Search

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.

An 87-year-old man with a history of osteoarthritis presented with worsening knee pain. He was prescribed acetaminophen with codeine. A few days later, he developed a rash on his right buttock and proximal thigh, similar to a rash he experienced in the past when he took over-the-counter (OTC) acetamenophen and an unknown lozenge to treat a presumed viral illness. A fixed drug eruption (FDE) was diagnosed and the patient was asked to avoid Tylenol and other OTC lozenges. Tylenol was entered as an allergy in the electronic medical records. However, since Tylenol, not acetaminophen was listed in the allergy profile, the order for acetaminophen and codeine did not generate an alert for the prescribing physician. Additionally, the dispensing pharmacist did not question the prescribing physician and the patient, unaware that acetaminophen in the pain medication is the same drug as Tylenol, took it and developed recurrent FDE.

This study sought to determine if there were any changes in opioid prescribing habits of providers at a single institution after the implementation of legislation to increase opioid prescribing regulations. Our study demonstrated a 39.5 percent decrease in overall morphine milligram equivalent (MME) prescribed the year after the laws took effect when compared with the year prior. It is clear that these laws have been effective in decreasing the number of opioids prescribed at discharge from Mercy Health Grand Rapids.Introduction: Opioid use disorder has become an epidemic with approximately 130 people dying every day in the United States due to prescription and illegal opioid overdoses. In December 2017, the Michigan legislature ratified a package of 10 acts to address a variety of problems through several layers of regulations including more restrictive prescribing rules, which took effect in June 2018. Objective: To evaluate the impact of legislation on the opioid prescribing habits of providers who discharged patients from a community-based academic teaching hospital.Design, setting, and participants: A retrospective cohort study was performed using data from a community-based academic teaching hospital with 303 beds, a medical ICU, labor and delivery unit, and a 42-room emergency department. All patients discharged from in-patient or observation status in the 12 months before and after June 1, 2018 were included.Main outcomes and measures: The primary outcome was MMEs of opioids prescribed at discharge before (June 1, 2017 to May 31, 2018) and after (June 1, 2018 to May 31, 2019) legislation. Medications included morphine, hydrocodone, oxycodone, fentanyl, methadone, hydromorphone, tramadol, codeine, and meperidine.Results: There were 17,227 patients discharged during the first 12-month period and 15,855 patients discharged in the second 12-month period. There were 14,064 new opioid prescriptions in total during these time periods. Total MME prescribed during the study period showed a 39.5 percent decrease from pre- (2,268,460 MME) to post-legislation (1,372,424 MME), while average MMEs/discharge significantly decreased (135.1 ± 321.2 vs. 87.6 ± 187.4; p < 0.001). Total pill/patch count decreased by almost 40 percent. For patients who were prescribed opioids, average MME/discharge showed significant decline after legislation implementation (309.6 ± 427.1 vs. 212.2 ± 242.1; p < 0.001). Average daily MME/patient prescribed an opioid remained similar between the time periods (52.4 ± 37.0 vs. 51.6 ± 35.0; p = 0.21). Significant reductions (p < 0.05) were seen in MMEs for each individual medication with the exception of acetaminophen-codeine and methadone.Conclusions and relevance: Our results indicate that the legislation implemented in Michigan to regulate opioid prescriptions was associated with a reduction in opioids prescribed to patients discharged from a community-based academic teaching hospital.

Opinion statementPharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person’s genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Acute postoperative pain is a constant challenge for medical professionals, who seek to choose drugs capable of generating a high degree of analgesia, without, however, inducing adverse effects, such as: intense sedation, gastrointestinal effects, addiction and breathing depression, inherent to opioids. It is already well known that narcotic analgesics constitute the pharmacological group most used in the immediate postoperative period. Here we present Viminol Hydroxybenzoate which has peculiar analgesic characteristics, being considered a potent non-narcotic analgesic of central action and equipotent to codeine. The aim of this study was to highlight the prescriptive importance of Viminol Hydroxybenzoate in the context of acute postoperative pain, explore its pharmacological aspects and warn about the prescriptive risk of opioids. Thus, we suggest the use of Viminol Hydroxybenzoate as an interesting therapeutic alternative to replace opioids, especially in conditions of mild to moderate acute postoperative pain, capable of providing a reduction in pain and, consequently, a better quality of life for patients, without the deleterious effects of opioids.

Objective: In this study, we aim to look at opioid prescription patterns in a large pediatric hospital with an emphasis on opioid potency as measured by morphine milligram equivalents (MMEs) to understand physician response to safe prescribing regulations and new research on opioid use in pediatrics.Design: Analgesic prescriptions in a pediatric hospital in California from 2012 to 2016 were included. Prescriptions that contained any type of opioid medication were analyzed total MME in each prescription, and medication prescribed. The MME for each opioid was assigned to the prescription and presented as mean ± standard deviation (SD). Statistical analysis was performed by using IBM SPSS statistics version 25.Setting: A pediatric hospital in California.Participants: All pediatric patients receiving analgesic prescriptions from a single institution between 2012 and 2016.Main outcome measure: Relative frequency of different opioid medications prescribed.Results: Of the 14,194 total opioid prescriptions, hydrocodone (11,247), codeine (2,117), and tramadol (411) were most prescribed. The relative frequency of opioid prescription decreased from 2012 to 2016 due to the decreased prescription of hydrocodone and codeine. Despite the decreased relative frequency of opioid prescription, the mean MME of prescribed opioids increased.Conclusion: The study demonstrated that recent efforts to limit pediatric exposure to opioids have been effective. However, recommendations limiting the use of weak opioids (codeine and tramadol) have caused an increase in average prescribed opioid potency. This may be a contributing factor to the overall increase in opioid-related pediatric hospitalizations. Revision of prescription guidelines for hydrocodone (MME = 1) may protect pediatric patients from unnecessary opioid exposure.

A rapid, simple extraction method followed by qualitative screening using liquid chromatography–tandem mass spectrometry (LC–MS-MS) for drugs in oral fluid is presented. The decision points were selected to be at, or lower, than those recommended as Tier I compounds by the National Safety Council’s Alcohol, Drugs and Impairment Division for toxicological investigation of driving under the influence of drug (DUID) cases and were also at, or lower, than those recommended by Substance Abuse and Mental Health Service Administration and the Department of Transportation for Federal workplace drug testing programs. The method included 30 drugs: delta-9-tetrahydrocannabinol, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, carisoprodol, meprobamate, zolpidem, alprazolam, clonazepam, 7-aminoclonazepam, diazepam, nordiazepam, lorazepam, oxazepam, temazepam, codeine, morphine, 6-acetylmorphine, buprenorphine, fentanyl, hydrocodone, hydromorphone, oxycodone, oxymorphone, methadone, tramadol and phencyclidine. Phencyclidine was included because it is in the Federal workplace program even though it is considered a Tier II drug for DUID cases. A liquid−liquid extraction method using isopropanol, hexane and ethyl acetate to extract drugs from the oral fluid−buffer mix collected in a Quantisal™ device, followed by LC–MS-MS screening, was developed and validated according to ANSI/ASB 2019 Standard Practices for Method Validation in Forensic Toxicology. Interference studies, limit of detection, precision at the decision point, ionization suppression/enhancement and processed sample stability were determined for each drug. The method was successfully applied to proficiency specimens and routine samples received in the laboratory.

