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

BACKGROUND: In 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. RESULTS: Morphine 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. CONCLUSIONS: The 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.

Functional phenotyping of the CYP2D6 probe drug codeine in the horse.

BACKGROUND: In 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). RESULTS: The 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). CONCLUSIONS: The 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.

Metabolism, pharmacokinetics and selected pharmacodynamic effects of codeine following a single oral administration to horses.

OBJECTIVE: To describe the pharmacokinetics and selected pharmacodynamic variables of codeine and its metabolites in Thoroughbred horses following a single oral administration. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 12 Thoroughbred horses, nine geldings and three mares, aged 4-8 years. METHODS: Horses were administered codeine (0.6 mg kg-1) orally and blood was collected before administration and at various times until 120 hours post administration. Plasma and urine samples were collected and analyzed for codeine and its metabolites by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were determined. Heart rate and rhythm, step counts, packed cell volume and total plasma protein were measured before and 4 hours after administration. RESULTS: Codeine was rapidly converted to the metabolites norcodeine, codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Plasma codeine concentrations were best represented using a two-compartment model. The Cmax, tmax and elimination t½ were 270.7 ± 136.0 ng mL-1, 0.438 ± 0.156 hours and 2.00 ± 0.534 hours, respectively. M3G was the main metabolite detected (Cmax 492.7 ± 35.5 ng mL-1), followed by C6G (Cmax 96.1 ± 33.8 ng mL-1) and M6G (Cmax 22.3 ± 4.96 ng mL-1). Morphine and norcodeine were the least abundant metabolites with Cmax of 3.17 ± 0.95 and 1.42 ± 0.79 ng mL-1, respectively. No significant adverse or excitatory effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Following oral administration, codeine is rapidly metabolized to morphine, M3G, M6G, C6G and norcodeine in horses. Plasma concentrations of M6G, a presumed active metabolite of morphine, were comparable to concentrations reported previously following administration of an analgesic dose of morphine to horses. Codeine was well tolerated based on pharmacodynamic variables and behavioral observations.

The Implausibility of Neonatal Opioid Toxicity from Breastfeeding.

The belief that newborns can develop opioid toxicity from breastfeeding is widely held but supported by very little data. Based largely on a single, highly publicized case report (the "Toronto case"), major health agencies worldwide now caution against codeine use by nursing mothers. As a result, "stronger" opioids with greater abuse liability are increasingly prescribed in its place, potentially to the detriment of maternal health. We re-examine aspects of this case report to demonstrate why such an occurrence is highly implausible. The Toronto case involved the death of a 13-day-old infant from opioid toxicity. The child's mother, who took codeine while breastfeeding, was found to have a duplication of CYP2D6*2, consistent with ultrarapid metabolizer status. This led to the conclusion that the child died from opioid toxicity due to enhanced maternal conversion of codeine to morphine, with the subsequent passage of large amounts of morphine into breast milk. We argue that this explanation is implausible based upon several factors: (1) the exceedingly small amount of opioids passed into breastmilk irrespective of maternal CYP genotype, (2) the observation that significant neonatal opioid accumulation can only occur in the setting of severely impaired renal function, and (3) the previously unreported finding of a markedly elevated codeine concentration in postmortem blood. Finally, a review of the literature identifies a paucity of convincing reports of neonatal opioid toxicity during breastfeeding, with no other confirmed cases of neonatal death despite the use of these drugs by millions of nursing mothers over the past 2 decades.

Adult and infant pharmacokinetic profiling of dihydrocodeine using physiologically based pharmacokinetic modeling.

We previously analysed the serum concentrations of dihydrocodeine in a 1-month-old infant with respiratory depression after being prescribed dihydrocodeine phosphate 2.0 mg/day divided t.i.d. for 2 days. The purpose was to develop a full physiologically based pharmacokinetic (PBPK) model that could account for these and other drug monitoring results. Based on experiments in Caco-2 cell monolayers, the effective permeability of dihydrocodeine in human jejunum was established as 1.28 × 10-4 cm/s. The in vitro Vmax /Km values for dihydrocodeine demethylation mediated by recombinant cytochrome P450 2D6 and 3A4 were 0.19 and 0.066 µl/min/pmol, respectively, and for dihydrocodeine 6-O-glucuronidation mediated by recombinant UGT2B4 and 2B7, the Vmax /Km values were 0.14 and 0.22 µl/min/mg protein, respectively. Renal clearance was calculated as 5.37 L/h on the total clearance value multiplied by the fraction recovered in urine. The reported plasma concentration-time profiles of dihydrocodeine after intravenous administration in healthy volunteers were used to adjust the tissue partitioning ratios. The developed model simulated the pharmacokinetic profiles of dihydrocodeine after single and multiple oral administrations reasonably well in the same population. Subsequently, the validated model was used to simulate pharmacokinetic profiles for five pediatric cases, including the 1-month-old Japanese boy and a 14-year-old Japanese girl who took an overdose of dihydrocodeine phosphate (37 mg). The simulated pharmacokinetic profiles for five virtual pediatric subjects matching the age, gender, and P450 2D6 phenotype of each case approximately reflected the observed values. These results suggested that our dihydrocodeine PBPK model reproduced the results of clinical cases reasonably well for subjects.

