Codeine Administration Research Articles

Evidence for peripheral and central actions of codeine to dysregulate swallowing in the anesthetized cat

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

Effects of Codeine on Esophageal Peristalsis in Patients With Ineffective Esophageal Motility: Studies Using High-resolution Manometry.

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

Ameliorative Capacity of Rice Husk Extract on Codeine-induced Testicular Dysfunction in Male Wistar Albino Rats

Rice husks (RHs) is an agro waste generated from rice production with limited application. Codeine belongs to the numerous drugs of abuse worldwide and its impact on reproductive injury has been reported. This study was designed to establish the ameliorative potential of brown rice husk extract (RHE) against reproductive damage induced by codeine misuse. Experimental rats were grouped into six groups with six rats per group: Group I received only rat chow and clean water for 30 days. Group II received only codeine 10 mg/kg body weight (b.w) of rats. Group III received only RHE 500 mg/kg b.w of rats. The 4th, 5th and 6th groups received codeine 10 mg/kg/b.w alongside 250 mg, 500 mg and 1000 mg RHE, respectively. Treatments (RHE and codeine) were administered once during the early hours between 9-10 am daily for 30 days, the animals were sacrificed, and blood and tissue samples were harvested. Male reproductive hormones such as testosterone, Follicle stimulating hormone (FSH) and luteinizing hormone (LH), and sperm quality parameters were assayed. The testis tissues were excised and examined for histopathological changes. The result revealed that high dose codeine administration significantly decreased epidermal morphology, motility, and sperm count as well as testosterone, FSH, and LH concentrations, respectively. The histopathological examination revealed distinct abnormal changes in the codeine control group when compared with the other experimental groups. RHE administration significantly improved the altered assayed parameters.

Ameliorative Effect of Rice Husk Methanol Extract on Liver and Kidney Toxicities Induced by Subchronic Codeine Administration.

Background and Objective. Rice husk remains a key by-product of rice milling generated in significant amount. Accumulated evidence indicates that rice husk contains numerous bioactive compounds; however, its application is limited. This study was designed to introduce an in vivo application of rice husk extract, against opioid-induced liver and kidney injuries. Codeine was considered a psychotic inducer in this study due to its global alarming misuse recently. The hepatorenal ameliorative proclivity of rice husk extract against codeine-induced toxicity on the liver and kidney in male albino Wistar rats was examined. To this effect, thirty-six (36) albino Wistar rats of weight 100-110 g were utilized and weight-matched animals placed in 6 groups of 6 rats each. After 30 days of the combined administration of codeine and the rice husk extract, the experimental animals were assayed for basic liver and renal markers such as AST, ALP, ALT, total protein, albumin, conjugated and total bilirubin, urea, creatinine, and electrolytes (sodium, potassium, chloride, and bicarbonate). Rice husks were collected from a local rice mill, and the extraction was done with methanol. Findings. Rice husk extract (RHE) significantly ameliorated the recorded hepatic damage. More so, the extract showed a significant action on the renal markers as well. A histopathology examination of the liver and kidney tissues revealed that RHE showed a hepatorenal ameliorative potential in a dose-dependent manner. Conclusion. Phytonutrient from RH possesses a healing ability against opioid-induced hepatorenal toxicity. Thus, RH is safe for human and may be adopted to obviate and manage codeine-induced hepatorenal damage or injury. Significance and Novelty. Data on the application of RHE as a phytonutrient to combat liver and kidney injuries were demonstrated. Future studies should evaluate its potential on other organs.