Tramadol is a widely used weak opioid; however, the evidence for its safety profile in respiratory system needs additional information. We aimed to examine whether tramadol use is associated with an increased risk of pneumonia in the general population.We conducted five propensity-score (PS) matched cohort studies in The Health Improvement Network database. Participants aged ≥50-years initiated tramadol were compared with those initiated one of the following analgesics: codeine (n = 144,506), naproxen (n = 113,028), diclofenac (n = 74,297), celecoxib (n = 42,538), or etoricoxib (n = 27,232). The outcome was incident pneumonia.During 6-month follow-up, 395 pneumonia (5.6/1000 person-years) occurred in the tramadol group and 414 pneumonia (5.9/1000 person-years) occurred in the PS matched codeine group. Compared with codeine group, the risk of pneumonia was lower in the tramadol group (hazard ratio [HR] = 0.63, 95% confidence interval [CI]: 0.49-0.82) during the first 30-day follow-up, but comparable between groups over the entire 6-month follow-up (HR = 0.95, 95%CI: 0.83-1.09). In addition, the risk of pneumonia was higher in the tramadol group than that in the PS matched naproxen (HR = 1.68, 95%CI: 1.37-2.06), diclofenac (HR = 1.63, 95%CI: 1.31-2.03), celecoxib (HR = 1.64, 95%CI: 1.20-2.24) or etoricoxib (HR = 1.61, 95%CI: 1.04-2.49) group.The present study indicated that tramadol initiators had a lower risk of incident pneumonia than codeine initiators during the short-time follow-up, but had a comparable pneumonia risk compared with codeine initiators and had a higher risk of pneumonia compared with NSAIDs initiators over the entire 6-month follow-up duration. Confirmation of the present findings and determination of the underlying mechanism will require more studies.Tramadol might not be a safer alternative analgesic to codeine or NSAIDs. Both of health-care providers and patients may need to be on alert for its safety profile in respiratory system in future clinical practice.

The rise in the abuse of codeine raises concerns about its impact on the health of users, and little has appeared on its effect on the female reproductive function. Therefore, this study evaluated the impact of codeine on female reproductive function. We administered codeine at low (2 mg/kg) and high (5 mg/kg) doses to female animals prior to mating for 8 weeks. In comparison with a vehicle-treated group, we then assessed the impact of codeine on body weight gain and ovarian weight, female sexual behaviour, ovarian steroidogenesis, and folliculogenesis. The role of oxidative stress, inflammation, and apoptosis were also evaluated. Codeine at either dose elicited a profound deficit in the absolute and relative ovarian weight, indicative of ovarian toxicity. Also, codeine induced female sexual dysfunction, and suppressed ovarian steroidogenesis and folliculogenesis, with degeneration of the ovarian cytoarchitecture and follicles. The effects of codeine were associated with a rise in ovarian hydroxyl radical generation and oxidative stress, evident by an increase in ovarian malondialdehyde, a reduction in reduced glutathione, and a decline in the activities of ovarian enzymatic antioxidants. In addition, codeine triggered an increase in the ovarian concentration of inflammatory cytokines, TNF-α and IL-1β, and myeloperoxidase activity. Furthermore, codeine caused an increase in 8-hydroxydeoxyguanosine (8OHdG), ovarian DNA fragmentation, and caspase-3 activity, suggestive of genotoxicity and apoptosis respectively. The current study provides some of the first evidence for the adverse effects of prolong codeine use on female sexual function, ovarian steroidogenesis, and folliculogenesis. It also emphasizes the reproductive health consequences of drug abuse.

AimsThere 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.MethodsA 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.ResultsThere 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).ConclusionsIn 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.

Opioids are effective analgesics for pain relief, however, inappropriate use may cause risks. The aims of the study were to evaluate trends of opioid consumption for pain management in Taiwan and compare them among neighboring Asian countries. Opioid consumption data, including fentanyl, morphine, oxycodone, hydromorphone, codeine, and pethidine, were collected from the Controlled Drugs Management Information System of Taiwan Food and Drug Administration from 2008 to 2018. Data of different continents and neighboring Asian countries were retrieved from the WHO website. The major findings include: (1) In Taiwan, the total annual opioid consumption has gradually increased from 2008 to 2018, with fentanyl being the most frequently consumed opioid analgesic, followed by morphine. Codeine and pethidine consumption dropped significantly over the years. (2) In neighboring Asian countries, the opioid consumption in order from highest to lowest consumption were South Korea, Japan, Taiwan, Singapore, Hong Kong (China), and China. We concluded that, from 2008 to 2018, the total opioid consumption trend for pain management in Taiwan has slowly increased, with fentanyl and morphine being the most commonly used opioids. When compared with neighboring Asian countries, level of opioid consumption in Taiwan was between Japan and Singapore. The research results may provide a reference for healthcare professionals worldwide.

The aim of this study is to show the effectiveness of the use of mylohyoid muscle flap in surgical treatment of stage 1 and 2 Krokodil drug-related ON of mandible. Retrospective study of patients with stage 2 Krokodil drug-related ON of distal mandible was performed. Regarding to the used surgical technique the patients were divided into two groups (groups 1 and 2). In group 1(control group) the wound was closed only by the local mucoperiosteal flaps, while in group 2 (experimental group) the wound was closed by combining mylohyoid muscle flap and local mucoperiosteal flaps. 24 patients were included in this study (15 patients in the group 1 and 9 patients in the group 2). In all patients of experimental group the postoperative period was uneventful and no recurrence occurred. In group 1 recurrence was found in 7 patients, which is significantly higher than in group 2 (χ2=5.9, p=0.015). Disease recurrence occurred as wound dehiscence during 4-10 postoperative days. Within the limitations of the study it seems that the adoption of the mylohyoid muscle flap as double-layer closure technique is an effective and predictable method for the treatment of such patients and, therefore, should be chosen whenever deemed appropriate.

IntroductionOpioid prescribing trends have been investigated in many countries. However, the patterns of over-the-counter purchases of opioids without a prescription, such as codeine combinations, are mostly unknown.ObjectiveWe aimed to assess national sales and expenditure trends of over-the-counter codeine-containing products purchased in countries with available data over six years.MethodsWe conducted a retrospective observational study using electronic point-of-sale data from the human data science company, IQVIA, for countries that had such data, including Argentina, Belgium, Brazil, Bulgaria, Canada, Croatia, Estonia, Finland, France, Germany, Greece, Ireland, Italy, Japan, Latvia, Lithuania, Mexico, The Netherlands, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, Spain, Switzerland, Thailand, the UK, and the USA. We calculated annual mean sales (dosage units per 1000 of the population) and public expenditure (GBP, £ per 1000 population) for each country between April 2013 and March 2019 and adjusted for data coverage reported by IQVIA. We quantified changes over time and the types of products sold.Results31.5 billion dosage units (adjusted: 42.8 billion dosage units) of codeine, costing £2.55 billion (adjusted: £3.68 billion), were sold over-the-counter in 31 countries between April 2013 and March 2019. Total adjusted sales increased by 11% (3911 dosage units/1000 population in 2013 to 4358 in 2019) and adjusted public expenditure increased by 72% (£263/1000 in 2013 to £451/1000 in 2019). Sales were not equally distributed; South Africa sold the most (36 mean dosage units/person), followed by Ireland (30 mean dosage units/person), France (20 mean dosage units/person), the UK (17.2 mean dosage units/person), and Latvia (16.8 mean dosage units/person). Types of products (n=569) and formulations (n=12) sold varied.ConclusionIn many parts of the world, substantial numbers of people may be purchasing and consuming codeine from over-the-counter products. Clinicians should ask patients about their use of over-the-counter products, and public health measures are required to improve the collection of sales data and the safety of such products.Study protocol pre-registrationhttps://osf.io/ay4mcThe pre-print version of this work is available on medRxiv:https://doi.org/10.1101/2021.04.21.21255888Key pointsCodeine is one of the most accessible pain medicines available worldwide, yet data on its use as an over-the-counter drug has been limited.We found that total sales and expenditure of over-the-counter products containing codeine increased from April 2013 to March 2019, but there was substantial variation in mean sales between countries and the coverage of data reported by IQVIA, with South Africa, France, Japan, the UK, and Poland accounting for 90% of all sales data.In countries with access to over-the-counter codeine products, sales data should be collected, made available, and reviewed to inform regulatory decisions and public health measures to ensure safety.

