P = 0.003). Codeine significantly increased esophagogastric junction-contractile integral (P = 0.028) but did not change the 4-second integrated relaxation pressure (P = 0.794). Codeine significantly decreased the frequency of weak (P = 0.039) and failed contractions (P = 0.009), resulting in increased frequency of normal primary peristalsis (P < 0.136). No significant differences in the ratio of impaired multiple rapid swallows inhibition and parameters of secondary peristalsis were detected. Conclusions In IEM patients, acute administration of codeine increases contraction vigor and reduces distal latency of primary esophageal peristalsis, but has no effect on secondary peristalsis. Future studies are required to further elucidate clinical relevance of these findings, especially in the setting of gastroesophageal reflux disease with IEM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: To describe the symptoms, patient demographics, and trends over time of adverse drug reactions (ADRs) related to weak opioid analgesics reported to the French vigilance networks. Methods: Retrospective study of data from French Poison Control Centers and Pharmacovigilance Centers databases of weak opioid analgesics‐related ADRs cases, with high causality score, in adults, in therapeutic analgesic use, without co‐exposure, between 2011 and 2020. Results: The number of cases was 388 in the Poisonings database and 155 in the Pharmacovigilance database; ratio of the number of these cases to all reported cases during the study period was 0.02% and 0.03%, respectively. Tramadol was most often involved (74% and 56.1%, respectively), followed by codeine (26% and 38.7%, respectively). There was no significant variation in the number of cases reported. Cases most often involved young adults (median age: 40 years) and mostly women (76%). Gastrointestinal symptoms were mostly reported (80% and 65%, respectively) as described in the Summary of Products Characteristics. Patterns of ADRs were comparable in both databases, except for codeine‐associated acute pancreatitis and anaphylaxis that were reported in the Pharmacovigilance database. No fatality was observed. Severity was more often observed in the Pharmacovigilance database (30%) than in the Poisonings database (moderate toxicity: 7%). Conclusion: ADRs mostly occurred among young women using tramadol, without significant variation in the number of reported cases over time. Serious ADRs were more frequently reported to the Pharmacovigilance database, particularly for codeine. Women seemed to be at greater risk of ADRs. [ABSTRACT FROM AUTHOR]

The family of calcium-activated chloride channels, TMEM16, plays a significant role in contributing to the pathogenesis of airway inflammatory diseases. Targeting these ion channels and aiming to modulate them may provide an interesting new approach to the therapy of these potentially fatal diseases. We tested this hypothesis in both healthy and ovalbumin (OVA)-sensitized male Dunkin-Hartley guinea pigs. The ion channel activity was modulated by TMEM16A-nonselective (benzbromarone) and TMEM16A-selective blockers (CaCCinh-A01). In vivo airway reactivity, induced by histamine and methacholine, was expressed as specific airway resistance (sRaw) values. The number of citric acid-induced coughs was counted using a double-chambered body plethysmograph, and the frequency of ciliary beating (CBF) was assessed in vitro by brushing method. For comparison, salbutamol and codeine were tested under the same conditions. The results showed significant differences in the responses of unsensitized and sensitized airways to both TMEM16 blockers administered. CaCCinh-A01 and benzbromarone significantly reduced the number of cough efforts in the group of OVA-sensitized guinea pigs. Significant improvement in sRaw values could be observed in OVA-sensitized TMEM16 blocker–treated animals compared to salbutamol when challenged with inhalational histamine, and the outcome was similar to salbutamol when challenged with methacholine. CBF was significantly inhibited in animals sensitized to OVA treated with selective inhibition of TMEM16A. The results demonstrated that treatment with blockers of TMEM16 can reduce both cough effort and sRaw, and the difference between TMEM16A-selective and TMEM16A-nonselective blocking is only negligibly in favor of CaCCinh-A01. It is also worthwhile to note the impairment of CBF in OVA-sensitized animals treated with CaCCinh-A01. [ABSTRACT FROM AUTHOR]

The nation's opioid epidemic requires a paradigm shift in the way patients with co-occurring opioid use disorder are treated during episodes of acute pain. Patients are often introduced to prescription opioids after an extremity fracture or sprain or resulting from musculoskeletal back, abdominal, or dental pain. Opioid naive patients who receive their first opioid prescription on discharge from the emergency department may be more likely to develop chronic opioid use compared to patients receiving non-opioid pain medications. This case report will highlight one patient's journey including initial prescription opioid use, escalation into illicit opioids, entry to a recovery and treatment program, discussions with her physician about alternative therapies, and barriers to satisfactory pain relief. A shared decision-making model will be explored. [ABSTRACT FROM AUTHOR]

Objective: Opioid‐related harm has risen in recent decades, but limited research describes the clinical burden of opioid poisoning to Australian EDs. We aimed to investigate hospital presentations with opioid poisoning over three decades. Methods: This is an observational series of prospectively collected data investigating presentations of opioid poisoning to an ED in Newcastle (1990–2021). Type of opioid, naloxone administration, intubation, intensive care unit (ICU) admission, length of stay and death were extracted from the unit's database. Results: There were 4492 presentations in 3574 patients (median age 36, 57.7% female), increasing from an average of 93 presentations annually in the first decade to 199 in the third decade. Deliberate self‐poisonings accounted for 3694 presentations (82.2%). Heroin dominated the 1990s, peaking in 1999 before decreasing. Prescription opioids then rose, with codeine (usually in paracetamol combination) predominating until 2018, after which oxycodone presentations exceeded them. Methadone consistently increased from six presentations annually in the first decade to 16 in the last decade. Naloxone was administered in 990 (22.0%) presentations and 266 (5.9%) were intubated, most frequently following methadone and heroin exposures. ICU admissions increased from 5% in 1990 to 16% in 2021. Codeine exposures resulted in less severe effects, whereas methadone had more severe effects overall. The median length of stay was 17 h (interquartile range 9–27 h). There were 28 deaths (0.6%). Conclusion: Opioid presentations increased in number and severity over three decades as the type of opioid changed. Oxycodone is currently the main opioid of concern. Methadone poisoning was the most severe. [ABSTRACT FROM AUTHOR]