Combating opioid addiction and abuse-2 ways to effectively intervene in the cycle of addiction through pharmacogenomics.

OBJECTIVES: The objectives of this commentary are to: (1) briefly describe the ongoing challenges of addressing opioid abuse, (2) examine codeine metabolism in terms of pharmacogenomics, (3) describe 2 points of patient contact where pharmacogenomics can be implemented to determine the appropriateness of opioid therapy, and (4) briefly explore the value of pharmacogenomics in opioid-abuse and dependency research. SUMMARY: Opioid abuse is one of the most significant medical, social, and economic threats facing our country today. Yet for some patients, opioids are the only effective treatment option in achieving pain relief. Differentiating patients who are susceptible to abuse and addiction from those who are not has been absent in standard statistics-based medication prescribing. Pharmacogenomics (PGX) is a burgeoning science that examines how gene variations (variants) influence drug metabolism. With an estimated 23% of the U.S. population unable to properly metabolize codeine and related analogs, PGX could play an immediate role in the management of opioid therapy if applied (1) as part of regular pre-operative screening assessments and (2) prior to or in conjunction with pain-management referral. CONCLUSION: Using PGX to identify patients who should not begin or continue treatment with opioids because of abnormal metabolic pathways could (1) reduce the number of opioid prescriptions written; (2) reduce related costs; (3) guide more patient-centric, pain-management treatment plans, away from opioids as necessary; and (4) reduce the potential for opioid abuse and addiction.

Metatox - Web application for generation of metabolic pathways and toxicity estimation.

Xenobiotics biotransformation in humans is a process of the chemical modifications, which may lead to the formation of toxic metabolites. The prediction of such metabolites is very important for drug development and ecotoxicology studies. We created the web-application MetaTox ( http://way2drug.com/mg ) for the generation of xenobiotics metabolic pathways in the human organism. For each generated metabolite, the estimations of the acute toxicity (based on GUSAR software prediction), organ-specific carcinogenicity and adverse effects (based on PASS software prediction) are performed. Generation of metabolites by MetaTox is based on the fragments datasets, which describe transformations of substrates structures to a metabolites structure. We added three new classes of biotransformation reactions: Dehydrogenation, Glutathionation, and Hydrolysis, and now metabolite generation for 15 most frequent classes of xenobiotic's biotransformation reactions are available. MetaTox calculates the probability of formation of generated metabolite - it is the integrated assessment of the biotransformation reactions probabilities and their sites using the algorithm of PASS ( http://way2drug.com/passonline ). The prediction accuracy estimated by the leave-one-out cross-validation (LOO-CV) procedure calculated separately for the probabilities of biotransformation reactions and their sites is about 0.9 on the average for all reactions.

Metabolism and metabolomics of opiates: A long way of forensic implications to unravel.