Haematopoietic Potential of Rice Husk Extract in Codeine Administered Male Wistar Rats

Oryza sativa (rice) is a widely consumed staple grain with significant amount of fibre, carbohydrate, and trace amount of other biomolecules such as minerals and vitamins. Thus, it’s a good energy source. The pre-clinical and clinical investigations of rice hull has revealed its numerous health benefits. Utilization of rice products as dietary supplements, additives and pharmacological adjuvants has become a global trend. Rice husk (RH), is a by-product of rice milling generated in tremendous quantity. Considering the global trend in codeine consumption especially by the youths, this study adopted codeine as a drug of abuse as against its therapeutic use as an analgesic. The study explored the haematopoietic potential of rice husk methanol extract (RHME) in codeine-administered male Wistar rats. A total of thirty-six (36) rats weighing between 100-110g were procured and assembled into 6 groups of 6 rats. Group I was the negative control (NC), Group II received codeine at 10mg/kg body weight, Group III received 10mg/kg body weight of RHME, while Groups IV, V, and VI received codeine with RHME concurrently but at three different concentrations of 250, 500, and 1000mg/kg respectively. After 30 days of treatment, blood samples of the specimens were subjected to haematological assay. From the assessment, codeine administration significantly decreased the haematological indices (PCV, haemoglobin, RBC, WBC, platelets, neutrophil, eosinophil, lymphocyte and monocyte), while RHME administration significantly upregulated the altered blood parameters concentration. Thus, RH showed haematopoietic efficacy and should be considered a possible therapeutic for prevention and/or management of anaemia as well as boosting of key haematology indices.

Assessment of Pharmacist's Awareness toward Rational Dispensing of Codeine-Containing Drugs in Dhamar City, Yemen

&#x0D; Abstract&#x0D; Objectives: The aim of this study was to investigate the level of awareness the pharmacists of Dhamar City in relation to dispensing codeine-containing drugs. As well as studying the relationship between the scientific degree and the wrong administration of codeine. Methods: The study used a descriptive and scientific approaches of quantitative research, in which a questionnaire was distributed to a sample of 143 pharmacists working in the pharmacies of Dhamar City during the academic year 2021 – 2022. The data were collected and analyzed using the SPSS22 software. Findings: Results show that Codeine is not safe at all for babies under 1 year old based on the participants' responses (95.8%). Most of the participants (55.9%) chose addiction and habituation. The majority of the participants (95.8%) replied that codeine is not safe for pregnant women. Conclusion: The researchers conclude that the pharmacists in Dhamar City are aware of the risks of dispensing codeine to people, especially for children, pregnant women and those who suffer from cardiac disorders. Despite the difficulties they face when dispensing codeine to people due to their addiction to it, the pharmacists do their best to overcome the problem of administrating codeine and the subsequent consequences. &#x0D; &#x0D; &#x0D; &#x0D; &#x0D;

Prolonged Codeine Administration Causes Degeneration of Myelinated Axons and Motor Dysfunction in Wistar Rats.

Over-the-counter (OTC) anti-cough medications which contain codeine (an opioid) are extensively available in Nigeria, and hence prone to overuse or abuse. The study aimed to understand the effects of oral codeine administration on the integrity of neurons of the cerebral cortex and cerebellum and its behavioral implications in male Wistar rats. Thirty adult male Wistar rats of comparable weights were obtained and randomly allocated into 5 groups: A, B, C, D, and E (n = 6). Drugs used for the study were ArchilinTM with codeine and dihydrocodeine 30mg. Group A served as control and was administered 0.5mL/kg of normal saline. Groups B and C were treated with 1mg/kg and 2mg/kg of dihydrocodeine, respectively; Group D and E received 2mL/kg and 4mL/kg of ArchilinTM codeine syrup, respectively. The ArchilinTM codeine syrup and dihydrocodeine solutions were administered to the animals based on their body weight, orally and daily with the aid of oropharyngeal tubes for 21 days. The experimental animals were subjected to neurobehavioral studies using beam walk and open field. At the end of the treatment period, the animals were anesthetized with ketamine-hydrochloride intraperitoneally. The brains were quickly dissected out, rinsed with normal saline, and tissue processed for myelin studies. The beam walking and open field result revealed that prolonged codeine administration interfered with motor function in the experimental animals. Sections of the prefrontal cortex and cerebellum of rats given normal saline showed normal myelin sheaths, whereas animals in the treatment group showed degenerating myelin compared to the control. Prolonged consumption of prescription codeine causes degeneration of the myelin sheaths and this may affect the conduction of electrical impulses in myelinated axons thus resulting in motor function insufficiency.