Background: Codeine‐containing compound analgesics (CCCAs) are associated with dependence and, when taken in excess, significant risks of harm. A previous audit showed significant costs related to admissions for gastrointestinal (GI) complications of CCCA. Based on this and other evidence of harm, the Australian Therapeutic Goods Administration changed CCCAs to prescription only in 2018. Aims: We aimed to identify the costs associated with codeine‐related GI complications and whether the schedule change in 2018 led to a reduced clinical and financial strain on the health care system. Methods: We conducted an audit of GI admissions and associated costs of CCCAs at a tertiary teaching hospital in Adelaide between 2016 and 2020. Patients were grouped by 2‐year time periods before (group 1) and following (group 2) schedule change. Costs for the index presentation were multiplied for subsequent presentations. Costs and outcomes were compared for groups (standard statistics; P value < 0.05 significant.) Results: Three hundred forty patients (group 1, n = 164; group 2, n = 119) were identified, with the majority of these admitted due to nonsteroidal anti‐inflammatory drugs (NSAIDs) only. For CCCAs (NSAID‐containing), the same patients were admitted repeatedly with a reduction from 31 to eight admissions (P = 0.005), following rescheduling. The total cost of CCCA admissions was reduced from AU$ 561 691 for group 1 to AU$ 261 764 for group 2 (P < 0.001). Conclusions: Australian rescheduling of CCCAs in 2018 resulted in a reduction in hospital admissions and costs related to GI complications. The cost savings, even in a single hospital department, were substantial. [ABSTRACT FROM AUTHOR]

Background: The comparative safety of serotonin and norepinephrine reuptake inhibitors (SNRIs) as adjuvants to short‐acting opioids in older adults is unknown even though SNRIs are commonly used. We compared the effects of SNRIs versus nonsteroidal anti‐Inflammatory drugs (NSAIDs) on delirium among nursing home residents when SNRIs or NSAIDs were added to stable regimens of short‐acting opioids. Methods: Using 2011–2016 national Minimum Data Set (MDS) 3.0 and Medicare claims data to implement a new‐user design, we identified a cohort of nursing home residents receiving short‐acting opioids who initiated either an SNRI or an NSAID. Delirium was defined from the Confusion Assessment Method in MDS 3.0 assessments and ICD9/10 codes using Medicare hospitalization claims. Propensity score matching balanced underlying differences for initiating treatments on 39 demographic and clinical characteristics (nSNRIs = 5350; nNSAIDs = 5350). Fine and Gray models provided hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for the competing risk of death. Results: Hydrocodone was the most commonly used short‐acting opioid (48%). Residents received ~23 mg daily oral morphine equivalent at the time of SNRIs/NSAIDs initiation. The majority were women, non‐Hispanic White, and aged ≥75 years. There were no differences in any of the confounders after propensity matching. Over 1 year, 10.8% of SNRIs initiators and 8.9% of NSAIDs initiators developed delirium. The rate of delirium onset was similar in SNRIs and NSAID initiators (HR(delirium in nursing home or hospitalization for delirium):1.10; 95% CI: 0.97–1.24; HR(hospitalization for delirium): 1.06; 95% CI: 0.89–1.25), and were similar regardless of baseline opioid daily dosage. Conclusions: Among nursing home residents, adding SNRIs to short‐acting opioids does not appear to increase risk of delirium relative to initiating NSAIDs. Understanding the comparative safety of pain regimens is needed to inform clinical decisions in a medically complex population often excluded from clinical research. [ABSTRACT FROM AUTHOR]

The article assesses the therapeutic benefits of codeine (3-methylmorphine), which is used to treat acute and chronic pain, versus the risk of overdosing. Adverse effects of codeine include nausea, vomiting, constipation, sedation and cognitive impairment. It discusses the limited role of codeine in pain treatment due to dose escalation, misuse and potential addiction. It cautions about opioid drug-related deaths, codeine misuse, and circumnavigation of restrictions on over-the-counter sales.

The substance combination of codeine and promethazine, commonly termed lean / sizzurp, has been identified as a method that some individuals use to cope with PTSD and other mental health symptomology. A sample of 1423 adults with self-reported past year lean use was recruited from substance-related Reddit pages to complete a survey about lean, including information about using lean to cope with emotions, thoughts, or feelings. To be included in the sample, persons needed to: (1) be ⩾18 years old, (2) report past year lean use, (3) complete lean use screeners, and (4) pass data quality checks (eg, bot detection). As Reddit is an online forum, no geographic restrictions were placed on study participation. Data on demographic characteristics, lean use, and mental health disorder symptomology were captured from participants. Logistic regression models included anxiety, depression, and trauma as independent variables along with covariates to examine using lean to cope with emotions, thoughts, or feelings in the past 30 days. Most participants were male (n = 1102; 77.4%), with an average age of 26.9 (SD = 5.2) years. Most participants used included codeine as an ingredient in lean (n = 1060; 74.5%); promethazine was added as an ingredient by 31.7% of the sample (n = 451), and the combination of codeine and promethazine was included as ingredients by 13.5% (n = 192) of the sample. Participants with anxiety, lifetime trauma exposure, and who were female had increased odds of using lean to cope with emotions, thoughts, or feelings in the past 30 days. Those with depression and unstable housing exhibited decreased odds of using lean to cope with emotions, thoughts, or feelings in the past 30 days. This study recruited persons via social media to learn more about lean use, especially lean use to cope with mental health symptoms; future population-level studies are needed. [ABSTRACT FROM AUTHOR]