The forensic analysis of stable isotopes is a valuable tool to geo-source natural or semisynthetic drugs such as cocaine and heroin. The present study describes a novel methodology to isolate morphine from opium for isotopic analysis. Furthermore, this isotopic data from regional sources is corroborated with morphine data obtained from seized heroin (deacetylated to morphine) from the same regions. All five primary alkaloids of opium, namely, morphine, codeine, thebaine, noscapine, and papaverine, were quantified using high performance liquid chromatography with photodiode array (PDA) detector before the preparative experiment to gather a complete major alkaloidal profile. Morphine fractions of authentic opium submissions from Mexico, South America, Southwest Asia, and Southeast Asia were isolated and collected using preparative high performance liquid chromatography, and the collected morphine samples were subsequently analyzed by isotope ratio mass spectrometry. Carbon and nitrogen isotope data are presented. The data demonstrate that nitrogen ratios are capable of differentiating samples from Mexico and South America while carbon ratios are able to distinguish Southwest Asian samples from other source regions. Analogous results have routinely been observed (as part of Heroin Signature Program analysis) for morphine obtained from deacetylated authentic heroin samples from the same source regions. The results suggest that the poppy growing region has a greater influence on the carbon and nitrogen isotope values than the heroin manufacturing processes employed. When utilized in conjunction with existing signature methodologies, carbon and nitrogen isotope ratio data can enhance the ability to geo-source heroin.

Objective The purpose of our study was to perform a systematic review and meta-analysis of randomized, blinded, placebo-controlled studies that, following third-molar extraction, utilized either a combination of acetaminophen (600 mg) with codeine (60 mg) or ibuprofen (400 mg) for pain management. Design We searched PubMed, and the trial registry ClinicalTrials.gov databases with the keywords “molar or molars,” “tooth or teeth,” “extraction,” and “pain.” Selected studies were: (1) randomized, blinded, placebo controlled, (2) utilized either a single-dose combination acetaminophen (600 mg) with codeine (60 mg) (A/C) or ibuprofen, and (3) recorded standardized pain relief (PR) at 6 hours, or summed total pain relief over 6 hours (TOTPAR6). Of the 2,949 articles that were identified, 79 were retrieved for full-text analysis, and 20 of these studies met our inclusion criteria. Results For A/C, the weighted, standardized mean difference (SMD) for TOTPAR6 was 0.796 (95% confidence interval [CI], 0.597–0.995), P Conclusions Our data indicate that single dose of ibuprofen (400 mg) is an effective pain reducer for post third molar extraction pain.

BACKGROUND The French Ministry of Health scheduled opioid cough suppressants as prescription-only drugs on July 12th , 2017. The present study assessed the impact of this regulation on the diversion modalities of the concerned drugs and the related drug pholcodine by analysing the national OSIAP (Ordonnances suspectes indicateur d'abus possible) database. METHODS Medical prescriptions with at least one mention of codeine, dextromethorphan, ethylmorphine, noscapine or pholcodine for cough suppression recorded in 2013-2019 were extracted from OSIAP. Annual mentioning rates were estimated by dividing numbers of mentions over those of prescriptions recorded the year considered. A descriptive analysis compared the characteristics of prescriptions before and after July 12th , 2017. RESULTS Overall, 832 mentions of the requested drugs were retrieved on 827 prescription forms. Codeine was the most frequent (n=809, 8.7%) with 6 additional mentions of codeine/ethylmorphine combination, followed by dextromethorphan (n=11, 0.1%) and pholcodine (n=6, 0.1%). There was no mention of noscapine. Annual mentioning rates varied between 0 and 0.3% for all drugs except codeine. Codeine mentioning rates ranged between 0.3% (n=2) and 0.7% (n=9) before July 12th , 2017 and increased to 10.1% (n= 61) thereafter in 2017, 16.1% (n=314) in 2018, and 19.8% (n=414) in 2019. The profile of subjects evolved accordingly with an arisen male/female ratio (10.0 versus 1.5 before), a younger age (23 years versus 40 before, p

Background: Across Canada, opioid-related hospitalizations, emergency department visits, and mortality have increased. A literature gap exists related to opioid prescribing and safety measure utilization patterns among nurse practitioners (NPs). Purpose: The objectives of this study were to (a) identify opioids prescribed by NPs in Ontario for pain, (b) examine safety measure utilization when prescribing opioids, (c) explore factors associated with safety measure utilization, and (d) survey NPs' opioid prescribing confidence. Methods: An explanatory sequential mixed method approach was used to measure quantitative and qualitative results in a sequential approach that achieves methodological triangulation. A survey was distributed to 2,094 NPs practicing in Ontario between May and August 2020. After quantitative analysis of 158 completed surveys, a qualitative phase was conducted that involved one-on-one semi-structured interviews with 14 NPs who completed the survey and agreed to follow up. Results: The top three opioids prescribed for acute and chronic pain reported by 158 NPs were hydromorphone followed by acetaminophen with codeine and oxycocet. The top three acute opioid-treated conditions were (1) fracture, (2) postoperative pain, and (3) joint or muscle strain/sprain. The top three chronic pain conditions were (1) cancer/palliative care, (2) chronic low back pain, and (3) osteoarthritis. Results from interviews demonstrated that inpatient NPs used safety measures less often than community NPs because of institutional policies that aid safe prescribing. NP preference for hydromorphone was rooted in its appealing side effect profile and ability to prescribe smaller doses. Limiting medication supply was considered the most effective opioid prescribing safety measure. NPs were more confident prescribing opioids with established diagnoses and less confident with unclear diagnoses, history of addiction, and chronic pain patients taking high dosages of opioids. Conclusion: Findings from this research can inform curricula changes to incorporate education related to opioid prescribing in the populations in which NPs expressed less confidence and opioid tapering for patients on high doses of opioids.

The adsorption and surface ionization of codeine molecules С18H21O3N ( m/z 299) on the surface of oxidized tungsten have been studied by a non-stationary method of voltage modulation under the same experimental conditions with a high-vacuum mass-spectrometric setup using a “black chamber” all walls of which are cooled with liquid nitrogen. For the codeine molecule dissociation with the [Formula: see text] bond breaking and formation of ionizable radicals, the rate constants K+ and K0, the activation energy Е+ and Е0 of thermodesorption, and the pre-exponential factors in the continuity equation for the radicals C9H7N+CH3 ( m/z 144) have been defined by surface ionization on the surface of oxidized tungsten WxOy. The results of determining the surface ionization coefficient and estimates of the ionization potentials of these radicals have been presented.

Objective This cross-sectional study aimed to assess the prevalence and awareness of drug and substance abuse among undergraduates in four southwestern universities in Nigeria. Methods The sample of 400 students included 100 male and female students in the 15- to 29-year age range from each of the four selected universities in southwest Nigeria between December 2019 and June 2020. Descriptive statistics and Pearson chi-square tests were used for data analysis using the statistical package for social sciences (SPSS). Results Four hundred students satisfied the inclusion criteria and suitably completed the questionnaire. Most respondents were in the 15- to 19-year and 20- to 24-year age groups and were female (68%). Drug and substance abuse prevalence was 45.7%; one in every four students abused substances despite an aggregate risk awareness level of 94.6%. Alcohol and cigarettes—legally and socially accepted substances—were the most abused (61.5% and 54.5%, respectively). Codeine-containing syrup and tramadol topped the list of drugs, ranking higher than cannabis. The major motive was to ‘get high’ and numb emotional problems caused by predominantly socioeconomic and societal factors. Conclusion The study showed a notable prevalence of drug and substance abuse across the selected universities in southwest Nigeria.

