Exploring Perceptions About Paracetamol, Tramadol, and Codeine on Twitter Using Machine Learning: Quantitative and Qualitative Observational Study.

BACKGROUND: Paracetamol, codeine, and tramadol are commonly used to manage mild pain, and their availability without prescription or medical consultation raises concerns about potential opioid addiction. OBJECTIVE: This study aims to explore the perceptions and experiences of Twitter users concerning these drugs. METHODS: We analyzed the tweets in English or Spanish mentioning paracetamol, tramadol, or codeine posted between January 2019 and December 2020. Out of 152,056 tweets collected, 49,462 were excluded. The content was categorized using a codebook, distinguishing user types (patients, health care professionals, and institutions), and classifying medical content based on efficacy and adverse effects. Scientific accuracy and nonmedical content themes (commercial, economic, solidarity, and trivialization) were also assessed. A total of 1000 tweets for each drug were manually classified to train, test, and validate machine learning classifiers. RESULTS: Of classifiable tweets, 42,840 mentioned paracetamol and 42,131 mentioned weak opioids (tramadol or codeine). Patients accounted for 73.10% (60,771/83,129) of the tweets, while health care professionals and institutions received the highest like-tweet and tweet-retweet ratios. Medical content distribution significantly differed for each drug (P<.001). Nonmedical content dominated opioid tweets (23,871/32,307, 73.9%), while paracetamol tweets had a higher prevalence of medical content (33,943/50,822, 66.8%). Among medical content tweets, 80.8% (41,080/50,822) mentioned drug efficacy, with only 6.9% (3501/50,822) describing good or sufficient efficacy. Nonmedical content distribution also varied significantly among the different drugs (P<.001). CONCLUSIONS: Patients seeking relief from pain are highly interested in the effectiveness of drugs rather than potential side effects. Alarming trends include a significant number of tweets trivializing drug use and recreational purposes, along with a lack of awareness regarding side effects. Monitoring conversations related to analgesics on social media is essential due to common illegal web-based sales and purchases without prescriptions.

L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling.

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

Orofacial antinociceptive effects of perillyl alcohol associated with codeine and its possible modes of action.

This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Accelerated wound healing and its promoting effects of topical codeine on the healing of full-thickness cutaneous wound, evidences for modulating cytokines involved in pain, inflammation and collagen biosynthesis.

INTRODUCTION: The inflammation and pain occur in all the wounds. Opioids drugs decrease pain and may act as an anti-inflammation. The current study was conducted to investigate the efficiency of the topical uses of Codeine on full-thickness excision wound models by focusing on relationship between pain mediators, inflammation and wound healing rate. METHODS: Following the induction of anesthesia, a skin wound with a size of 7-mm punch was induced on the dorsal surfaces of each mouse. The mice were divided into five categories: groups I-III were daily administered 2.5%, 5%, and 10% Codeine gel; those in group IV were administered phenytoin cream, and group V (controls) received base ointment. To assess the effects of Codeine gel on the wound healing process, the wound area, histological parameters, and the relative protein expression of CXCR1, CXCR2, IL-6, IL-6R, PDGF, PDGFR, and COL1A along with the plasma concentrations of IL-1ß, IL-10, and TNF-α were investigated on days 3, 7, and 14. RESULTS: On days 7 and 14, the wound area was significantly lower in the treated mice compared to the controls (P < 0.05). Angiogenesis, collagen deposition, and epithelium thickness were significantly higher in the treatment groups compared to the control group (P < 0.05). The relative protein expressions of CXCR1, CXCR2, IL-6, and IL-6R and the plasma concentrations of IL-1ß and TNF-α were significantly lower in the treated groups. Meanwhile, the relative protein expressions of PDGF, PDGFR, and COL1A and the plasma concentration of IL-10 were significantly higher in the treated mice (P < 0.05). CONCLUSION: Administration of Codeine gel accelerated wound healing through decreasing the pain mediators, inflammation and promoting proliferative phase.

Chemical characteristics and significant antitussive effect of the Erigeron canadensis polyphenolic polysaccharide-protein complex.