Aims: There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. We aim to assess the association between weak opioids and cancers of the GI tract. Methods: A series of nested case‐control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n = 2432), gastric (n = 1443) and colorectal cancer (n = 8750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use. Results: There was no association between weak opioids and colorectal cancer (adjusted OR = 0.96, CI 0.90, 1.02, P = 0.15). There was an increased risk of oesophageal (adjusted OR = 1.16, CI 1.04, 1.29, P = 0.01) and gastric cancer (adjusted OR = 1.26, CI 1.10, 1.45, P = 0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR = 1.03 CI 0.86, 1.22, P = 0.76 and adjusted OR = 1.29 CI 1.02, 1.64, P = 0.04 respectively). Conclusions: In this large population‐based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication. [ABSTRACT FROM AUTHOR]

The two-component compound formed by codeine and cyclopentobarbital was produced using grinding techniques and through evaporation from alcoholic solutions. The cocrystal nature of this phase was established unequivocally through single crystal X-ray structure determination. The asymmetric unit contains one formula unit. In the cyclopentobarbital molecule, the cyclopentenyl ring is disordered over two positions related by a rotation of approximately 180° about its C—C bond to the pyrimidine ring. The two NH groups of the cyclopentobarbital molecule form N—H⋯N and N—H⋯O bonds to piperidine and hydroxyl groups, respectively, belonging to different codeine molecules. In addition, the hydroxyl and methoxy groups of neighboring codeine molecules are linked by O—H⋯O interactions, resulting in a H-bonded framework structure of codeine and cyclopentobarbital molecules. The cocrystal was also characterized using thermal analysis, X-ray powder diffraction and IR spectroscopy. [ABSTRACT FROM AUTHOR]

In the present paper, Mn/UiO-66 material was synthesized by hydrothermal process. The obtained material was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) with mapping and nitrogen adsorption/desorption techniques. The doped manganese was shown to highly disperse and might be grafted into the lattice of UiO-66. A simple, fast, and inexpensive differential pulse voltammetric (DPV) method were developed using Mn/UiO-66 as an electrode modifier for the simultaneous determination of acetaminophen (ACE) and codeine (CDE) in pharmaceutical formulations. The experimental parameters, which might affect the peak currents of ACE and CDE, such as the pH of the solution, accumulation time, and scan rate, were optimized. Under optimal conditions, this technique provided low limits of detection for the quantification of ACE and CDE, of 0.45 and 0.31 μM, respectively. The proposed DPV method was successfully applied to simultaneously determine ACE and CDE in samples of three pharmaceutical formulation with acceptable recoveries. Clearly, the proposed method might be an alternative option for the simultaneous determination of ACE and CDE. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy. • We investigated the effects of opioids use on narcolepsy symptom severity. • Opioids mainly improved disturbed nocturnal sleep and excessive daytime sleepiness. • Narcolepsy symptom relief was clearest for oxycodone or codeine. • Randomised controlled trials are needed to verify the therapeutic potency of opioids. • Concurrent opioid and sodium oxybate use should be more carefully monitored. [ABSTRACT FROM AUTHOR]

Codeine and acetaminophen in combination have proven to be an effective analgesic treatment for moderate‐to‐severe and postoperative pain in humans. Studies have demonstrated that codeine and acetaminophen, when administered as sole agents, are well tolerated by horses. In the current study, we hypothesized that administration of the combination of codeine and acetaminophen would result in a significant thermal antinociceptive effect compared with administration of either alone. Six horses were administered oral doses of codeine (1.2 mg/kg), acetaminophen (20 mg/kg), and codeine plus acetaminophen (1.2 mg/kg codeine and 6–6.4 mg/kg acetaminophen) in a three‐way balanced crossover design. Plasma samples were collected, concentrations of drug and metabolites determined via liquid chromatography–mass spectrometry, and pharmacokinetic analyses were performed. Pharmacodynamic outcomes, including effect on thermal thresholds, were assessed. Codeine Cmax and AUC were significantly different between the codeine and combination group. There was considerable inter‐individual variation in the pharmacokinetic parameters for codeine, acetaminophen, and their metabolites in horses. All treatments were well tolerated with minimal significant adverse effects. An increase in the thermal threshold was noted at 1.5 and 2 h, from 15 min through 6 h and 0.5, 1, 1.5, and 3 h in the codeine, acetaminophen, and combination groups, respectively. [ABSTRACT FROM AUTHOR]

Purpose: Combining analgesics with different mechanisms of action may increase the analgesic efficacy. The multidimensional pharmacodynamic profiles of ibuprofen 400 mg/paracetamol 1000 mg, ibuprofen 400 mg/paracetamol 1000 mg/codeine 60 mg, and paracetamol 1000 mg/codeine 60 mg and placebo were compared. Methods: A randomized, double-blind, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 200 patients of both sexes and homogenous ethnicity after third molar surgery (mean age 24 years, range 19–30 years). Primary outcome was sum pain intensity over 6 h (SPI). Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference (SPID), maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat, prevent remedication and harm values, adverse effects, and patient-reported outcome measure (PROM). Results: Analgesia following ibuprofen and paracetamol combination with or without codeine was comparable. Both were better than paracetamol combined with codeine. Secondary variables supported this finding. Post hoc analysis of SPI and SPID revealed a sex/drug interaction trend in the codeine-containing groups where females experienced less analgesia. PROM showed a significant sex/drug interaction in the paracetamol and codeine group, but not in the other codeine-containing group. Especially females reported known and mild side effects in the codeine-containing groups. Conclusion: Codeine added to ibuprofen/paracetamol does not seem to add analgesia in a sex-mixed study population. Sex may be a confounding factor when testing weak opioid analgesics such as codeine. PROM seems to be more sensitive than traditional outcome measures. Trial registration: ClinicalTrials.gov June 2009 NCT00921700. [ABSTRACT FROM AUTHOR]