Background. Today in Ukraine, acute poisoning by narcotic drugs and psychotropic substances is an extremely urgent medical and social problem, which is far out of being solved, that’s why there is a need for in-depth study of the causes of deaths from poisoning to prevent them. The purpose of this study is to analyze the cases of fatal poisonings by narcotic and psychotropic substances with the involvement of epidemic, clinical, forensic, and laboratory research methods, aimed at finding measures to improve the health care system for acute domestic poisoning. Materials and methods. There were studied the medical data of patients treated with the diagnosis: “Acute drug poisoning” (ICD-10: T40.0–T40.3) in the Kyiv Toxicological Center, the statistical data of the State Statistics Service of Ukraine, the Center for Medical Statistics of the Ministry of Health of Ukraine, the data from reports of the Bureau of Forensic Medical Examinations. The laboratory studies of narcotic and psychotropic substances in the biological environment were performed using immunochromatographic analysis and chromatography-mass spectrometry (device — Aligent 6850/5973N, column — HP-5MS). The statistical analysis was performed using the program Statistica 12.6 (Windows 10/7): the reliability of the difference in indicators in the study groups was assessed using Student’s t-test with a significance level of p < 0.05. Results. In the last 5 years, the most common narcotic and psychotropic substances are synthetic and semi-synthetic opioids, psychostimulants, smoking mixtures, sedatives, or hypnotics. At the same time, the number of poiso-nings associated with the combined use of drugs and psychotropic substances, pharmaceuticals, and ethanol is increasing. During the period 2015–2019, more than 40 groups of substances that led to acute poisoning were found in the laboratory of the Kyiv Toxicological Center. The number of positive tests increased 2.3 times during the study period. The leaders in the structure of opioid drugs are methadone, heroin, and morphine. According to the State Statistics Service of Ukraine, in 2014–2018, 1365 deaths were registered as a result of poisoning by narcotic and psychotropic substances. In 2018, a total of 399 cases of deaths related to narcotic and psychotropic substances use and poisoning were recorded in Ukraine. Of these, 64 (16.04 %) cases were related to mental and behavioral disorders due to drug and psychotropic substance abuse and 335 (98.82 %) cases were related to external causes of death related to poisoning or overdose. Among those who died in 2018, there were 90.5 % men (361 cases) and 9.5 % women (38 cases). The largest number of deaths, 340 cases (85.2 %), occurred in the age group from 25 to 44 years, 13 ca-ses — in the age group from 15 to 24 years, and 46 cases — from 45 years and older. Three hundred and fifty-five cases of death from poisoning by psychotropic substances were investigated, it was established that opioid poisoning occurred in 153 cases (codeine and morphine — 54 cases (43.1 %), methadone — 76 cases (21.4 %), opium — 15 cases (4.2 %), synthetic opioids — 8 cases (2.3 %)). One hundred and forty-four cases of death from other drug poisonings were studied, including 31 (21.5 %) cases of psychodysleptic poisoning (hallucinogens), 2 (1.4 %) cases of cocaine poisoning, and 5 (3.5 %) cases of psychostimulant poisoning. According to state statistics, the number of deaths from poisoning in 2018 compared to 2017 increased by half and much. In particular, methadone poisoning increased 2.5 times, and unidentified drug poisoning was three-fold increased. According to the intent, the deaths were distributed as follows: 268 deaths — accidental poisoning; 66 deaths — poisoning by indefinite intent; one case — self-poisoning. The opioid poisoning accounted for 28 % of all cases of the psychotropic substances revealed in biological material, 24.4 % cases were drugs containing narcotic and psychotropic substances or precursors, 15 % — of unidentified substances, the rest consisted of other psychoactive substan-ces. The age characteristics of the group of deaths resulted from narcotic and psychotropic substances revealed in the biological material, and in the group of deaths from overdose are the same (p ≤ 0.05). It means that in the samples of both groups, the age group of 25–44 years presented over 75 % of cases. In Ukraine in 2018, the frequency of deaths related to drug and psychotropic substance abuse and poisoning among the population aged 15 to 64 was 10 people per 1,000,000. Conclusions. The results of the epidemic, clinical, forensic, and laboratory studies conducted by various government agencies in the period 2014–2019, demonstrate a threatening dynamic of increasing both the number of cases of narcotic and psychotropic poisoning and their diversity, resulting in a progressive increase in lethality and mortality, mainly among the male population aged 25–44 years. The main way of the use of narcotic and psychotropic substances in Ukraine continues to be the injection of opioids (methadone, heroin, buprenorphine, etc.) and amphetamine-type stimulants. There has been an increase in the number of deaths associated with the simultaneous use of several narcotic and psychotropic substances (methadone, amphetamine, marijuana, benzodiazepines, ethanol, etc.) in various combinations.

Oral care providers frequently prescribe analgesics for the management of dental pain. To get an overview of the analgesics prescribed in the Netherlands from 2016 through 2020, we collected data from the Stichting Farmaceutische Kengetallen (foundation [for] pharmaceutical indicators). Annually, more than 300,000 analgesics are prescribed by dentists in general practice and dental specialists. The largest group concerns NSAIDs (88%), followed by weak opioids (9%), acetaminophen (2%) and strong opioids (1%). Of the NSAIDs, ibuprofen is the most prescribed by all groups of oral care providers (84-91%). Of the weak opioids, dentists and oral and maxillofacial surgeons mainly prescribe codeine and codeine/ acetaminophen (64% and 78%, respectively), while orthodontists mainly prescribe tramadol (53%). Of the strong opioids, oxycodone is the most frequently prescribed by all groups of oral care providers (77-87%). Analgesics are a large part of the prescription medications in Dutch oral care and mainly concern NSAIDs (ibuprofen) and weak opioids (codeine/ acetaminophen). There are no major differences in prescription behaviour among different oral care providers.Mondzorgverleners schrijven frequent pijnstillers voor om dentogene pijn te bestrijden. Om inzicht te krijgen in de pijnstillers die van 2016 tot en met 2020 werden voorgeschreven, werden gegevens van de Stichting Farmaceutische Kengetallen opgevraagd. Jaarlijks worden er ruim 300.000 pijnstillers verstrekt door tandartsen-algemeen practici en tandarts-specialisten. De grootste groep betreft NSAID’s (88%), gevolgd door zwakwerkende opioïden (9%), paracetamol (2%) en sterkwerkende opioïden (1%). Van de NSAID’s wordt ibuprofen door alle mondzorgverleners het meest voorgeschreven (84-91%). Van de zwakwerkende opioïden schrijven tandartsen en mka-chirurgen vooral codeïne en codeïne/paracetamol voor (respectievelijk 64% en 78%), terwijl orthodontisten vooral tramadol voorschrijven (53%). Van de sterkwerkende opioïden wordt oxycodon door alle mondzorgverleners het meest voorgeschreven (77-87%). Pijnstillers maken een groot deel uit van de voorgeschreven geneesmiddelen in de mondzorg. Het betreffen vooral NSAID’s (ibuprofen) en zwakwerkende opioïden (codeïne/paracetamol). Er zijn geen grote verschillen in het voorschrijfgedrag tussen verschillendemondzorgverleners.