Opium poppy has important medical, socioeconomic, forensic and political implications. More than 80 benzylisoquinoline alkaloids have been described, many of them with relevant therapeutic properties such as morphine, codeine, papaverine and noscapine. Heroin, a semi-synthetic drug produced from morphine is a worldwide serious cause of morbidity and mortality. Heroin dependence is complex phenomenon with environmental and genetic influence, and several biomarkers of exposure have been proposed. This work aims to review the metabolism and metabolomics of opiates with particular interest on their relevance as potential clinical and forensic antemortem and postmortem biomarkers. It is known that the heroin is mainly a prodrug that is rapidly deacetylated in blood to its active metabolite, 6-acetylmorphine, which is then subsequently slowly deacetylated to morphine. Therefore, 6-acetylmorphine has been used as the main target metabolite to prove heroin abuse in clinical, but mostly in forensic routine. Nevertheless, its applicability is limited due to the reduced detection window. Therefore, morphine (and its metabolites morphine-3-glucuronide and morphine-6-glucuronide), codeine, codeine-6-glucuronide, 6-acetylcodeine, noscapine (and its metabolites meconine, desmethylmeconine, and cotarnine), papaverine (and its metabolites 6-desmethylpapaverine, hydroxypapaverine, dihydroxypapaverine, 6-desmethylpapaverine-glucuronide) and thebaine (and acetylthebaol and the non-acetylated analog thebaol) have been additionally recommended to obtain the most reliable results possible. More recently, the identification by metabolomics analysis of several endogenous compounds offered an alternative approach of significant importance to uncover toxic effects. Profound alterations in the neurotransmitters levels and energy and amino acid metabolism have been reported with l-tryptophan, 5-hydroxytryptamine and 5-hydroxyindoleacetate being suggested as potential non-specific biomarkers of long-term heroin addiction. These endogenous metabolic profiles and exogenous components that together comprise the exposome will certainly help to uncover metabolic disturbances and patterns that may be associate to addiction with relevant clinical and forensic implications.

Postmortem tissue distribution of morphine and its metabolites in a series of heroin-related deaths.

The abuse of heroin (diamorphine) and heroin-related deaths are increasing around the world. The interpretation of the toxicological results from suspected heroin-related deaths is notoriously difficult, especially in cases where there may be limited samples. To help forensic practitioners with heroin interpretation, we determined the concentration of morphine (M), morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas), and vitreous humor in 44 heroin-related deaths. The presence of 6-monoacetylmorphine (6-MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with solid-phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6-MAM (100% of cases), and thus heroin use. The results of the M, M3G, and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in four cases in muscle (three cases in bone marrow) no morphine, M3G, or M6G were detected, even though they were detected in other case samples. As always, postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible.

Visualization of the penetration modifying mechanism of laurocapram by Mass Spectrometry Imaging in buccal drug delivery.

The aim of the study was to visualize the penetration modifying effect of laurocapram on the delivery of diazepam and codeine across buccal mucosa by MALDI Mass Spectrometry Imaging (MALDI-MSI). A qualitative ex vivo study was carried out by mounting porcine buccal mucosa in Ussing chamber sliders and applying a pre-treatment of phosphate buffered saline (PBS) or a 50% (v/v) laurocapram:ethanol solution apically before incubation for 1 or 3 h with a 0.1 M diazepam or 0.1 M codeine solution. MALDI-MSI analysis was performed on vertical cryo-sections of porcine buccal mucosa. The analysis provided detailed images of the localisation of the drugs, laurocapram and endogenous lipids in the epithelium and connective tissue. While diazepam in the absence of laurocapram was distributed with a steady concentration gradient through the connective tissue, indicating passive diffusion, pre-treatment with laurocapram fundamentally altered the penetration of diazepam through the buccal mucosa. In the presence of laurocapram, the distribution of diazepam was restricted to areas where laurocapram itself was present, in particular in the outer epithelial cell layers and in certain islands in the connective tissue. In contrast, the penetration of codeine was unaffected by the presence of laurocapram in similar experiments. The co-localization of laurocapram and diazepam indicates a reservoir effect, which has previously been found in diffusion experiments in Ussing chambers. The major difference in the penetration of codeine and diazepam through the buccal mucosa in presence of laurocapram was explained by the physicochemical properties of the drugs. Codeine is characterized by being more hydrophilic than diazepam and was partly charged under the given experimental conditions.

The Use of Codeine and Tramadol in the Pediatric Population-What is the Verdict Now?

Codeine and tramadol are opioid analgesics approved for the management of pain in the United States. Both agents are metabolized in the liver to active compounds via the cytochrome P450 2D6 enzyme. Case reports of pediatric patients with overactive CYP2D6 enzymes have been reported. These ultra-rapid metabolizers experience an increase in the production of active metabolites of codeine and tramadol, which can lead to oversedation, respiratory depression, and death. In 2017, the U.S. Food and Drug Administration updated their warnings regarding codeine and tramadol use in the pediatric population, making their use contraindicated in patients under the age of 12 years.

Preparation, Characterization and Pharmacokinetics Evaluation of the Compound Capsules of Ibuprofen Enteric-Coated Sustained-Release Pellets and Codeine Phosphate Immediate-Release Pellets.