Invasive mucinous adenocarcinoma is a rare variant of lung adenocarcinoma. Here, we present the case of a patient with invasive mucinous adenocarcinoma with cavitary lung lesions. A 61-year-old painter-and-bricklayer. She was admitted due to mMRC2 dyspnea, a dry cough that during hospitalization mobilizes dense, abundant secretions, and becomes demanding. Differential diagnoses were made based on clinical symptoms and images, performing multiple laboratory tests ruling out immunosuppression, and two video-bronchofibroscopies finding the diagnosis in the transbronchial lung biopsy: Invasive mucinous adenocarcinoma that would explain the abundant bronchorrhea, advanced stage and poor prognosis led to ventilatory failure and death of the patient. [ABSTRACT FROM AUTHOR]

Background: Oxycodone is increasingly prescribed for postpartum analgesia in lieu of codeine owing to concerns regarding the neonatal safety of codeine during lactation. We examined whether initiation of oxycodone after delivery was associated with an increased risk of persistent opioid use relative to initiation of codeine. Methods: We conducted a population-based cohort study of people who filled a prescription for either codeine or oxycodone within 7 days of discharge from hospital after delivery between Sept. 1, 2012, and June 30, 2020. The primary outcome was persistent opioid use, defined as 1 or more additional prescriptions for an opioid within 90 days of the first postpartum prescription and 1 or more additional prescriptions in the 91 to 365 days thereafter. We used inverse probability of treatment weighting to assess the risk of persistent postpartum opioid use, comparing people who initiated oxycodone with those who initiated codeine. Results: Over the 8-year study period, we identified 70 607 people who filled an opioid prescription within 7 days of discharge from hospital: 21 308 (30.2%) received codeine and 49 299 (69.8%) oxycodone. Compared with people who filled a prescription for codeine, receipt of oxycodone was not associated with persistent opioid use (relative risk [RR] 1.04, 95% confidence interval [CI] 0.91–1.20). We found an association between a prescription for oxycodone and persistent use after vaginal delivery (RR 1.63, 95% CI 1.31–2.03), but not after cesarean delivery (RR 0.85, 95% CI 0.73–1.00). Interpretation: Initiation of oxycodone (v. codeine) was not associated with an increased risk of persistent opioid use, except after vaginal delivery. [ABSTRACT FROM AUTHOR]

Objectives: This study was done to evaluate the knowledge of community pharmacists--working in Saudi Arabia--regarding over-the-counter opioid-related and opioid-containing medications. Materials and Methods: A quantitative cross-sectional study was conducted using an online questionnaire that was distributed through social media and taken to the community pharmacists in person. A total of 101 responders were reached in a period of around 3 weeks. Results: Most of the pharmacists working in community pharmacies in Saudi Arabia are non-Saudi (85.15%), males (88.12%), and the majority are holders of bachelor's degrees (85.15%). More than half of the participants spend a considerably sufficient time with the patient 6-10 minutes (60.4%). The availability of a private counseling room in community pharmacies is significantly low (21.78%). Only (69.41%) of participants always counsel the patient before dispensing opioid-related medications. Most of the participants (84.76%) believe that all over-the-counter opioid-related and opioid-containing medications should be restricted to avoid drug abuse. Conclusion: A little neglect from pharmacists' side regarding dispensing such medications was observed; thus, there is a significant need to raise their awareness regarding over-the-counter opioid abuse. [ABSTRACT FROM AUTHOR]

Insects on corpses could be a useful tool for the detection of exogenous substances such as drugs of abuse. The identification of exogenous substances in carrion insects is critical for proper estimation of the postmortem interval. It also provides information about the deceased person that may prove useful for forensic purposes. High-performance liquid chromatography coupled with Fourier transform mass spectrometry is a highly sensitive analytical technique that can identify substances even at very low concentrations, such as in the case of searching for exogenous substances in larvae. In this paper, a method is proposed for the identification of morphine, codeine, methadone, 6-monoacetylmorphine (6-MAM) and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in the larvae of Lucilia sericata, a common carrion fly widely distributed in temperate areas of the world. The larvae, which were reared on a pig meat substrate, were killed once they reached their third stage by immersion in hot water at 80 °C and aliquoted into 400 mg samples. The samples were fortified with 5 ng of morphine, methadone and codeine. After solid-phase extraction, the samples were processed with a liquid chromatograph coupled to a Fourier transform mass spectrometer. This qualitative method has been validated and tested on larvae from a real case. The results lead to the correct identification of morphine, codeine, methadone and their metabolites. This method could prove useful in cases where toxicological analysis must be conducted on highly decomposed human remains, where biological matrices are very limited. Furthermore, it could help the forensic pathologist to better estimate the time of death, as the growth cycle of carrion insects can undergo changes if exogenous substances are taken. [ABSTRACT FROM AUTHOR]

Morphine and codeine, two of the most common opioids, are widely used in the clinic for different types of pain. Morphine is one of the most potent agonists for the μ-opioid receptor, leading to the strongest analgesic effect. However, due to their association with serious side effects such as respiratory depression, constriction, euphoria, and addiction, it is necessary for derivatives of morphine and codeine to be developed to overcome such drawbacks. The development of analgesics based on the opiate structure that can be safe, orally active, and non-addictive is one of the important fields in medicinal chemistry. Over the years, morphine and codeine have undergone many structural changes. The biological investigation of semi-synthetic derivatives of both morphine and codeine, especially morphine, shows that studies on these structures are still significant for the development of potent opioid antagonists and agonists. In this review, we summarize several decade-long attempts to synthesize new analogues of morphine and codeine. Our summary placed a focus on synthetic derivatives derived from ring A (positions 1, 2, and 3), ring C (position 6), and N-17 moiety. [ABSTRACT FROM AUTHOR]