Background Overuse and misuse of opioids is a continuing crisis. The most common reason for children to receive opioids is postoperative pain, and they are often prescribed more than needed. The amount of opioids prescribed varies widely, even for minor ambulatory procedures. This study uses a large national sample to describe filled opioid prescriptions to preteen patients after all ambulatory surgical procedures and common standard procedures. Methods We analyzed Truven Health MarketScan data for July 2012 through December 2016 to perform descriptive analyses of opioid fills by age and geographic area, change over time, second opioid fills in opioid-naive patients, and variation in the types and amount of medication prescribed for 18 common and standard procedures in otolaryngology, urology, general surgery, ophthalmology, and orthopedics. Results Over 10% of preteen children filled perioperative opioid prescriptions for ambulatory surgery in the period 2012 to 2016. The amount prescribed varied widely (median 5 days’ supply, IQR 3–8, range 1–90), even for the most minor procedures, for example, frenotomy (median 4 days’ supply, IQR 2–5, range 1–60). Codeine fills were common despite safety concerns. Second opioid prescriptions were filled by opioid-naive patients after almost all procedures studied. The rate of prescribing declined significantly over time and varied substantially by age and across census regions. Conclusions We identified opioid prescribing outside of the norms of standard practice in all of the specialties studied. Standardizing perioperative opioid prescribing and developing guidelines on appropriate prescribing for children may reduce the opioids available for misuse and diversion.

Aim: Nicomorphine is rapidly metabolized mainly to the biologically active 6-nicotinoyl morphine and morphine. In sport, morphine and nicomorphine use is prohibited whereas codeine use is permitted. Accredited laboratories routinely test for morphine hence must be able to distinguish morphine, as a metabolite of a prohibited substance, from that whose use is permitted. Results: Here we show a relatively simple method to synthesize the nicomorphine metabolites, 3-nicotinoyl and 6-nicotinoyl morphine, and indicate how they may be used to identify nicomorphine administration. Conclusion: This approach should help confirm that it is not codeine, an allowable analgesic in sport, that has been administered.

Compound opioid analgesics (COA) are widely used for cancer pain relief, but few studies investigated the use of that. We aimed to report the characteristics and trend of COA consumption in different regions and health facilities in China. The procurement data of two types of COA, compound codeine phosphate (CCP) and oxycodone and acetaminophen (OAA), in all medical institutions of 20 provinces from 2015 to 2018 were used. Data were presented as Defined Daily Dose for Statistical purpose (SDDD) and expenditures per million inhabitants per day. The annual consumption of COA and ratio of two combinations were compared among regions and institutions. We found, during 2015 - 2018, COA consumption increased at an average rate of 7.32% in SDDD and 19.19% in expenditures, while OAA accounted for most of the consumption. Highest COA consumption appeared in Northern China, with 121.72 SDDD and 1689.87 RMB (2015), whereas the lowest COA consumption was only 11.28 SDDD appearing in Southern China. The ratio of OAA and CCP (in SDDD) was highest in Southern China (53.14 in 2018), whereas lowest in West North (0.37 in 2018). In terms of institutions, tertiary had the highest COA consumption, with 16.74 SDDD and 292.73 RMB (2018). The SDDD of OAA was 27.44 times of that of CCP in tertiary, while it was only 0.11 in primary. Overall, COA consumption is on an upward trend and different among regions and health institutions in either amount or types of COA. These findings call for establishment of COA management regulations.

As one of the largest and most representative families of natural medicines harvested from plants, the mass production of opioids legitimately occupies large, worldwide farmland cultivation of opiu...

We aimed to review the literature to find the specific effect of opioids on the activity of cholinesterase (ChE) enzyme which plays a substantial role in the functioning of cholinergic system. Literature search was performed by two independent reviewers in order to find relevant articles about the changes in the activity of ChE in mice or rat following opioid administration. Based on findings from literature review, opioid administration is able to induce cholinergic modulation via decreasing or increasing the activity of ChE enzyme. However, the degree of variation of ChE in various brain regions is different. No gender differences was reported in the effect of opioids on ChE activity. Although chronic opioid administration may decrease enzyme function, ChE activity might be unchanged following opioid withdrawal using naloxone or the development of tolerance. Opioid type affects whether or not naloxone can reverse the changes of ChE. Direct inhibitory action of morphine and the other opioid ligands believed responsible for the decrease in the ChE activity. Moreover, the potency of codeine to induce allosteric enhancement of acetylcholine receptor signaling might be involved in the cholinergic modulation of codeine and other opioids. Animal studies on rat and mice showed that opioids may change the activity of ChE. These changes can pertain an increase or decrease in enzyme activity; as there might be no change. The type of opioid used may have an effect on the cholinergic modulation. It is beneficial to conduct cross-sectional and cohort studies on addicted individuals, especially opium abusers, to find the precise association of opioids with alterations in human acetyl cholinesterase or butyrylcholinesterase. Simulation studies can also examine the structure-function relationships and provide important details to better understand the mechanism of action of opioid compounds on ChE activity. In addition, understanding how opioids impact ChE activity may help perform proper interventions for drug abstinence.

Background and aim Opioid receptors agonists have been demonstrated to impair lower esophageal sphincter (LES) relaxation and induce spastic esophageal dysmotility, but little was known for their impact on distension-induced secondary peristalsis. The aim of the study was to investigate the hypothesis whether acute administration of codeine can influence physiological characteristics of primary and secondary peristalsis in healthy adults. Methods Eighteen healthy volunteers (13 men, mean age 27.5 years, aged 20-43 years) underwent high resolution manometry (HRM) with a catheter containing an injection port in mid-esophagus. Secondary peristalsis was performed with 10 and 20 mL rapid air injections. Two different sessions including acute administration of codeine (60 mg) or the placebo were randomly performed. Results Codeine significantly increased 4-second integrated relaxation pressure (IRP-4s) (P = 0.003) and shortens distal latency (DL) (P = 0.003) of primary peristalsis. The IRP-4s of secondary peristalsis was also significantly higher after codeine than the placebo during air injections with 10 mL (P = 0.048) and 20 mL (P = 0.047). Codeine significantly increased the frequency of secondary peristalsis during air injections with 10 mL than the placebo (P = 0.007), but not for air injection with 20 mL (P = 0.305). Conclusions In addition to impair LES relaxation and reduce distal latency of primary peristalsis, codeine impairs LES relaxation of secondary peristalsis and increases secondary peristaltic frequency. Our study supports the notion in human esophagus that the impact of opioids on peristaltic physiology appears to be present in both primary and secondary peristalsis.

Objectives Pediatric patients undergoing subcutaneous implantable cardioverter–defibrillator (S-ICD) placement usually have substantial postoperative pain. The aim of this study was to investigate the effect of the transversus thoracic muscle plane (TTMP) block combined with serratus anterior plane block (SAPB) in patients undergoing S-ICD placement. Design A double-blind, randomized controlled study. Setting First Affiliated Hospital of Nanchang University. Participants Patients aged nine-to-18 years undergoing S-ICD placement were included. Interventions A group of 102 patients randomly were allocated to either receive combined nerve blocks (NER group) or no nerve block (CON group). Measurements and Main Results The primary endpoint was perioperative fentanyl consumption. The secondary outcome measures included pain at rest and after movement at two, four, six, 12, 24, and 48 hours after extubation; 48-hour acetaminophen administration; time to extubation; length of stay in the postanesthesia care unit (PACU); length of hospital stay; codeine tablet consumption; and percentage of patients who had codeine tablets after discharge. The NER group reported significantly less intraoperative (4.1 μg/kg v 3.1 μg/kg, p = 0.04) and postoperative fentanyl consumption (3.8 μg/kg v 1.5 μg/kg, p = 0.006) than the CON group. Compared with the NER group, the CON group had higher Numerical Rating Scale (NRS) pain scores at 24 hours after surgery both at rest and after movement. The time to extubation (20.5 minutes v 12.6 minutes, p = 0.03) and length of stay in the PACU (30.5 minutes v 15.6 minutes, p = 0.02) were significantly decreased in the NER group compared with the CON group. The CON group had a significantly higher postoperative acetaminophen requirement than did the NER group (32 mg/kg v 16 mg/kg, p = 0.01). Conclusion TTMP block combined with SAPB in pediatric S-ICD placement could provide effective analgesia.