ETHNOPHARMACOLOGICAL RELEVANCE: Erigeron canadensis has been used in traditional medicine to treat a variety of respiratory diseases, including acute upper and lower respiratory tract infections and cough-related asthma. There is as yet no relevant experimental or clinical study in the scientific literature evaluating the efficacy of plants in these disorders. AIM OF THE STUDY: To investigate the active ingredients in Erigeron canadensis, a complex isolated from flowering parts of a plant was tested for airway defense reflexes, in particular for cough reflexes and airway reactivity. Both were experimentally induced by a chemical irritant that simulated the inflammatory conditions of their formation. MATERIAL AND METHODS: The polyphenolic polysaccharide-protein (PPP) complex was isolated from the flowering parts of Erigeron canadensis by hot alkaline extraction and a multi-stage purification process. The antitussive activity was confirmed as a decrease in the number of citric acid-induced coughs and the bronchodilator effect was verified as a decrease in specific airway resistance (sRaw) in conscious guinea pigs. RESULTS: The dark brown Erigeron complex with a molecular weight of 38,000 g/mol contained phenolics (13.2% wt%), proteins (16.3% wt%), and uronic acids (6.3% wt%). The neutral carbohydrate part of Erigeron consisted mainly of xylose (12.1 wt%), glucose (13.3 wt%), arabinose (24.1 wt%), and galactose (41.0 wt%) residues. Arabinogalactan and 4-OMe-glucuronoxylan have been found to be the major polysaccharides in the Erigeron complex. Using a method of chemically-induced cough reflex and guinea pigs test system the Erigeron complex exhibited statistically significant, the dose-dependent antitussive activity, which was similar to that of the centrally-acting opioid agonist codeine. CONCLUSION: Pharmacological tests have revealed a new pharmacodynamic effect of the Erigeron complex, namely an antitussive effect. Its activity was most pronounced in comparison with all previously tested compounds from other medicinal plants and approached the effect of codeine, the most potent antitussive used in clinical practice. The results provide the scientific basis for the application of this herb in traditional medicine.

Effects of codeine on esophageal peristalsis in humans using high resolution manometry.

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-s integrated relaxation pressure (IRP-4s) (P = 0.003) and shortened 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.

The effect of codeine administration on oxidative stress biomarkers and the expression of the neuron-specific enolase in the brain of Wistar rats.

The study aimed to assess the effects of codeine medication on some oxidative stress parameters and how it affects the expression of enolase in neuronal cells. The codeine medication used for the study was Archilin™ with codeine syrup and dihydrocodeine 30 mg. The study used 30 male Wistar rats which were grouped in five: A, B, C, D, and E (n = 6), while treatments were administered for 21 days. Based on the LD50s of 6.09 ml/kg body weight (b.wt.) Archilin™ with codeine syrup and 3.145 mg/kg b.wt. dihydrocodeine, group A served as control and were given normal saline; groups B and C were treated with 1 mg/kg and 2 mg/kg b.wt. dihydrocodeine, respectively; while groups D and E were treated with 2 ml/kg and 4 ml/kg b.wt. Archilin™ with codeine syrup, respectively. After treatments, animals were sacrificed via cervical dislocation and the brains were harvested and prepared for determination of oxidative stress biomarkers as well as immunohistochemical studies of neuron-specific enolase (NSE) to assess for neuronal cell integrity. Significantly decreased mean values (p < 0.05) of superoxide dismutase (SOD) and catalase (CAT) activities were observed while malondialdehyde (MDA) is significantly increased (p < 0.05) among treated groups. The expression of enolase was downregulated in treatment groups when compared to control. Animals in group A which are control showed strong staining intensity of the prefrontal cortex compared to groups C, D, and E which showed mild staining. The scoring of group A for cerebellum showed strong staining intensity, groups B and C showed mild staining, while groups D and E showed weak staining intensity. From the findings of this study, prolonged codeine syrup administration causes oxidative stress and this affects the expression of enolase in neuronal cells resulting in glucose hypometabolism which eventually results in functional brain failure.

Effect of protein composition of enteral formula on gastric content volume during continuous feeding: A randomized controlled cross-over study in healthy adults.