In Saudi Arabia, there are concerning rates of non-compliance with pharmaceutical regulations prohibiting the pharmacy dispensing of prescription-only medications without a physician prescription. This is the first study in the Middle East which examines physicians' perceptions regarding misuse of codeine, listed as a narcotic, controlled, and prescription-only drug. The CODEMISUSED survey was adapted to the Saudi Arabian context and pilot tested, prior to cross-sectional administration to physicians in Riyadh, Jeddah, Abha, and Jazan (n = 105). Descriptive statistics (frequencies and percentage) present physician level of agreement, neutrality, and disagreement with statements regarding codeine prescribing, patient awareness and use, online and community pharmacy availability, and dependence. The study indicates concern by physicians regarding patient intentional use of codeine to enhance mood, misuse patterns, lack of awareness around habit-forming use and iatrogenic dependence, and sourcing via illegal dispensing. It underscores the imperatives to address pharmacy compliance with pharmaceutical regulatory controls, implement enhanced pharmacovigilance, and improve awareness around safe use. [ABSTRACT FROM AUTHOR]

Keratinized matrices, including nails, are among the most resistant matrices that can be analyzed in cases where remains are deeply decomposed and relatively non-invasive for living people. In order to exploit these new matrices in the search for exogenous substances, it is necessary to develop analytical technologies capable of achieving high levels of sensitivity. In this technical note, an easy method is presented for the simultaneous extraction and quantification of three narcotic substances (morphine, codeine and methadone), two benzodiazepines (BDZs) (clonazepam and alprazolam) and an antipsychotic (quetiapine) from nail matrix by analysis in ultra-high-performance liquid chromatography at high-resolution mass spectrometry. The method has been validated following the Standard Practices for Method Validation in Forensic Toxicology of the Scientific Working Group for Forensic Toxicology. Nail specimens from eight authentic postmortem (PM) cases and 13 living donor samples were extracted and analyzed. Of the eight PM samples, five resulted positive for at least one of the three substances searched. Ten of the 13 living donor specimens were positive for at least one of the targeted BDZs or quetiapine. [ABSTRACT FROM AUTHOR]

A whole cell Escherichia coli biotransformation platform converting thebaine to oripavine and codeine to morphine was demonstrated with industrially applicable yields (∼1.2 × 10−2 g L−1 h−1 or ∼1.2 × 10−1 g L−1 h−1), improving >13 400-fold upon morphine production in yeast. Mutations enhanced enzyme performance and the use of a purified substrate with rich raw poppy extract expanded applicability. [ABSTRACT FROM AUTHOR]

Background and Aims: The current opioid epidemic in the United States began 20 years ago and has become the leading cause of accidental deaths in the country. This crisis prompted us to explore trends in opioid abuse and dependence worldwide. We sought to identify other countries at high‐risk of opioid use disorders, using the World Health Organization's (WHO) pharmacovigilance database. Methods: We performed a disproportionality analysis using VigiBase, the WHO Global Individual Case Safety Report (ICSR) database. Five opioids used worldwide were included: oxycodone, fentanyl, morphine, tramadol, and codeine. We extracted all ICSRs associated with the drugs of interest, considered as suspect medication and recorded up until 5 June 2021, using the narrow Standardised MedDRA Query (SMQ) for drug abuse and dependence. Countries with at least one ICSR for each of the five opioids were retained. The relationship between the use of a drug (i.e. an opioid) and the occurrence of an adverse drug reaction (i.e. drug abuse and dependence) for each country was assessed by calculating the information component (IC) and its 99.9% CI [IC0005; IC9995], using a quasi‐Bayesian confidence propagation neural network (BCPNN). A hierarchical cluster analysis (Ward's method) of the IC0005 value for each of the five opioids was performed to identify subgroups of countries with similar reported risks of opioid abuse and dependence. Results: Among 21 countries, the optimal number of clusters was calculated to be four, each with a Jaccard index >0.5 (0.95, 0.78, 0.65 and 0.75, respectively). Six countries with the highest signals of drug abuse and dependence were identified in cluster 1, with significant CIs for the five opioids of interest (IC0005 > 0), ranging from 0.9 to 5.8 for the lower endpoint. Conclusions: There appear to be four distinct clusters of countries with similar opioid abuse and dependence profiles. The group with the highest reported risk for the opioids oxycodone, fentanyl, morphine, tramadol and codeine includes Australia, Canada, France, Germans, the United Kingdom and the United States. [ABSTRACT FROM AUTHOR]

Objective: Opioids (except for tramadol) have not been shown to be effective in patients with fibromyalgia, but they can increase the risk of adverse drug reactions. The aim was to determine the treatment patterns of a group of patients with fibromyalgia and to identify the factors associated with the use of opioids in Colombia. Methods: This was a cross‐sectional study of a group of patients with fibromyalgia from a pain clinic in Colombia. Sociodemographic, clinical and pharmacological variables were identified. Descriptive, bivariate, and multivariate analyses were performed. Results: A total of 559 patients were analysed, 88.6% of whom were women, and the mean age was 53.4 ± 12.6 years. A total of 40.6% received nonpharmacological management, and the majority were treated with acetaminophen (96.1%) and pregabalin (62.8%). A total of 69.6% received opioids, the most common of which was hydrocodone (36.3%). The average morphine equivalent milligrammes was 36.9 ± 91.2 (range: 2.3–750 mg), and 43.8% had intermediate/high doses. Being male (OR: 3.12; 95% CI: 1.40–6.91), having arterial hypertension (OR: 1.67; 95% CI: 1.04–2.69), obesity (OR: 2.23; 95% CI: 1.18–4.24), degenerative disease of vertebral discs (OR: 2.32; 95% CI: 1.10–4.88) and comedication with gabapentinoids (OR: 1.75; 95% CI: 1,15–2.65) were associated with a higher probability of receiving opioids, while patients treated with muscle relaxants had a lower risk of opioid treatment (OR: 0.64; 95% CI: 0.41–0.98). Conclusions: A significant proportion of patients were treated with opioids, the most common of which was hydrocodone, which goes against the recommendations of clinical practice guidelines. [ABSTRACT FROM AUTHOR]

