Orofacial antinociceptive activity of codeine-associated geraniol in mice: a controlled triple-blind study.

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Binding studies of promethazine and its metabolites with human serum albumin by high-performance affinity chromatography and molecular docking in the presence of codeine.

"Purple Drank", a soft drink containing promethazine (PMZ) and codeine (COD), has gained global popularity for its hallucinogenic effects. Consuming large amounts of this combination can lead to potentially fatal events. The binding of these drugs to plasma proteins can exacerbate the issue by increasing the risk of drug interactions, side effects, and/or toxicity. Herein, the binding affinity to human serum albumin (HSA) of PMZ and its primary metabolites [N-desmethyl promethazine (DMPMZ) and promethazine sulphoxide (PMZSO)], along with COD, was investigated by high-performance affinity chromatography (HPAC) though zonal approach. PMZ and its metabolites exhibited a notable binding affinity for HSA (%b values higher than 80%), while COD exhibited a %b value of 65%. To discern the specific sites of HSA to which these compounds were bound, displacement experiments were performed using warfarin and (S)-ibuprofen as probes for sites I and II, respectively, which revealed that all analytes were bound to both sites. Molecular docking studies corroborated the experimental results, reinforcing the insights gained from the empirical data. The in silico data also suggested that competition between PMZ and its metabolites with COD can occur in both sites of HSA, but mainly in site II. As the target compounds are chiral, the enantioselectivity for HSA binding was also explored, showing that the binding for these compounds was not enantioselective.

The misuse of codeine containing medicines: Perceptions and behaviours of qualified pharmacy professionals.

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

A near-infrared plasmonic biosensor for detection of morphine and codeine in biological samples based on the end-to-end assembly of modified gold nanorods.

The analytical determination of opiates in biological samples is a critical mission and remains a challenge for almost all judicial and clinical drug testing panels due to their high abuse potential. Based on the high sensitivity of the longitudinal surface plasmon resonance (LSPR) peak of gold nanorods (AuNRs), we successfully developed a novel and simple refractive index sensing platform for detection of morphine (MOR) and codeine (COD) by means of 2-amino-5-mercapto-1,3,4-thiadiazole functionalized gold nanorods (AMTD-AuNRs) in aqueous solution, which is, to the best of our knowledge, the first report on the assay of MOR and COD using AuNRs. AMTD molecules strongly anchor onto the tips of AuNRs via the mercapto group and subsequent hydrogen-bonding interactions between AMTD and the analytes induced end-to-end chain assembly of AuNRs and a consequent decrease of the LSPR absorption band at 850 nm along with a bathochromic shift and emergence of a new hybridized plasmon mode at 1050 nm which was characterized using a Vis-NIR spectrophotometer. After systematic optimization, the absorbance ratio (A1050/A850) was proportional to the concentration of MOR in the ranges of 0.08-5 µM and 0.2-8 µM for COD without any significant effect from possible interferents. Furthermore, detection limits of 40 and 62 nM were achieved for MOR and COD, respectively, which are much lower than the cut-off level of 2000 ng mL-1 for opiates in urine samples set by the Substance and Abuse Mental Health Services Administration (SAMHSA). Eventually, as proof-of-applicability, human urine and blood serum samples spiked with MOR and COD were analyzed and excellent recoveries ranging from 94.4 to 108.9% were obtained, demonstrating the successful applicability of the designed refractive index probe in real biological specimens.

Synchronous analysis of acetaminophen, codeine, and caffeine in human fluids employing graphite screen-printed electrodes.

A facile electrochemical approach is proposed for the synchronous determination of acetaminophen (ACP), codeine (COD) and caffeine (CAF) utilizing unmodified screen-printed electrodes (SPEs). The determination of ACP, COD and CAF has been explored across different supporting electrolytes including sulfuric acid (H2SO4), hydrochloric acid (HCl), phosphoric acid (H3PO4) and Briton Robinson (B.R) buffer solutions. It was found that a 0.05 mol L-1 sulfuric acid solution is an optimal supporting electrolyte utilized for voltammetric analysis of ACP, COD, and CAF with improved sensitivity, stability, and reproducibility. The electro-analytical sensing of ACP, COD and CAF was investigated using SPEs within linear concentration ranges of 3.0-35.0 µmol L-1, 10-160 µmol L-1 and 10-160 µmol L-1 and revealed competitively low limits of detection (3S/N) of 0.9, 4.8 and 6.3 µmol L-1 for ACP, COD and CAF, respectively. The results indicated the possibility of such a simple and quick electroanalytical protocol for online monitoring of pharmaceutical formulations comprising ACP, COD, and CAF drugs in human fluids with satisfactory recovery.

The impact of more restrictive hydrocodone rescheduling on unintentional pediatric opioid exposures.

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

[Source Apportionment of Morphine in Wastewater].

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

Adverse childhood experiences, individual-level risk and protective factors, and recent drug use in a community sample of Nigerian women.

Adverse childhood experiences (ACEs) are associated with a wide range of health problems and health-compromising behaviors, including drug use, but are understudied in sub-Saharan Africa. Further, some data suggest that some types of ACEs are more strongly associated with outcomes than others. We investigated associations between different types of ACEs and recent drug use among 2,011 women living in Katsina State, Nigeria. This community-based survey included questions on ACE exposure, modifiable individual-level risk and promotive factors, and past-year drug use. Tobacco, cannabis, and the nonmedical use of cough syrup with codeine and tramadol were the most frequently used drugs. Logistic regressions revealed that across most drugs, ACEs reflecting abuse, neglect, and household dysfunction, but not community violence, increased the likelihood of drug use, odds ratios (ORs) = 1.30-3.10. Ease of access to drugs, ORs = 1.33-2.98, and personal religiosity, ORs = 1.19-2.27, also enhanced the risk of drug use, and higher depressive affect was associated with codeine, OR = 1.27, and tramadol use, ORs = 2.42. Practicing religious rites, ORs = 0.38-0.70; disapproval of drug use, ORs = 0.36-0.57; and perceived harm from drug use, ORs = 0.54-0.71, reduced the likelihood of drug use. Efforts to prevent abuse, neglect, and household dysfunction; reduce access to drugs; treat depression; and increase disapproval and harm associated with drug use may reduce drug use in the context of ACE exposure.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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