BACKGROUND & AIMS: Enteral nutrition with polymeric intact protein formula is the preferred medical nutrition strategy in critically ill patients when oral intake is insufficient. Enteral nutrition formulas are often rich in casein protein, which has coagulating properties. Coagulation in the stomach impedes gastric emptying and might result in high gastric residual volumes which are a clinical sign of gastrointestinal intolerance and a major reason to decrease or to discontinue enteral feeding. In this study the impact of protein composition of enteral formula on gastric content volume (GCV) during and after continuous feeding was tested in healthy volunteers in whom gastrointestinal conditions of critically ill patients were mimicked. METHODS: An enteral formula including 4 proteins (P4) with non-coagulating properties was compared to a casein-dominant formula (Cas) with coagulating properties. Esomeprazole and codeine were administered to mimic stress ulcer prophylaxis and induce gastroduodenal motor dysfunction, both being hallmarks of critically ill patients. GCV was measured with magnetic resonance imaging during and after continuous enteral feeding (100 mL/h for 4h) in a randomized single-center cross-over study. Results are provided as mean (SD). Significance level of p < 0.05 was applied. RESULTS: Twenty subjects completed the study (14 women, 6 men, 25.8 (4.6) years old, BMI: 22.5 (1.5) kg/m2). The GCV as change from baseline at T = 240 (primary endpoint) did not differ between study products (P4: 124.3 (83.4) vs. Cas: 137.1 (102.0) mL, 95% CI: -57.4, 27.0, p = 0.457). During feeding and after cessation of feeding, the area under the GCV-curve (AUC0-360 GCV) for P4 and Cas was 44631.1 (15546.1) and 52822.2 (19686.1) mL∗min, respectively (p = 0.061). During feeding the GCV was lower at T = 180 min (175.4 (64.8) vs. 205.2 (75.4) mL, p = 0.038) and after cessation of feeding at T = 300 min (81.3 (71.1) vs. 116.3 (84.3) mL, p = 0.004) and T = 330 min (39.9 (53.9) vs. 73.6 (81.1) mL, p = 0.031). With P4 it took less time to reach half of the GCV at T = 240 min compared to Cas (52.8 (27.6) vs. 65.4 (29.9) min, p = 0.020). CONCLUSIONS: In this study in which healthy volunteers received esomeprazole and codeine to mimic gastrointestinal conditions of critically ill patients, observations of secondary endpoints suggest faster gastric emptying with P4 compared to Cas, and less gastric accumulation, possibly due to the non-coagulating properties of the P4 protein blend. Considering the small effect and the possible clinical relevance of reduced intragastric accumulation of enteral nutrition, the potential impact of protein coagulation should be further investigated in relevant study populations. Registered under Netherlands Trial Register identifier no. NTR6423.

MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through ß-Arrestin and Lack of Correlation with the FcεRI Pathway.

Codeine stimulates skin mast cells and is therefore used in skin tests and as an inducer of experimental itch. MRGPRX2 responds to various drugs, including opioids, to elicit pseudoallergic reactions, but whether it represents the main opiate receptor of skin mast cells remains unknown. By combining a number of approaches, including the silencing of MRGPRX2, we now report that MRGPRX2 is indeed the dominant codeine receptor of dermal mast cells. Activation by codeine displayed profound subject variability and correlated with secretion elicited by compound 48/80 or substance P but not by FcεRI aggregation. Degranulation by codeine was attenuated by stem cell factor, whereas the opposite was found for FcεRI. Compound 48/80 or codeine alone was able to achieve maximum MRGPRX2 activation. MRGPRX2 was rapidly internalized on codeine binding in a ß-arrestin-1‒dependent manner. Codeine-triggered ß-arrestin activation was also established by the Tango assay. Prestimulation with MRGPRX2 agonists (but not C3a or FcεRI aggregation) resulted in refractoriness to further stimulation by the same or another MRGPRX2 ligand (cross desensitization). This was duplicated in a cell line (RBL-MRGPRX2). Collectively, codeine degranulates skin mast cells through MRGPRX2, at which it acts as a balanced ligand. It has yet to be determined whether codeine-induced refractoriness could be exploited to desensitize MRGPRX2 to prevent severe pseudoallergic reactions.

Codeine induces increased resistance at the esophagogastric junction but has no effect on motility and bolus flow in the pharynx and upper esophageal sphincter in healthy volunteers: A randomized, double-blind, placebo-controlled, cross-over trial.