Background and aim: From 1 February 2018, codeine was rescheduled from an over‐the‐counter (OTC) to a prescription‐only medicine in Australia. We used wastewater‐based epidemiology to measure changes in population codeine consumption before and after rescheduling. Methods: We analysed 3703 wastewater samples from 48 wastewater treatment plants, taken between August 2016 and August 2019. Our samples represented 10.6 million people, 45% of the Australian population in state capitals and regional areas in each state or territory. Codeine concentrations were determined by liquid chromatography–tandem mass spectrometry and converted to per‐capita consumption estimates using the site daily wastewater volume, catchment populations and codeine excretion kinetics. Results: Average per‐capita consumption of codeine decreased by 37% nationally immediately after the rescheduling in February 2018 [95% confidence interval (CI) = 35.3–39.4%] and substantially in all states between 24 and 51% (95% CI = 22.4–27.0% and 41.8–59.4%). The decrease was sustained at the lower level to August 2019. Locations with least pharmacy access decreased by 51% (95% CI = 41.7–61.7%), a greater decrease than 37% observed for those with greater pharmacy access (95% CI = 35.1–39.4%). Regional areas decreased by a smaller margin to cities (32 versus 38%, 95% CI = 30.2–34.1% versus 34.9–40.4%, respectively) from a base per‐capita usage approximately 40% higher than cities. Conclusion: Wastewater analysis shows that codeine consumption in Australia decreased by approximately 37% following its rescheduling as a prescription‐only medicine in 2018. Wastewater‐based epidemiology can be used to evaluate changes in population pharmaceutical consumption in responses to changes in drug scheduling. [ABSTRACT FROM AUTHOR]

Consumption of poppy seed-containing food products can result in opiate-positive urine drug test results and may pose challenges in distinguishing poppy seed consumption from opiate administration. In this context, guidance has suggested that codeine concentrations exceeding 300 ng/mL coupled with morphine-to-codeine ratios <2 are indicative of codeine consumption and, therefore, exclude poppy seed consumption as a legitimate explanation for the test result. In recent years, we performed independent medical examinations of three individuals who produced codeine-positive/morphine-negative (300 ng/mL) forensic urine drug test results but denied codeine administration, attributing their test results to the consumption of specific poppy seed-containing food products. In the present study, 11 participants consumed one of the 10 unique poppy seed-containing food products, including the three implicated food products. Six of 33 non-baseline urine samples (18%)—representing three food products—were positive for codeine and negative for morphine at 300 ng/mL cut-offs (and therefore featured morphine-to-codeine ratios <2). This study adds to a small literature indicating that consumption of poppy seed-containing food products cannot reliably be distinguished from codeine administration based on previously published urinary opiate concentrations and ratios. An important caveat is that in none of these cases did maximum urinary codeine concentrations exceed 1,300 µg/g creatinine. [ABSTRACT FROM AUTHOR]

The substance combination of codeine and promethazine, commonly termed lean/sizzurp, has been identified as a method that some individuals use to cope with PTSD and other mental health symptomology. A sample of 1423 adults with self-reported past year lean use was recruited from substance-related Reddit pages to complete a survey about lean, including information about using lean to cope with emotions, thoughts, or feelings. To be included in the sample, persons needed to: (1) be ≥18 years old, (2) report past year lean use, (3) complete lean use screeners, and (4) pass data quality checks (eg, bot detection). As Reddit is an online forum, no geographic restrictions were placed on study participation. Data on demographic characteristics, lean use, and mental health disorder symptomology were captured from participants. Logistic regression models included anxiety, depression, and trauma as independent variables along with covariates to examine using lean to cope with emotions, thoughts, or feelings in the past 30 days. Most participants were male (n = 1102; 77.4%), with an average age of 26.9 (SD = 5.2) years. Most participants used included codeine as an ingredient in lean (n = 1060; 74.5%); promethazine was added as an ingredient by 31.7% of the sample (n = 451), and the combination of codeine and promethazine was included as ingredients by 13.5% (n = 192) of the sample. Participants with anxiety, lifetime trauma exposure, and who were female had increased odds of using lean to cope with emotions, thoughts, or feelings in the past 30 days. Those with depression and unstable housing exhibited decreased odds of using lean to cope with emotions, thoughts, or feelings in the past 30 days. This study recruited persons via social media to learn more about lean use, especially lean use to cope with mental health symptoms; future population-level studies are needed. [ABSTRACT FROM AUTHOR]

An in-capillary derivatization (in-CAP-D) integrated with field amplified sample stacking (FASS) has been developed for the determination of morphine (MOR) and its metabolite, morphine-6-glucuronide (MOR-6-G) in human serum using capillary zone electrophoresis (CZE) and fluorescence detection (in-Cap-D-FASS-CZE). Acetonitrile was employed in removing proteins and extracting MOR and MOR-6-G into the clear supernatant containing codeine (COD) as an internal standard (IS). The derivatization was achieved in an in-capillary mode by introducing the acetonitrile-treated samples into a running electrolyte containing an oxidizing agent of potassium ferricyanide, whereas MOR, MOR-6-G and COD were oxidized into dimer derivatives with highly fluorescent intensity. The effectiveness and sensitivity of the in-Cap-D-FASS-CZE method were affected by many parameters, and the following conditions were found to be optimal: 70 m Mdisodium tetraboratedecahydrate (pH, 10.5), 0.30 mM ferrricyanide and a separation voltage of 10 kV. In order to perform the FASS, samples were electrokinetically injected for 20 s at 20 kV into the capillary that was pre-field with a 4 s water plug. Analysis was performed at ambient temperature (22 ± 1 °C). The method's validation revealed good linearity with respect to peak area ratios of MOR and MOR-6-G with the IS and the corresponding concentrations over the ranges of 1–2000 and 1.2 to 2000 ng/mL, respectively. Following one oral dose of controlled-release MOR sulphate tablet, the validated in-Cap-D-FASS-CZE method successfully enabled the determination of MOR and MOR-6-G in clinical serum samples. [ABSTRACT FROM AUTHOR]