Poppy Seed Consumption May Be Associated with Codeine-Only Urine Drug Test Results.

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

Pharmacokinetics and transplacental transfer of codeine and codeine metabolites from Papaver somniferum L.

Ethnopharmacological relevancePapaveris Pericarpium, which is the dried husk of Papaver somniferum L., has been used as a phytomedicine to relieve cough, diarrhea and pain. The alkaloid codeine contained therein via biotransformation converts to morphine and potentially produces addictive and toxic effects. Due to the healthy concern for a pregnant woman, our hypothesis is that codeine and its metabolites can penetrate the placental barrier to reach the foetus and amniotic fluid, and these processes may be modulated by the transporter. Aim of the studyBecause codeine is also considered a prodrug of morphine, it has a good analgesic effect. It is often used by pregnant women but may expose the foetus to the risk of morphine harm. The aim of this study is to investigate the metabolic rate, distribution and transplacental transfer mechanism of codeine and its metabolites morphine and morphine-3-glucuronide (M3G) in pregnant rats and to assess the risk of medication for pregnant women. Materials and methodsUltrahigh-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) combined with a microdialysis system was developed to monitor codeine, morphine and M3G in multiple sites of maternal blood, placenta, foetus and amniotic fluid after codeine administration. A compartmental model was used to calculate the pharmacokinetic parameters of codeine in blood after codeine administration (10 mg/kg, i.v.). The area under the concentration (AUC) ratio of AUCmetabolite/AUCcodeine and AUCtissue/AUCblood was used to represent the metabolic biotransformation ratio and the drug from blood-to-tissue transfer ratio, respectively. ResultsThe pharmacokinetic results demonstrated that codeine fit well with a two-compartment model and went through rapid metabolism to morphine and M3G in pregnant rats after codeine administration (10 mg/kg, i.v.). The biotransformation ratios of AUCmorphine/AUCcodeine, AUCM3G/AUCmorphine and AUCM3G/AUCcodeine were 0.12 ± 0.03, 54.45 ± 20.61 and 6.53 ± 2.47, respectively, after codeine administration (10 mg/kg, i.v.), which suggested that codeine was easily metabolized into M3G through morphine. The tissue distribution results demonstrated that all of the analytes penetrated into the foetus through the placenta; however, the blood-to-tissue transfer ratio (AUCtissue/AUCblood) of morphine and M3G was relatively lower than that of codeine after codeine administration (10 mg/kg, i.v.), which suggested that the blood-placenta barrier blocks the penetration of morphine and M3G into the foetus. Thus, the tissue transfer of morphine in the placenta and foetus was significantly enhanced by treatment with corticosterone, an inhibitor of organic cation transporter (OCT). ConclusionBased on microdialysis coupled to a validated UHPLC–MS/MS system, the pharmacokinetics and metabolic biotransformation of codeine and its metabolites were analyzed and clarified. The potential mechanism of morphine placental transfer was modulated by OCT transporters.

Pharmacokinetics, adverse effects and effects on thermal nociception following administration of three doses of codeine to horses