Codeine is an opioid analgesic and antitussive that has been widely abused. Some adverse effects noted with its abuse include adrenocortical insufficiency and activation of the hypothalamic-pituitary-adrenal axis. The structural basis for these dysfunctions is not clearly understood. Twenty-five adult male rats were used for the study. They were divided into intervention and control groups that were administered 40 mg/kg of codeine phosphate and normal saline respectively by gavage daily for 50 days. Subsequently, both groups were given normal saline for a further fourteen days to note recovery changes. At day 0, 50 and 64, rats were randomly selected from both groups, euthanized and adrenal glands harvested for histological processing and analysis. At day 50 of codeine administration, the adrenal glands demonstrated an increase in zona fasciculata thickness but a decrease in zona reticularis thickness. Lower values were noted in the volume density of zona reticularis and cells count of the medulla in the experimental compared to the control groups (P-value

Opioids are commonly prescribed following childbirth, but data are lacking on trends in postpartum opioid prescribing over time. We examined whether a highly-publicized 2006 case report questioning the safety of codeine during lactation was associated with changes in postpartum opioid prescribing. We conducted a cross-sectional time series analysis of all publicly-funded prescriptions for opioids to postpartum women in Ontario, Canada from April 1, 2000 to March 31, 2017. The intervention was the publication of a case report in 2006 attributing the death of a breastfeeding neonate to maternal codeine use. The primary outcome was the rate of opioid prescribing to postpartum women. Among postpartum women eligible for prescription drug coverage, 17.5% filled an opioid prescription in the third quarter of 2006 (immediately prior to publication of the case report), with codeine representing 89.8% of all prescriptions. By the fourth quarter of 2010, only 12.2% of postpartum women filled an opioid prescription, representing a decline of 30% (p

The interindividual variability in opioid response is an issue that contributes to the ongoing opioid crisis. Current evidence suggests this variability can be attributed to genetic factors. The pharmacogenetics of Opioid Treatment for acute post-operative Pain (OTP) project was a prospective study that aimed to identify genetic markers associated with opioid treatment outcomes. Healthy patients undergoing third-molar extractions were recruited from dental offices located within the Greater Toronto Area. Participants were evaluated using the Brief Pain Inventory Short Form, the Opioid Related Symptom Distress Scale, and the Leeds Dependence Questionnaire. Seventy-two participants had an active opioid prescription. Participants were prescribed one of the following opioids: codeine, morphine, hydromorphone, tramadol, or oxycodone. The majority of participants were female (57%), ranging from 16 to 44 years of age. Pain severity, pain interference, and side effects declined over the seven-day post-operative period. Additionally, 4% of participants displayed medium to high risk of dependence. It is anticipated that OTP will enable the development of a genetic test for opioid use and facilitate the introduction of this test into routine healthcare practice. The OTP study represents a novel approach to opioid treatment and has significant implications for future interventions targeting the ongoing opioid crisis. Employing a pharmacogenomic-guided strategy for prescribing opioids may improve patients' response to this treatment and, in so doing, increase adherence to the target treatment plan. Optimized prescriptions may also provide public healthcare systems with beneficial savings and reduce the risks associated with opioid use.

Considering that the use of psychoactive substances (PSs) is a risk factor to either higher intensity or frequency of suicidal behavior, hair analysis was conducted to investigate the most consumed PSs (opiates, amphetamine stimulants, marijuana, cocaine and heroin) in patients who attempted suicide and received urgent care at emergency service. Hair samples were extracted using methanol and sonicated under heating and then analyzed using liquid chromatography-tandem mass spectrometry. During validation, the method complied with international recommended criteria, with limits of detection between 0.0025 and 0.05 ng/mg and linearity between 0.1 and 4 ng/mg for methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), morphine, amphetamine, 6-acetylmorphine, 3,4-methylenedioxyamphetamine (MDA), fenproporex, diethylpropion and codeine; between 0.025 and 1 ng/mg for tetrahydrocannabinol (THC), benzoylecgonine and cocaethylene and between 0.25 and 10 ng/mg for cocaine and mazindol. A total of 109 hair samples were analyzed and segmented in 404 parts. Among all analyzed samples, 30.3% were positive for at least one PS (n = 33), such as cocaine (90.9%), codeine (12.1%), morphine (3.0%), MDMA (3.0%) and THC (3.0%). In segmental analysis of cocaine positive samples (n = 30), 76.7% of the samples indicated recent exposure to cocaine (

Background Concerns about the misuse of codeine led to the introduction of guidance restricting the supply of over-the-counter (OTC) codeine-containing products in Ireland in 2010. The aim of this study was to examine the impact of this guidance on the national rate of hospital-presenting self-harm involving codeine-related intentional drug overdose (IDO). Methods Presentations involving IDO to Irish general hospitals between 1 January 2007 and 31 December 2013, as recorded by the National Self-Harm Registry Ireland, were analyzed. Event-based rates per 100 000 were calculated using national population data. Poisson regression models were used to assess rate changes between pre- and post-guidance periods and to calculate excess presentations. Results Between January 2007 and December 2013, a total of 57 759 IDOs were recorded, with 4789 (8.3%) involving a codeine-containing product. The rate of codeine-related IDOs was 20% lower in the period following implementation of the guidance (incidence rate ratio: 0.80; 95% CI: 0.75 to 0.85), representing a total of 509 (95% CI: −624, −387) fewer codeine-related IDOs in that period. Reductions were observed across all ages and were more pronounced for females (0.76, 0.71 to 0.82) than males (0.87, 0.79 to 0.97). The rate of IDOs involving other drugs decreased by 3% in the same period (0.97, 0.95 to 0.98). Conclusion Our findings indicate that the rate of codeine-related IDOs was significantly lower in the period following the implementation of the guidance. There is a large body of evidence supporting the restriction of potentially harmful medication as an effective strategy in suicide prevention.

BACKGROUND AND AIMS Over-the-counter codeine products were up-scheduled to prescription only in Australia from February 2018. This trend study aimed to identify changes in codeine supply before and after the February 2018 implementation. DESIGN, SETTING AND CASES Time-series regression analysis of monthly medicine supplies in Australia from 2014 to 2018. The February 2018 up-scheduling was pre-specified as the intervention; outlier analysis was used to detect automatically sudden unexpected changes before February 2018. MEASUREMENTS Per-capita supplies based on national data for pharmaceutical wholesales and population exposure. Weight of supplies in milligrams for low-dose codeine (≤ 15 mg per tablet or ≤ 1.92 mg per ml, originally sold over the counter but up-scheduled after February 2018), high-dose combination codeine (30 mg per tablet, prescription only throughout the study period) and all codeine. FINDINGS Several level shifts in supply occurred during the 5 years, led by one of -4.4% [95% confidence interval (CI) = -6.6 to -2.1%] in high-dose codeine in 2015, followed by shifts in low-dose codeine of -40.0% (CI = -46.9 to -32.3%) and -82.2% (CI = -84.3 to -79.9%), respectively, before and after February 2018. High-dose codeine supply increased by 4.4% (CI = 1.8-7.1%) immediately after up-scheduling. Also detected were transient increases and decreases in 2016 and 2017. Compared with pre-2015 levels, the February 2018 up-scheduling was associated with reductions of 45.7% (CI = 43.2-48.0%) and 89.3% (CI = 87.9-90.6%), respectively, in all and low-dose codeine supply but no change in high-dose codeine supply. The level shifts and transient changes were located around various regulatory activities, including public announcements and expert advisory meetings on up-scheduling. CONCLUSION Up-scheduling of over-the-counter codeine products in Australia in 2018 appears to have been associated with a near halving of Australia's national codeine supply. The transition occurred in multiple forms and phases.