Codeine N‐oxide 2 is an active metabolite of codeine obtained by oxidation and observed as a degradant in codeine drug products such as syrups. Oxidation of codeine's N‐methyl function can deliver two regio‐isomers due to chirality of the tetra‐substituted nitrogen. Hydrogen peroxide oxidation of codeine was performed and induced two different isomers in a 9:1 ratio; these isomers were isolated using preparative high performance liquid chromatography (HPLC) and fully characterized by nuclear magnetic resonance (NMR) techniques. We describe the complete assignment of the minor isomer of codeine N‐oxide 3 and attribute a (S) configuration (N‐methyl axial) of the tetra‐substituted nitrogen. The effects of N‐oxidation on the 15N chemical shifts of the codeine are presented. The 15N shifts were determined using the CIGAR‐HMBC experiment at natural abundance, and the nitrogen resonance of codeine shifted downfield from 42.8 to 118.7 ppm for both N‐oxide isomers. [ABSTRACT FROM AUTHOR]

In this study, magnetic pomelo peel‐derived biochar composite was fabricated and applied as a low‐cost adsorbent for the simultaneous extraction of morphine‐like opioids named morphine, codeine, and 6‐monoacetylmorphine from wastewaters, prior to their determination via liquid chromatography‐mass spectrometry. A total of four biochar products were synthesized under different pyrolytic temperatures of 400, 500, 600, and 700°C, respectively, and the 400°C biochar was found to have the greatest extraction ability, with enrichment factors of 34, 58, and 61 for the three drugs. The primary adsorption mechanism includes π‐π interaction and H‐bonding. Parameters affecting the extraction of opioids were optimized. Under optimum conditions (such as pH = 7; adsorbent amount = 15 mg; sample volume = 20 ml; eluent solvent, 200 µl of methanol), the method was proved to be linear in the range of 0.05–10.0 µg/L, with coefficients of determination greater than 0.99, and the limits of detection were 0.006–0.010 µg/L. In‐batch and inter‐batch precisions were 1.8%–6.5% and 4.8%–10.6%, respectively. The method was successfully applied to the determination of the target opioids in the samples of influent and effluent wastewater. The developed method by using magnetic pomelo peel‐derived biochar could potentially be applied for the effective estimation of illicit drug consumption. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous drug administration is an interesting approach for symptom control in hospice and palliative care. However, most drugs have no marketing authorization for subcutaneous administration and are therefore used off-label. In order to meet the requirements of a safe and effective drug therapy, especially in highly vulnerable patients, it is essential to investigate the scope of evidence of these common practices.Objectives: The purpose of this scoping review was to provide an overview of available data on the tolerability and/or effectiveness of subcutaneously administered and off-label used drugs.Method: We performed a scoping review according to the PRISMA extension to identify data available on the tolerability and/or effectiveness of 17 predefined drugs that are commonly administered subcutaneously in Swiss hospices and hospice-like institutions and that have no marketing authorization (off-label use).Results: The scoping review identified 57 studies with most data available on their tolerability (68% local, 54% systemic), clinical effects (82%), details on dosage (96%) and routes of application (100%). Information on pharmacokinetic properties was mostly missing and only available for fentanyl, levetiracetam, midazolam, and ondansetron. For seven drugs, less than five articles were identified and no studies on codeine or clonazepam were available.Conclusion: This work provides an overview of current evidence on subcutaneous and off-label used drugs in hospice and palliative care. Although both are common practices, evidence on tolerability and effectiveness, particularly pharmacokinetic data, is limited and the identified information gaps need to be closed. This work establishes a basis for further research in this area. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the change in codeine and tramadol dispensing for treatment of pain to children aged <18 years after the 2017 Drug Safety Communication (DSC) issued by the U.S. Food and Drug Administration. Topics covered include the association between the DSC and the monthly number of patients dispensed codeine or tramadol prescription, and the association of the DSC to declines in codeine dispensing to children and adolescents.

Introduction: Concerns over serious respiratory depression in children led to two European Union (EU) referral procedures (in 2013 and 2015) to review the benefit-risk balance of codeine in this population when used for pain relief, cough or cold. Consequently, codeine should no longer be used in children aged < 12 years and restrictions were introduced for treatment in children ≥ 12 years.Objective: This multinational collaborative study aimed to assess the effectiveness of these risk minimisation measures by evaluating changes in prescribing of codeine and alternative treatments.Method: Children under 12 and 12-18 years old were followed between 2010 and 2017 to analyse quarterly trends in prescribing of codeine and alternative treatments in electronic health records from France, Germany, Norway, Spain and the United Kingdom using interrupted time series analysis.Results: Overall prescribing of codeine in children decreased in all five countries, reaching near zero prevalence in children under 12 years of age. This was accompanied by an increase in use of other opioid analgesics in France (from 0.15 to 0.56 prevalence per 100 person-years immediately after the first referral), Norway (from 0.0006 to 0.0013 at the end of the study), the United Kingdom (from 0.018 to 0.05 at the end of the study), and an increase in non-opioid analgesics in Norway (from 0.045 to 0.075 at the end of the study) after the referral on pain relief indication. The referral on cough/cold indication led to a decrease in use of opioid and non-opioid antitussives in children aged < 12 years in France (from 10 to 7 and 20 to 16, respectively) and had no impact in other countries. Overall prescribing trends for codeine and alternatives were similar across both age groups within each country.Conclusion: The decrease in use of codeine shows that healthcare professionals followed the adopted measures and switched prescribing practices for pain management in children aged < 18 years towards opioid or non-opioid analgesics depending on national clinical and reimbursement settings. Whist the magnitude of the first referral on pain differed between countries, the second referral on cough/cold had only a minimal impact on the use of codeine and antitussives. [ABSTRACT FROM AUTHOR]