The objective of this study was to prepare ibuprofen enteric-coated sustained-release pellets (IB-SRPs) and codeine phosphate immediate-release pellets (CP-IRPs) to play a synergistic role in analgesia. The pellets were developed by extrusion-spheronization and fluidized bed coating technology. The single-factor investigation was used to determine the optimal prescription and process. The sustained-release membrane of IB-SRPs was water-insoluble ethyl cellulose (EC), triethyl citrate (TEC) was used as plasticizer, and hydroxypropyl methylcellulose (HPMCP) was chose as porogen. Besides, the immediate-release layer of CP-IRPs was gastric-soluble coating film. The ibuprofen and codeine phosphate compound capsules (IB-CP SRCs) were prepared by IB-SRPs and CP-IRPs packed together in capsules with the optimum doses of 200 and 13 mg, respectively. The prepared pellets were evaluated by scanning electron microscopy and dissolution test. Pharmacokinetic studies in beagle dogs indicated that the optimized IB-CP SRCs had smaller individual differences and better reproducibility comparing with commercial available tablets. Additionally, IB-CP SRCs achieved consistency with in vivo and in vitro tests. Therefore, IB-CP SRCs could play a great role in rapid and long-term analgesic.

Interaction between CYP2D6 inhibitor antidepressants and codeine: is this relevant?

INTRODUCTION: Co-occurring pain impairs depression's prognosis. Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) are first-line pharmacotherapies for depression and inhibit many cytochrome 2D6 enzymes. Codeine is a first-line treatment for pain and needs to be metabolized into morphine by cytochrome 2D6 to exert its analgesic effect. Concomitant prescription of both pharmacotherapies leads to inadequate analgesia. Areas covered: We performed a systematic review of the literature to amalgamate the current knowledge regarding the clinical effect of this association and quantified its prevalence in clinical practice in the French Pays de la Loire area using a retrospective observational cohort study design. Expert opinion: The literature review highlighted that antidepressants with moderate-to-strong inhibition of CYP2D6 should be avoided in patients receiving codeine. However, 0.44% of the 12,296 sampled patients received concomitant codeine and CYP2D6 inhibitor between January 2015 and June 2015. Switching drugs in both painful and depressive patients depends on the pain and depression subtypes. Promising drugs that both show an effect on pain and depression are currently being studied but are not usable in clinical practice. Until then, tailored communication reinforcement toward health-care professionals is needed to prevent these problematic occurrences of concomitant prescription administration.

In vitro metabolism of desomorphine.

Desomorphine is reported to be the principal pharmacologically active opioid in Krokodil, a homemade injectable drug that is perceived to be a cheaper alternative to heroin. There have been limited studies regarding its pharmacology or detection in biological matrices. The goal of this study was to contribute further knowledge regarding its metabolism. Recombinant human cytochrome P450 enzymes (rCYPs) and recombinant uridine 5'-diphospho-glucuronosyltransferases (rUGTs) were used to investigate the biotransformational pathways involved. Samples were analyzed by liquid chromatography/quadrupole-time of flight-mass spectrometry (LC-Q/TOF-MS). Seven rCYP (rCYP2B6, rCYP2C8, rCYP2C9, rCYP2C18, rCYP2C19, rCYP2D6 and rCYP3A4) enzymes were found to contribute to desomorphine metabolism and eight phase I metabolites were identified, including nordesomorphine, desomorphine-N-oxide, norhydroxydesomorphine, and five hydroxylated species. Inhibition assays were used to confirm individual rCYP isoenzyme activity. Nine rUGTs (rUGT1A1, rUGT1A3, rUGT1A8, rUGT1A9, rUGT1A10, rUGT2B4, rUGT2B7, rUGT2B15, and rUGT2B17) were found to contribute to the formation of desomorphine-glucuronide.

The Pharmacokinetics of Morphine and Codeine in Human Plasma and Urine after Oral Administration of Qiangli Pipa Syrup.

Papaveris pericarpium, a natural source of morphine and codeine, is the principal active component in many antitussive traditional Chinese medicines. We herein report the first PK study of papaveris pericarpium in human plasma and urine following oral administration of single (15, 30, 60 mL) and multiple dose (15 mL) of Qiangli Pipa Syrup (MOR 0.1 mg/mL, COD 0.028 mg/mL) by monitoring morphine and codeine using a HPLC-MS/MS method. Their Tmax and t1/2 values are independent of dosages, while the AUC0-t linearly increased with higher dosages, indicating linear PK characteristics. AUC0-t increased obviously after multiple doses, indicating possible risk of accumulative toxicity. Urine studies suggested risks of positive opiate drug tests with a cutoff of 300 ng/mL, which lasted 6-14 h at different doses. These results provide important information for clinical safety, efficacy and rational drug use of Qiangli Pipa Syrup and also guide the related judicial expertise of its administration.