BACKGROUND: Chronic opioid use can induce esophageal dysfunction with symptoms resembling achalasia and a manometric pattern of esophagogastric junction-outflow obstruction (EGJ-OO). However, the effect of opioids in acute setting on pharyngeal function and esophageal body contractility has not been investigated. METHODS: After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60 mg) or placebo (glucose syrup) was infused intragastrically. Forty-five minutes post-infusion, participants received liquid, semi-solid, and solid boluses to assess esophageal and pharyngeal function. HRiM analysis was performed adhering to the Chicago classification v3.0. (CC v3.0). Pressure flow analysis (PFA) for the esophageal body and the pharynx was performed using the SwallowGateway™ online platform. KEY RESULTS: Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4 s values resulted in significantly reduced deglutitive EGJ relaxation and distal latency was significantly shorter. Distal contractility was similar in both conditions. Bolus flow resistance at the EGJ and distention pressures increased significantly after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV (p = 0.0003 vs. placebo). Codeine administration induced no significant alterations in any of the pharyngeal PFA metrics. CONCLUSIONS & INFERENCES: In HV, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES. ClinicalTrials.gov number, NCT03784105.

Pharmacological Aspects of Over-the-Counter Opioid Drugs Misuse.

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

Structural characteristics and biological effects of exopolysaccharide produced by cyanobacterium Nostoc sp.

Complex structure of cyanobacterium Nostoc sp. exopolysaccharide (EPS), with apparent molecular weight 214 × 103 g/mol, can be deduced from its composition. Chemical and NMR analyses found four dominant sugar monomers, namely (1 → 4)-linked α-l-arabinopyranose, ß-d-glucopyranose, ß-d-xylopyranose and (1 → 3)-linked ß-d-mannopyranose, two different uronic acids and a lactyl group, with (1 → 4,6)-linked ß-d-glucopyranose as the only branch point suggest a complex structure of this polymer. The dominant uronic acid is α-linked, but it remained unidentified. ß-d-Glucuronic acid was present in lower amount. Their position as well as that of lactyl remained undetermined too. Different doses of orally administered EPS in guinea pigs evoked a significant decrease in cough effort and a decrease in airway reactivity. The antitussive efficacy and bronchodilator effect of higher doses of EPS were found to be similar to that of the antitussive drug codeine and the antiasthmatic salbutamol. Without significant cytotoxicity on the RAW 264.7 cells, EPS stimulated the macrophage cells to produce pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and prostaglandins (PGs) and nitric oxide (NO) via induction of COX-2 and iNOS expression, respectively, suggesting that this biopolymer potentiates an early innate immune response and can therefore be used as a new immune modulator.

Efficacy of the World Health Organization analgesic ladder in the paclitaxel-induced pain syndrome in rats.

Paclitaxel use in cancer treatment is limited by a painful syndrome that has no effective treatment. Despite new therapies, drugs of the World Health Organization (WHO) analgesic ladder remain a useful therapeutic tool for cancer pain relief. Since cancer pain is caused by both tumor and chemotherapy, we assessed the efficacy of drugs from the WHO analgesic ladder for cancer pain relief in a paclitaxel-induced pain syndrome (P-IPS) model. P-IPS was induced in rats by one or four injections of paclitaxel on alternate days. The acute and chronic phases were assessed 24 h and 15 days after the first paclitaxel injection, respectively. The mechanical allodynia was evaluated after (step 1 of the ladder) paracetamol, (step 2) codeine alone or plus paracetamol and (step 3) morphine treatment in the acute or chronic phase of P-IPS. Paracetamol, codeine and morphine were equally efficacious in reducing the acute phase of the P-IPS. Codeine plus paracetamol had similar efficacy and potency when administered together in the acute phase of the P-IPS, but produced a longer-lasting effect than when separately managed. Moreover, paracetamol, codeine and morphine partially reduced the chronic phase of P-IPS, losing their efficacy and, in the case of codeine, potency when compared to the acute phase. However, paracetamol plus codeine increased the potency and efficacy of the codeine when compared to codeine administered alone in the chronic phase of P-IPS, producing a long-lasting anti-allodynic effect. Together, analgesics of WHO analgesic ladder reduce both acute and chronic phases of P-IPS, with codeine plus paracetamol presenting more potent, efficacious and long-lasting effect. Thus, in addition to tumor pain, drugs of WHO analgesics ladder could also be useful to treat P-IPS.

Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate.

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund's Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Cortical morphology of chronic users of codeine-containing cough syrups: association with sulcal depth, gyrification, and cortical thickness.

OBJECTIVES: The study aimed to explore the effects of codeine-containing cough syrup (CCS) exposure on cortical morphology and the relationship between cortical characteristics and CCS dependence. METHODS: Cortical morphometry based on Computational Anatomy Toolbox (CAT12) was used to compare changes in sulcal depth, gyrification, and cortical thickness of the cerebral cortex from 40 CCS users and 40 healthy controls (HCs) with two-sample t tests (p < 0.05, multiple comparison corrected). Relationships between abnormal cortical morphological changes and the duration of CCS use, impulsivity traits, and age of first use were investigated with correlation analysis (p < 0.05, uncorrected). RESULTS: CCS users exhibited significantly increased sulcal depth in the bilateral insula, bilateral lingual, bilateral superior frontal, right precuneus, and right middle frontal regions; increased gyrification in the right precentral cortex; and increased cortical thickness in the bilateral precentral, bilateral precuneus, and right superior temporal cortices compared to HCs. In addition, we found significant correlations between the bilateral insula, right superior frontal cortex, and right precentral gyrus and Barratt Impulsiveness Scale (BIS) total scores. CONCLUSIONS: Chronic CCS abuse may be associated with aberrant sulcal depth, gyrification, and cortical thickness. These morphological changes might serve as an underlying neurobiological mechanism of impulsive behavior in the CCS users. KEY POINTS: • Cortical morphological changes were detected in CCS users. • Increased sulcal depth, gyrification, and cortical thickness of some regions were found in the CCS users. • Positive correlations between cortical morphological changes and BIS total scores were identified.

Characterization of Cancer-Induced Nociception in a Murine Model of Breast Carcinoma.

Severe and poorly treated pain often accompanies breast cancer. Thus, novel mechanisms involved in breast cancer-induced pain should be investigated. Then, it is necessary to characterize animal models that are reliable with the symptoms and progression of the disease as observed in humans. Explaining cancer-induced nociception in a murine model of breast carcinoma was the aim of this study. 4T1 (104) lineage cells were inoculated in the right fourth mammary fat pad of female BALB/c mice; after this, mechanical and cold allodynia, or mouse grimace scale (MGS) were observed for 30 days. To determine the presence of bone metastasis, we performed the metastatic clonogenic test and measure calcium serum levels. At 20 days after tumor induction, the antinociceptive effect of analgesics used to relieve pain in cancer patients (acetaminophen, naproxen, codeine or morphine) or a cannabinoid agonist (WIN 55,212-2) was tested. Mice inoculated with 4T1 cells developed mechanical and cold allodynia and increased MGS. Bone metastasis was confirmed using the clonogenic assay, and hypercalcemia was observed 20 days after cells inoculation. All analgesic drugs reduced the mechanical and cold allodynia, while the MGS was decreased only by the administration of naproxen, codeine, or morphine. Also, WIN 55,212-2 improved all nociceptive measures. This pain model could be a reliable form to observe the mechanisms of breast cancer-induced pain or to observe the efficacy of novel analgesic compounds.

Combination of Acetaminophen/Codeine Analgesics Does Not Avoid Bleaching-Induced Tooth Sensitivity: A Randomized, Triple-Blind Two-Center Clinical Trial.