Background Optimizing analgesia after cesarean delivery is a priority and requires balancing adequate pain relief with the risk of analgesics-associated adverse effects. Current recommendations are for use of a multimodal, opioid-sparing analgesic regimen that includes neuraxial morphine combined with scheduled nonsteroidal anti-inflammatory drugs (NSAIDs) and scheduled acetaminophen. Furthermore, recent studies recommend scheduled acetaminophen with as-needed opioids in lieu of acetaminophen-opioid combination drugs to reduce opioid consumption and optimize analgesia. However, the extent of utilization of this recommended regimen in the United States is unclear. We therefore performed this retrospective study to evaluate postoperative analgesic regimens utilized after cesarean delivery under neuraxial anesthesia, examine variability across institutions, evaluate changes over time in postoperative analgesic practice, and examine factors associated with the use of neuraxial morphine and of multimodal analgesia. Methods This retrospective cohort study was approved by the Duke University Institutional Review Board. Parturients who underwent cesarean delivery under neuraxial anesthesia from 2008 to 2018 were included. Data were extracted from a nationwide inpatient administrative-financial database (Premier Inc, Charlotte, NC) and included parturient characteristics, comorbidities, hospital characteristics, and charges for administered medications. The primary outcome was the postoperative analgesic regimen utilized during hospitalization, including utilization of neuraxial morphine and of multimodal analgesia for postoperative pain control. We also examined the factors associated with the use of neuraxial morphine and of the multimodal regimen incorporating neuraxial morphine, NSAIDs, and acetaminophen. Results Data from 804,752 parturients were analyzed. Of this cohort, 75.8% received neuraxial morphine, 93.2% received NSAIDs, 28.4% received acetaminophen, and 81.3% received acetaminophen-opioid combination drugs. Only 6.1% received the currently recommended regimen of neuraxial morphine with NSAIDs and acetaminophen, with this percentage increasing from 1.3% in 2008 to 15.0% in 2018. On the other hand, 58.9% received neuraxial morphine, NSAIDs, and an acetaminophen-opioid combination drug, with this regimen being utilized in 57.0% of cases in 2008 and 58.1% in 2018. The hospital in which the patient was treated accounted for 54.7% of the variation in receipt of neuraxial morphine and 41.2% in the variation in receipt of multimodal analgesia with neuraxial morphine, NSAIDs, and acetaminophen, with this variability in receipt of neuraxial morphine and of multimodal analgesia being largely independent of patient characteristics. Conclusions Relatively few parturients received the currently recommended multimodal analgesic regimen of neuraxial morphine with NSAIDs and acetaminophen after cesarean delivery. Additionally, the majority received acetaminophen-opioid combination drugs rather than plain acetaminophen. Further studies should investigate the implications for patient outcomes.

Background The observation that patients presenting for bariatric surgery had a high incidence of neuromuscular blocking agent (NMBA) anaphylaxis prompted this restricted case-control study to test the hypothesis that obesity is a risk factor for NMBA anaphylaxis, independent of differences in pholcodine consumption. Methods We compared 145 patients diagnosed with intraoperative NMBA anaphylaxis in Western Australia between 2012 and 2020 with 61 patients with cefazolin anaphylaxis with respect to BMI grade, history of pholcodine consumption, sex, age, comorbid disease, and NMBA type and dose. Confounding was assessed by stratification and binomial logistic regression. Results Obesity (odds ratio [OR]=2.96, χ2=11.7, P=0.001), ‘definite' pholcodine consumption (OR=14.0, χ2=2.6, P Conclusions Obesity is a risk factor for NMBA anaphylaxis, the risk increasing with BMI grade. Pholcodine consumption is also a risk factor, and this is consistent with the pholcodine hypothesis. Rocuronium use is associated with an increased risk of anaphylaxis compared with vecuronium in this population.

الملخص: أهداف البحث: دراسة تأثير التعرض المتكرر عن طريق الفم لنوعين من شراب السعال تحتوي على الكوديين وديكستروميثورفان على الفئران ويستار الذكور. طرق البحث: قسمنا ٣٥ جرذا إلى سبع مجموعات من خمسة فئران لكل منها. المجموعة ''أ'' أعطيت ٠.٥ مل من الماء المقطر، وأعطيت المجموعات ''ب “ و''ج'' و'' د'' ٠.١ و٠.٢ و ٠.٤ مل/كغ وزن الجسم من شراب السعال الذي يحتوي على الكوديين، على التوالي، بينما أعطيت المجموعات'' ه'' و'' و'' ''ز'' ٠.١ و ٠.٢ و ٠.٤ مل/كغ من شراب السعال الذي يحتوي على ديكستروميثورفان، على التوالي. واستمر العلاج لمدة ٢٨ يوما. تم التضحية بالجرذان تحت تخدير الإثير الخفيف. وتم فحص الكلى والكبد والدم للفئران لإجراء المزيد من التحاليل. النتائج: لوحظت تغييرات كبيرة في اختبارات وظائف الكبد؛ ناقلة أمين الأنين، ناقلة أمين الأسبارتات، الفسفاتاز القلوي، الزلال والبيليروبين الكلي. وزادت جميع جرعات شراب السعال التي تحتوي على الكوديين وديكستروميثورفان بشكل كبير مستويات ناقلة أمين الأنين. وعلاوة على ذلك، لوحظت تغيرات كبيرة مماثلة لعلامات وظائف الكلى مثل الكرياتينين واليوريا وحمض اليوريك. تسبب جميع جرعات ديكستروميثورفان ارتفاعات كبيرة في مستويات اليوريا. كما أظهرت التقييمات الهستولوجية تغيرات طفيفة في بنية أنسجة الكبد والكلى والدماغ. الاستنتاجات: تشير النتائج الواردة في دراستنا إلى أن الجرعة الزائدة من شراب السعال قد تهيئ المستهلكين للإصابات الكبدية والكلوية. Abstract: Objective: This study investigates the impact of repeated oral exposure to two cough syrups containing codeine and dextromethorphan (DXM) on male Wistar rats. Methods: We divided 35 rats into seven groups of five rats each. Group A was given 0.5 mL of distilled water, Groups B, C, and D were given 0.1, 0.2 and 0.4 mL/kg body weight (b. w) of cough syrup containing codeine (CSC), respectively, and Groups E, F, and G were administered 0.1, 0.2 and 0.4 mL/kg b. w of cough syrup containing DXM, respectively. The treatment was continued for 28 days. The rats were euthanised under mild diethyl ether anaesthesia. The kidney, liver, and blood of the rats were examined for further analyses. Results: Significant (p

This project contains the study materials, results and code for a study on the sales of over-the-counter codeine-containing products in 31 countries