CYP2D6 drug-gene and drug-drug-gene interactions among patients prescribed pharmacogenetically actionable opioids.

PURPOSE: When codeine and tramadol are used for pain management, it is imperative that nurses are able to assess for potential drug-gene and drug-drug-gene interactions that could adversely impact drug metabolism and ultimately pain relief. Both drugs are metabolized through the CYP2D6 metabolic pathway which can be affected by medications as well the patient's own pharmacogenotype. The purpose of this brief report is to identify drug-gene and drug-drug-gene interactions in 30 adult patients prescribed codeine or tramadol for pain. METHODS: We used three data sources: (1) six months of electronic health record data on the number and types of medications prescribed to each patient; (2) each patient's CYP2D6 pharmacogenotype, and (3) published data on known CYP2D6 gene-drug and drug-drug-gene interactions. RESULTS: Ten patients (33%) had possible drug-gene or drug-drug-gene interactions. Five patients had CYP2D6 drug-gene interactions indicating they were not good candidates for codeine or tramadol. In addition, five patients had potential CYP2D6 drug-drug-gene interactions with either codeine or tramadol. CONCLUSION: Our findings from this exploratory study underscores the importance of assessing and accounting for drug-gene and drug-drug-gene interactions in patients prescribed codeine or tramadol.

Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response.

Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Nicotine induction of rat brain CYP2D increases acute codeine conversion to morphine, and analgesia, however the role of brain CYP2D on the effects of repeated codeine exposure and tolerance is unknown. Rats were pretreated with nicotine (brain CYP2D inducer; 1mg/kg subcutaneously) or vehicle (saline; 1ml/kg subcutaneously). Codeine (40-60mg/kg oral-gavage) or morphine (20-30mg/kg oral-gavage) was administered daily and analgesia was assessed daily using the tail-flick reflex assay. Nicotine (versus saline) pretreatment increased acute codeine analgesia (1.32-fold change in AUC0-60min; p<0.05) and the rate of loss of peak analgesia (11.42%/day versus 4.20%; p<0.006) across the first four days of codeine administration (time to negligible analgesia). Inducing brain CYP2D with nicotine did not alter acute morphine analgesia (1.03-fold; p>0.8), or the rate of morphine tolerance (8.1%/day versus 7.6%; p>0.9). The rate of both codeine and morphine tolerance (loss in peak analgesia from day 1 to day 4) correlated with initial analgesic response on day 1 (R=0.97, p<001). Increasing brain CYP2D altered initial analgesia and subsequent rate of tolerance. Variation in an individual's initial response to analgesic (e.g. high initial dose, smoking) may affect the rate of tolerance, and thereby the risk for dose escalation and/or opioid dependence.

Desomorphine (Krokodil): An overview of its chemistry, pharmacology, metabolism, toxicology and analysis.

BACKGROUND: "Krokodil" or "Crocodile" is an illegal homemade desomorphine drug obtained from chemical reactions of commercial codeine drugs with several other powerful and highly toxic chemical agents increasing its addiction and hallucinogenic effects when compared with other morphine analogues. METHODS: This paper summarizes a complete review about an old drug called desomorphine (Krokodil), presenting its chemistry, pharmacology, metabolism, toxicology and analysis. RESULTS: It is of particular interest and concern because this cheaper injectable semisynthetic opioid drug has been largely used in recent years for recreational purposes in several Eastern European as well as North and South American countries, despite known damage to health that continuous use might induce. These injuries are much stronger and more aggressive than morphine's, infecting and rotting skin and soft tissue to the bone of addicts at the point of injection in less than three years, which, in most cases, evolves to death. On this basis, it is imperative that literature reviews focus on the chemistry, pharmacology, toxicology and analysis of dangerous Krokodil to find strategies for rapid and effective determination to mitigate its adverse effects on addicts and prevent consumption. CONCLUSIONS: It is crucial to know the symptoms and consequences of the use of Krokodil, as well as METHODS: for identification and quantification of desomorphine, contaminants and metabolites, which can help the forensic work of diagnosis and propose actions to control and eradicate this great danger to public health around the world.