Bleaching-induced tooth sensitivity (TS) is highly prevalent. OBJECTIVE: This study aimed to determine if the combination of opioids and nonopioids analgesics (Tylex) may provide a better analgesic effect. METHOD: A triple-blind, parallel, randomized two-center clinical trial was conducted with 105 healthy patients who received either a placebo or a combination of acetaminophen/codeine. The first dose of Tylex 30 mg (acetaminophen 500 mg/codeine 30 mg) or placebo was administered one hour before the in-office bleaching (35% hydrogen peroxide), and extra doses were administered every six hours for 48 hours. The TS was recorded using a visual analog scale of 0 to 10 and a numeric rating scale of 0 to 4 in different periods: during bleaching, one hour up to 24 hours, and 24 hours up to 48 hours postbleaching. The color was measured before and one month after dental bleaching with a visual shade guide (Vita Classical), Vita Bleachedguide 3D-MASTER, and the spectrophotometer Vita Easyshade. The absolute risk of TS was evaluated using the Fisher exact test. Data of TS intensity with numeric rating scale of the two groups were compared with the Mann-Whitney U-test and the Friedman test, while data from the visual analog scale were evaluated by two-way repeated measures analysis of variance and the Tukey test for pairwise comparison. The color changes between groups were compared using the Student t-test (α=0.05). RESULTS: No significant differences between the groups were observed in the risk and intensity of TS. The overall absolute risk of TS was approximately 96%. No significant differences between groups were observed in terms of color change ( p>0.05) for any scale. CONCLUSION: The use of an acetaminophen/codeine combination prior to in-office bleaching does not reduce the risk and intensity of bleaching-induced TS.

Effects of naloxegol on whole gut transit in opioid-naïve healthy subjects receiving codeine: A randomized, controlled trial.

BACKGROUND: Nausea, vomiting, and constipation (OIC) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu-opiate opioid receptor antagonist. AIM: To compare the effects on pan-gut transit of treatment with codeine, naloxegol, or combination in healthy volunteers. METHODS: We conducted a randomized, double-blind, placebo-controlled, single-center, parallel-group study in 72 healthy opioid-naïve adults, randomized to: codeine (30 mg q.i.d.), naloxegol (25 mg daily), codeine and naloxegol, or matching placebo. During 3 days of treatment, we measured gastric emptying (GE) T1/2 , colonic filling at 6 hours (CF6), colonic geometric center at 24 and 48 hours, and ascending colon emptying (ACE) T1/2 . KEY RESULTS: Participants were 59.7% women, median BMI 25.0 kg/m2 , and median age 33.8 years. Codeine significantly retarded GE T1/2, CF6, overall colonic transit, and ACE T1/2 . There was significant difference (P = .026) in GE T1/2 between codeine (144.0 min [IQR 110.5-238.6]) and naloxegol (95.5 min [89.1-135.4]). There was a significant overall group difference in CF6 (P = .023), with significant difference (P = .019) between codeine (11.0% [0.0-45.0]) and naloxegol (51% [18.8-76.2]). However, no significant differences were found between codeine-treated participants concomitantly receiving placebo or naloxegol. CONCLUSIONS AND INFERENCES: Short-term administration of naloxegol (25 mg) in healthy, opioid-naïve volunteers does not reverse the retardation of gastric, small bowel, or colonic transit induced by acute administration of codeine. Further studies with naloxegol at higher dose are warranted to assess the ability to reverse the retardation of transit caused by acute administration of codeine in opioid-naïve subjects.

Pain Treatment Practices of Community-Dwelling Black Older Adults.

Black older adults often experience disparities in pain treatment that results in unmet pain needs. The aims of this study were to assess the pain management experiences of a group of community dwelling Black older adults and identify gaps in clinical practice. A qualitative, descriptive design was employed using the methodology of ethnography. The setting was an urban, low-income, community elderly housing high-rise facility. Participants included facility residents (n = 106); of these, 20 completed structured qualitative interviews. The Brief Pain Inventory and qualitative interviews were used to determine pain prevalence, treatment practices, and barriers. Eighty-six percent of the participants had severe pain with a mean worst pain rating of 7 on a 0 to 10 scale. Pain interfered moderately with general activity (5.59), walking (5.73) and normal work (5.70), also measured on 0 to 10 scales. Participants preferred non-opioid analgesics, topical over-the-counter treatments, and nonpharmacological interventions such as prayer/meditation, and exercise for treatment. Medications most commonly used by participants for pain management included, hydrocodone with acetaminophen (28.6%), nonsteroidal anti-inflammatory drugs (13.2%), acetaminophen with codeine (12%), and tramadol (9.9). Qualitative interviews revealed that pain management barriers were centered around communication concerns about side effects, fears of addiction, and provider mistrust. A communication gap exists between patients and providers. Discussing patient treatment preferences, providing balanced treatment information, and following-up with patients on treatment plan effectiveness by phone can improve how pain is managed for Black older adults.