Background: Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear. On the other hand, arginine has been speculated to enhance penile reflexes by upregulating NO/cGMP Signaling. Aim: The study evaluated the effect of maternal codeine exposure and prepubertal codeine and arginine treatments on F1 male sexual function and fertility indices, as well as the outcome of F2 progenies. In addition, the epigenetic programming mechanism was also explored. Methods: Forty three-week-old female rats were randomized into two groups (n = 20 rats/group); the control that received 0.5 ml of distilled water and the codeine-treated that received 5 mg/kg of codeine via gavage for eight weeks. Afterward, the female rats were paired for mating with sexually mature male rats. Rats were maintained on their pre-pregnancy treatments throughout pregnancy and lactation. FI progenies from each cohort (control and codeine-treated cohorts) were weaned at three weeks and randomized into four groups; the control, codeine-treated, L-arginine-treated (300mg/kg), and codeine + L-arginine-treated (n = 10 rats/group). Administration commenced a week post-weaning and lasted for eight weeks via gavage. Key findings: Maternal codeine exposure did not alter body weight, but significantly reduced anogenital distance and anogenital index of F1 male offspring. Also, maternal codeine delayed preputial membrane separation, impaired male sexual competence, and penile reflexes of F1 male offsprings. These were associated with reduced dopamine, gonadotropins, and testosterone levels as well as suppressed expression of androgen receptor mRNA. In addition, maternal codeine downregulated NO/cGMP signaling, impaired fertility indices, and reduced the litter size, weight, and survival of F2 progenies. These alterations were observed to be aggravated by prepubertal codeine exposure but improved by prepubertal arginine treatment. Significance: In conclusion, codeine programmed sexual dysfunction by suppressing the levels of dopamine and testosterone, as well as repressing the expression of androgen receptor mRNA. In addition, codeine-induced epigenetic reprogramming was expressed in the F2 offsprings as reduced litter size and weight, and survival rate. Notably, these observations were worsened by prepubertal codeine exposure, but dampened by prepubertal arginine treatment. [ABSTRACT FROM AUTHOR]

Cervical spondylotic myelopathy (CSM) is the leading cause of acquired spinal cord dysfunction worldwide and may be expected to increase in prevalence due to an aging global population. Clinical features of CSM are highly variable, and chiropractors frequently manage patients with common signs and symptoms of CSM such as neck pain, extremity weakness, and gait imbalances. Early recognition of signs consistent with myelopathy may mitigate future disability and improve quality of life. Key predictors of patient outcome are the age of initial presentation, baseline CSM severity (as measured by mJOA score), and the presence of gait disturbances. This report describes three cases of CSM presenting to a chiropractic clinic. Each case illustrates a unique manifestation of CSM, including myelopathy, myeloradiculopathy, and distal neuropathic pain (funicular referral). In addition, a review of CSM terminology, epidemiology, pathobiology, clinical features, imaging, and management is provided. [ABSTRACT FROM AUTHOR]

Objective: To determine if a 2-day protocol measuring pharmacokinetic and pharmacodynamic characteristics can demonstrate drug-drug interactions when smoked cannabis is added to orally administered hydrocodone/acetaminophen combination products. Case Summary: A 51-year-old non-Hispanic white male with chronic pain diagnoses participated in a 2-day pilot protocol. The participant attended two 7-hour in-lab days where he received 10 blood draws each day and completed self-administered pain and anxiety surveys. For both days, the participant took his prescribed dose of hydrocodone/acetaminophen (1/2 tablet of 7.5 mg/325 mg combination product) with the addition of 1 smoked pre-rolled marijuana cigarette (labeled as 0.5 g; 22.17% Δ9-tetrahydrocannabinol; 0.12% cannabidiol) on Day 2. Blood specimens were analyzed using mass spectrometry to quantify the difference of plasma hydrocodone levels between Day 1 and Day 2. Results: Compared to Day 1, lower levels of pain and anxiety were reported during Day 2 with the addition of cannabis to oral hydrocodone/acetaminophen. Day 2 pharmacokinetic analysis also revealed more rapid absorption and overall lower levels of hydrocodone in plasma. Discussion: Lower hydrocodone plasma levels in Day 2 may indicate cannabis's effect on metabolism and reduce the risk of opioid toxicity. The quicker absorption rate of hydrocodone could explain lower pain and anxiety scores reported on the second day. Conclusion and Relevance: A 2-day protocol was able to capture differences across time in pharmacokinetic and pharmacodynamic measurements. Larger studies can be designed to better characterize the potential drug-drug interaction of cannabis and opioids. [ABSTRACT FROM AUTHOR]

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven‐step, asymmetric chemical synthesis of (−)‐codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo‐redox hydroamination protocol provides a novel, atom‐economical means for assembling the piperidine D‐ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N‐demethyl codeine. Our work highlights the capacity for contemporary, stand‐alone chemical synthesis regimes to diversify access to essential opiate medicines. [ABSTRACT FROM AUTHOR]

Morphinans are essential medicines derived entirely from poppy supply chains rendered increasingly volatile by climate change. Here, we report a seven‐step, asymmetric chemical synthesis of (−)‐codeine from simple materials that requires a total combined reaction time of fewer than 24 hours. The efficiency of our approach arises from a double‐Heck cyclization reaction that generates two rings and two contiguous stereogenic carbon centres in the one pot. A subsequent photo‐redox hydroamination protocol provides a novel, atom‐economical means for assembling the piperidine D‐ring of codeine. Simple modifications to the closing stages of our sequence offer effective access to pharmacologically valuable derivatives of N‐demethyl codeine. Our work highlights the capacity for contemporary, stand‐alone chemical synthesis regimes to diversify access to essential opiate medicines. [ABSTRACT FROM AUTHOR]