The prescribing of opioids has increased [1], but it is not known whether codeine-containing medicines sold over-the-counter (OTC) are following similar trends to prescribed opioids. Products containing codeine, an opioid related to morphine, have been associated with dependence, death, and collateral toxicity from combinations with paracetamol and ibuprofen [2,3]. However, access to granular data on OTC sales is limited. The full picture of the growing opioid problem will not be known until both prescription and OTC data on opioid sales are evaluated. Regulation of codeine-containing products varies across the world. In the UK, combination products called co-codamol, containing 8 mg of codeine (a low dose) and 500 mg of paracetamol, can be purchased without a prescription from pharmacies. However, 15 of the 28 European Union member countries do not allow codeine to be sold OTC [4]. More recently, Australia and Manitoba, Canada, changed the status of codeine-containing medicines to prescription-only [5,6]. Thus, there is building pressure to upregulate and restrict access to OTC codeine products. To the best of our knowledge, data on sales of OTC codeine medicines have not been described before. Thus, the aim of our repeat cross-sectional observational study is to describe national sales of over-the-counter (OTC) codeine-containing products purchased from pharmacies across 31 countries between 2013 and 2019. Our objectives are: 1. to determine the total volume (e.g. number of tablets) of OTC codeine-containing products purchased nationally each year, adjusted for population; 2. to determine the total public expenditure (converted to GBP, £ sterling as of 20/09/3019) of OTC codeine-containing products purchased nationally each year; and 3. to assess trends in volume and public expenditure nationally from 2013 to 2019.

The safety of cough and cold products for pediatric use has been a concern of regulatory agencies and advocacy groups for decades. Most recently, the Food and Drug Administration requested input from Pulmonary-Allergy Drugs and Drug Safety and Risk Management advisory committees on the safety of codeine for cough in children aged 18 years and younger. There is little evidence of efficacy for codeine in the treatment of acute cough in children, but mounting evidence for risks of respiratory depression and death. Similarly, dextromethorphan, benzonatate, antihistamines, guaifenesin, and mucolytics lack efficacy in controlled trials or there are no data with which to evaluate efficacy, and dextromethorphan may cause respiratory depression. Honey and topical use of aromatic oils (camphor, menthol, and eucalyptus) have limited evidence of efficacy, but may have the greatest margin of safety for treatment of acute cough in children.

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

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.This multinational collaborative study aimed to assess the effectiveness of these risk minimisation measures by evaluating changes in prescribing of codeine and alternative treatments.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.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.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.

Pain is a common problem for children, and pain management comprises both pharmacologic and nonpharmacologic measures. For moderate to severe pain, oral opioids have been a popular choice for the last few decades. Codeine has historically been the best-known oral opioid for use in children. However, availability and use of codeine have sharply declined due to safety concerns. A variety of other opioids have been used in place of codeine, but data are limited regarding their efficacy and safety in children. While the same pathways metabolize oral oxycodone as codeine, oxycodone’s pharmacokinetics varies widely. There are also limited data on the safety and efficacy of oral hydromorphone and tramadol use for children. Oral morphine is the opiate alternative to codeine for which there is the most evidence of safety and efficacy in children. Research is needed to investigate both other opioids and non-opioid approaches to guide evidence-based analgesic therapy and treatment for moderate-to-severe pain in children.

Several papers have reported that tramadol can induce hypoglycemia. However, in some reports, confounding factors can be found, like coadministration of hypoglycemic drugs. We used the WHO pharmacovigilance database (VigiBase® ) to investigate whether tramadol alone could be associated with hyponatremia. All 2010-2019 ICSRs (Individual Case Safety Reports) with the PT term "hyponatremia" and tramadol were included. Two disproportionality analyses were performed: 1/after inclusion of all reports, 2/after exclusion of concomitant hypoglycemic drugs. Results are expressed as Reporting Odds Ratios (ROR; 95% CI). Among 10 038 436 ICSRs, 97 639 were included. In comparison with codeine, a significant association was found between tramadol use and reports of hypoglycemia before [ROR = 1.54 (1.43-1.66)] or after [ROR = 1.43 (1.31-1.56)] exclusion of hypoglycemic drugs. Tramadol use is associated with a higher risk of hypoglycemia reports than codeine, the other step 2 analgesic, in the presence as well as in the absence of other hypoglycemic drugs. We concluded that hypoglycemia is an adverse drug reaction of tramadol, which can be observed in diabetic as well as in non-diabetic patients.

Cytochrome P450 2D6 (CYP2D6) O-demethylates codeine to the active drug, morphine. However, the utility of testing for CYP2D6 metabolizer status in patients receiving codeine in real-world clinical practice is poorly defined. Using data from a DNA bank linked to de-identified electronic health records, we studied 157 patients with a baseline pain score higher than 4 (0-10 scale) who received codeine. Based on CYP2D6 genotyping, 69 were classified as poor/intermediate and 88 as normal/ultrarapid CYP2D6 metabolizers. Pain response was defined as a score of 4 or lower while receiving codeine. In a propensity-score adjusted model, poor/intermediate metabolizers had lower odds (OR = 0.35, p = 0.02) of achieving a pain response than normal/ultrarapid metabolizers. To discriminate between codeine responders and nonresponders, a score including CYP2D6 phenotype and clinical variables was built. The response rate was 38.5% among patients in the high, 17.3% in the intermediate, and 9.4% in the low-score groups, respectively (p = 0.001).

Study objective We compare the efficacy and adverse effects of 5 oral analgesics in emergency department (ED) patients aged 21 to 64 years with acute musculoskeletal pain. Methods This was a randomized clinical trial conducted in 2 urban EDs. Patients received 400 mg ibuprofen/1,000 mg acetaminophen, 800 mg ibuprofen/1,000 mg acetaminophen, 30 mg codeine/300 mg acetaminophen, 5 mg hydrocodone/300 mg acetaminophen, or 5 mg oxycodone/325 mg acetaminophen. The primary outcome was change in pain before administration of medication (baseline) to 1 hour postbaseline. A numeric rating scale was used, varying from 0="no pain" to 10="worst imaginable pain." Secondary outcomes included receipt of rescue medication and adverse effects at 1 and 2 hours postbaseline. ANOVA was used to test differences in the primary outcome between treatment groups. Results Six hundred participants, predominantly men and Latino, were enrolled. Change in pain from baseline to 60 minutes did not differ by treatment (P=.69). The mean change in pain in numeric rating scale units was 400 mg ibuprofen/1,000 mg acetaminophen 3.0 (95% confidence interval [CI] 2.6 to 3.5); 800 mg ibuprofen/1,000 mg acetaminophen 3.0 (95% CI 2.5 to 3.5), 30 mg codeine/300 mg acetaminophen 3.4 (95% CI 2.9 to 3.9), 5 mg hydrocodone/300 mg acetaminophen 3.1 (95% CI 2.7 to 3.5), and 5 mg oxycodone/325 mg acetaminophen 3.3 (95% CI 2.8 to 3.7). Rescue medication was received before 1 hour had elapsed by 2 patients receiving 400 mg ibuprofen/1,000 mg acetaminophen (1.7%), 3 patients receiving 800 mg ibuprofen/1,000 mg acetaminophen (2.5%), zero patients receiving 30 mg codeine/300 mg acetaminophen (0.0%), 3 patients receiving 5 mg hydrocodone/300 mg acetaminophen (2.5%), and zero patients receiving 5 mg oxycodone/325 mg acetaminophen (0.0%) (P=.21). More patients who received opioids were nauseated or vomited compared with those who did not: 6.7% versus 1.7% (5.0% difference; 95% CI 1.7% to 8.2%). The findings at 2 hours were similar. Conclusion No analgesic was more efficacious than others 1 or 2 hours after baseline. There was significantly more nausea and vomiting among patients treated with opioids.

Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone, and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes that have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1, and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone, and methadone, and for OPRM1 and COMT for clinical use.