BackgroundIn humans, codeine is a commonly prescribed analgesic that produces its therapeutic effect largely through metabolism to morphine. In some species, analgesic effects of morphine have also been attributed to the morphine-6-glucuronide (M6G) metabolite. Although an effective analgesic, administration of morphine to horses produces dose-dependent neuroexcitation at therapeutic doses. Oral administration of codeine at a dose of 0.6 mg/kg has been shown to generate morphine and M6G concentrations comparable to that observed following administration of clinically effective doses of morphine, without the concomitant adverse effects observed with morphine administration. Based on these results, it was hypothesized that codeine administration would provide effective analgesia with decreased adverse excitatory effects compared to morphine. Seven horses received a single oral dose of saline or 0.3, 0.6 or 1.2 mg/kg codeine or 0.2 mg/kg morphine IV (positive control) in a randomized balanced 5-way cross-over design. Blood samples were collected up to 72 hours post administration, codeine, codeine 6-glucuronide, norcodeine morphine, morphine 3-glucuronide and M6G concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Pre- and post-drug related behavior, locomotor activity, heart rate and gastrointestinal borborygmi were recorded. Response to noxious stimuli was evaluated by determining thermal threshold latency.ResultsMorphine concentrations were highest in the morphine dose group at all times post administration, however, M6G concentrations were significantly higher in all the codeine dose groups compared to the morphine group starting at 1 hour post drug administration and up to 72-hours in the 1.2 mg/kg group. With the exception of one horse that exhibited signs of colic following administration of 0.3 and 0.6 mg/kg, codeine administration was well tolerated. Morphine administration, led to signs of agitation, tremors and excitation. There was not a significant effect on thermal nociception in any of the dose groups studied.ConclusionsThe current study describes the metabolic profile and pharmacokinetics of codeine in horses and provides information that can be utilized in the design of future studies to understand the anti-nociceptive and analgesic effects of opioids in this species with the goal of promoting judicious and safe use of this important class of drugs.

Effect of Oral Administration of 3-Methylmorphine (Codeine) Induced Renal Toxicity in Adult Wistar Albino

Codeine (3-Methylmorphine) is the most common opiate consumed worldwide, it is widely used for its analgesic, antitussive and antidiarrheal activities. The study aims to determine the effect of oral administration of codeine induced renal toxicity in adult Wistar Albino Rats. Twenty albino rats weighing between 150-200g were used. Animals were divided into 4 groups (A, B, C and D). Group A served as the control group. Group B received 30mg/kg, group C received 60mg/kg and group D received 90mg/kg codeine orally for 28 days. Data obtained were calculated for one-way analysis of variance (ANOVA), followed by a Post Hoc test. Results were expressed as mean ± standard error of the mean. Statement of differences was based on significance level at p&lt;0.05. The results showed a slight decrease in the mean values of Na+ , Cl- , and HCO3 – levels which are not significant, while K+ level showed an increase in group B and C followed by a decrease in group D which were not statistically significant (p&lt;0.05). Creatinine level did not show any variation when compared with the control group but there was an increase in urea level which was also not statistically significant at p&lt;0.05. Photomicrographs of rat’s kidneys in the treatment group showed; degeneration of the glomerulus, hydrophobic changes in the renal tubular lumen, fatty tissue, multi-focal interstitial haemorrhages, infiltration of inflammatory lymphoid cells, mild mononuclear cells infiltration in the renal cortex and mass aggregation of lymphoid cells in the cellular medullar when compared to control.

Effects Of High Dosage of Codeine - Containing Cough Syrup Administration on Some Biochemical Parameters of Liver in Albino Rats

The study aimed to determine the effect of a high dosage of codeine-containing cough syrup administration on some biochemical parameters of the liver in albino rats. Codeine at 80 mg/kg/day, 160 mg/kg/day, 240 mg/kg/day, 320 mg/kg/day cough syrup were administered orally to albino rats for 21 days, biochemical parameters were analyzed for the activities of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Bilirubin, Total protein and Albumin. Results obtained revealed that a high dosage of codeine administration significantly increased plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin and albumin while it reduced total protein level when compared with the control rats. The study confirmed the risk of increased hepatotoxicity due to a high dosage of codeine administration. Although codeine is reported to be effective in pain management, its toxicity should be kept in mind.

Oral and intravenous pharmacokinetics of metformin with and without oral codeine intake in healthy subjects: A cross‐over study

The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five doses of tablet codeine 25 mg; the last dose was administered together with oral metformin (1 g), and (D) five doses of tablet codeine 25 mg; the last dose was administered together with metformin (0.5 g) intravenously. Blood samples were drawn for 24 h after administration of metformin, and for 6 h after administration of codeine and analyzed using liquid chromatography and tandem mass spectrometry. Healthy volunteers genotyped as CYP2D6 normal metabolizers (*1/*1) without known reduced function variants in the OCT1 gene (rs12208357, rs34130495, rs34059508, and rs72552763) were invited. The median absorption fraction of metformin was 0.31 and was not influenced by codeine intake. The median time to maximum concentration (Tmax) after oral intake of metformin was 2 h without, and 3 h with codeine (p = 0.06). The geometric mean ratios of the areas under the plasma concentration time‐curve (AUCs) for morphine and its metabolites M3G and M6G for oral intake of metformin‐to‐no metformin were 1.21, 1.31, and 1.27, respectively, and for i.v. metformin‐to‐no metformin 1.28, 1.34, and 1.30, respectively. Concomitant oral and i.v. metformin increased the plasma levels of morphine, M3G and M6G. These small pharmacokinetic changes may well contribute to an increased risk of early discontinuation of metformin. Hence, a clinically relevant drug‐drug interaction between metformin and codeine seems plausible.

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

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. Eighteen healthy volunteers (13 men, mean age 27.5years, aged 20-43years) underwent high resolution manometry (HRM) with a catheter containing an injection port in mid-esophagus. Secondary peristalsis was performed with 10 and 20mL rapid air injections. Two different sessions including acute administration of codeine (60mg) or the placebo were randomly performed. 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 10mL (P=0.048) and 20mL (P=0.047). Codeine significantly increased the frequency of secondary peristalsis during air injections with 10mL than the placebo (P=0.007), but not for air injection with 20mL (P=0.305). 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.

Microscopic features of the rat adrenal gland associated with chronic codeine phosphate administration.

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<0.05). The experimental group also showed an increase in vascularization and connective tissue in the glands. After 14 days of recovery, most of the changes observed in experimental animals were reversed and the adrenal glands in both groups had similar features. A decrease in cell count of the adrenal medulla was however observed (P-value<0.05). In conclusion administration of codeine phosphate causes discernible changes in the microscopic structure of the adrenal gland, most of which appear to be reversed after two weeks recovery period.

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 30mg. 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 21days. Based on the LD50s of 6.09ml/kg body weight (b.wt.) Archilin™ with codeine syrup and 3.145mg/kg b.wt. dihydrocodeine, group A served as control and were given normal saline; groups B and C were treated with 1mg/kg and 2mg/kg b.wt. dihydrocodeine, respectively; while groups D and E were treated with 2ml/kg and 4ml/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.

Intra-Arterial, but Not Intrathecal, Baclofen and Codeine Attenuates Cough in the Cat.

Centrally-acting antitussive drugs are thought to act solely in the brainstem. However, the role of the spinal cord in the mechanism of action of these drugs is unknown. The purpose of this study was to determine if antitussive drugs act in the spinal cord to reduce the magnitude of tracheobronchial (TB) cough-related expiratory activity. Experiments were conducted in anesthetized, spontaneously breathing cats (n = 22). Electromyograms (EMG) were recorded from the parasternal (PS) and transversus abdominis (TA) or rectus abdominis muscles. Mechanical stimulation of the trachea or larynx was used to elicit TB cough. Baclofen (10 and 100 μg/kg, GABA-B receptor agonist) or codeine (30 μg/kg, opioid receptor agonist) was administered into the intrathecal (i.t.) space and also into brainstem circulation via the vertebral artery. Cumulative doses of i.t. baclofen or codeine had no effect on PS, abdominal muscle EMGs or cough number during the TB cough. Subsequent intra-arterial (i.a.) administration of baclofen or codeine significantly reduced magnitude of abdominal and PS muscles during TB cough. Furthermore, TB cough number was significantly suppressed by i.a. baclofen. The influence of these drugs on other behaviors that activate abdominal motor pathways was also assessed. The abdominal EMG response to noxious pinch of the tail was suppressed by i.t. baclofen, suggesting that the doses of baclofen that were employed were sufficient to affect spinal pathways. However, the abdominal EMG response to expiratory threshold loading was unaffected by i.t. administration of either baclofen or codeine. These results indicate that neither baclofen nor codeine suppress cough via a spinal action and support the concept that the antitussive effect of these drugs is restricted to the brainstem.

Functional phenotyping of the CYP2D6 probe drug codeine in the horse

BackgroundIn humans, the drug metabolizing enzyme CYP2D6 is highly polymorphic resulting in substantial differences in the metabolism of drugs including anti-arrhythmics, neuroleptics, and opioids. The objective of this study was to phenotype a population of 100 horses from five different breeds and assess differences in the metabolic activity of the equine CYP2D6 homolog using codeine as a probe drug. Administration of a probe drug is a common method used for patient phenotyping in human medicine, whereby the ratio of parent drug to metabolite (metabolic ratio, MR) can be used to compare relative enzyme function between individuals. A single oral dose of codeine (0.6 mg/kg) was administered and plasma concentrations of codeine and its metabolites were determined using liquid chromatography mass spectrometry. The MR of codeine O-demethylation [(codeine)/(morphine + morphine-3-glucuronide + morphine-6-glucuronide)] was determined using the area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-∞) for each analyte and used to group horses into predicted phenotypes (high-, moderate-, and low-MR).ResultsThe MR of codeine O-demethylation ranged from 0.002 to 0.147 (median 0.018) among all horses. No significant difference in MR was observed between breeds, age, or sex. Of the 100 horses, 11 were classified as high-MR, 72 moderate-MR, and 17 low-MR. Codeine AUC0-∞ and O-demethylation MR were significantly different (p < 0.05) between all three groups. The mean ± SD MR was 0.089 ± 0.027, 0.022 ± 0.011, and 0.0095 ± 0.001 for high-, moderate-, and low-MR groups, respectively. The AUC for the morphine metabolites morphine-3-glucuronide and morphine-6-glucuronide were significantly different between high-and low-MR groups (p < 0.004 and p < 0.006).ConclusionsThe MR calculated from plasma following codeine administration allowed for classification of horses into metabolic phenotypes within a large population. The range of codeine metabolism observed among horses suggests the presence of genetic polymorphisms in CYP2D82 of which codeine is a known substrate. Additional studies including CYP2D82 genotyping of high- and low-MR individuals are necessary to determine the presence of CYP2D polymorphisms and their functional implications with respect to the metabolism of therapeutics.

Application of Model Informed Precision Dosing to Address the Impact of Pregnancy Stage and CYP2D6 Phenotype on Foetal Morphine Exposure.

Guidance regarding the effect of codeine and its metabolites on foetal development is limited by small studies and inconsistent findings. The primary objective was to use physiologically based pharmacokinetic modelling to investigate the impact of gestational stage and maternal CYP2D6 phenotype on foetal morphine exposure following codeine administration. Full body physiologically based pharmacokinetic models were developed and verified for codeine and morphine using Simcyp (version 19.1). The impact of gestational age and maternal CYP2D6 phenotype on foetal and maternal morphine and codeine exposure following oral codeine administration was modelled in a cohort of 250 pregnant females and foetuses at gestational weeks 0 (mothers only), 6, 12, 24 and 36. Consistent with the known effect on codeine metabolism, a clinically meaningful (> 1.65-fold) increase in foetal morphine AUC was observed in the CYP2D6 UM phenotype cohort compared to the CYP2D6 EM and PM phenotype cohorts. The mean (95% CI) foetal morphine AUC in the CYP2D6 UM cohort of 0.988 (0.902 to 1.073)ng/mL.h was 1.8-fold higher than the CYP2D6 EM cohort of 0.546 (0.492 to 0.600)ng/mL.h (p < 0.001). Despite a 2.8-fold increase in maternal CYP2D6 protein abundance between gestational weeks 6 and 36, the mean foetal morphine AUC in the CYP2D6 EM and UM phenotype cohorts reduced by 1.55- and 1.75-fold, respectively, over this period. Maternal CYP2D6 phenotype is a significant determinant of foetal morphine AUC. Simulations suggest that the greatest risk with respect to foetal morphine exposure is during the first trimester of pregnancy, particularly in CYP2D6 UM phenotype mothers.

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.

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. After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60mg) 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. Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4s 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. 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.