Morphine Concentrations Research Articles

Urine andhair drug test results associated with daily consumption ofcodeine-predominant poppy seed food products.

This study examined the urine and hair opiate profiles associated with the daily consumption of presumptive codeine-predominant poppy seed food products. Ten participants consumed one of five food products at breakfast for 10 consecutive days. Baseline urine and hair samples were collected on Day 1. The urine samples were collected 4, 8 and 12 h following poppy seed consumption on Days 1 and 10, and the first morning void urine samples were collected on Days 2-10. A second hair specimen was collected on Day 20 ± 2. Urine drug test results: Three of the food products were associated with opiate-negative urine drug test results at all time points at a 300 ng/mL cut-off. Two of the food products were associated with opiate-positive drug test results at all non-baseline time points at a 300 ng/mL cut-off. Of these, all samples (n = 60) were codeine-positive, and 27 (45%) were morphine-positive. Codeine concentrations exceeded morphine concentrations in every sample and always by multiples. Thirty-nine of the 60 samples (65%) were codeine-positive at a 2,000 ng/mL cut-off, while none of these samples were morphine-positive at this cut-off. None of the 60 samples reached an opiate threshold of 15,000 ng/mL, although one participant produced a maximum codeine concentration of 13,161 ng/mL (13,854 ng/mg creatinine). There was no clear trend toward increasing urinary opiate concentrations over the course of the study. Hair drug test results: The hair samples of two participants produced quantifiable codeine (41 pg/mg and 51 pg/mg), but no sample reached a common reporting threshold of 200 pg/mg for codeine or morphine.

A descriptive coronial study of heroin toxicity deaths in Australia, 2020-2022: Characteristics, toxicology and survival times.

Mortality rates among people who use heroin are estimated to be 15 times that of the general population. The study aimed to determine (1) the case characteristics and circumstances of death of heroin-related toxicity deaths in Australia, 2020-2022; (2) their toxicological profile and major autopsy findings; (3) the proportion of cases in which blood 6-acetyl morphine (6AM) was detected, as a proxy measure of survival times; and (4) compare 6AM positive and negative cases on toxicology, circumstances of death and acute clinical presentation. Retrospective study of heroin toxicity deaths in Australia, 2020-2022, retrieved from the National Coronial Information System. This study was conducted Australia-wide. There were 610 cases of fatal heroin-related drug toxicity. Information was collected on characteristics, manner of death, toxicology and autopsy results. The mean age was 42.6 years (range 18-73 years), 80.5% were male and 7.5% were enrolled in a drug treatment programme. The circumstances of death were as follows: unintentional drug toxicity (86.2%), combined unintentional drug toxicity/disease (11.3%) and intentional drug toxicity (2.5%). The median free morphine concentration was 0.17 mg/L (range 0.00-4.20 mg/L). Psychoactive drugs other than heroin were present in 95.2% (Confidence Interval 93.1%-96.8%), most commonly hypnosedatives (62.3%, 58.2%-66.4%) and psychostimulants (44.8%, 40.7%-49.1%). Major autopsy findings of clinical significance included acute bronchopneumonia (14.8%, 11.3%-18.8%), emphysema (16.9%, 13.2%-21.1%), cardiomegaly (30.1%, 12.7%-28.2%), coronary artery disease (27.4%, 23.0%-32.3%), coronary replacement fibrosis (13.4%, 10.1%-17.3%), hepatic cirrhosis (8.8%, 6.6%-12.2%) and renal fibrosis (10.3%, 7.3%-14.0%). In 47.0% (42.3%-51.2%), 6AM was present in blood. The 'typical' heroin overdose case in Australia from 2020 to 2022 was a male who injected heroin, aged in the 40s, not enrolled in a treatment programme and had used multiple drugs. In over half of cases, there had been a sufficient survival time for 6-acetyl morphine to have been metabolised, which may indicate times in excess of 20-30 min.

Distribution of morphine and methadone to the brain in a developmental chicken embryo model

The use and/or misuse of opioids by pregnant women would expose the fetuses to these drugs during critical stages of development with serious effects for the newborn, like the neonatal abstinence syndrome (NAS). We have revisited an established chicken model for NAS to describe the distribution of morphine and methadone to the brain and explore its validity as a valuable alternative to rodent models. For this purpose, chicken eggs were injected with a single dose of 10 mg/kg or 20 mg/kg morphine or 20 mg/kg methadone onto the chorioallantoic membrane (CAM) on embryonal day 13. Whole brains and lungs were harvested and the concentrations of morphine, methadone and their subsequent metabolites (morphine-3-glucuronide and EDDP, respectively) determined in the brain and lungs at different time points using LC-MS/MS. Morphine and methadone, as well as their metabolites, were detected both in the brain and lungs, with significantly higher concentrations in the lungs. Pharmacokinetic modelling showed that the distribution of morphine to the brain followed a first-order absorption with transit compartments and linear elimination, with concentrations linearly dependent on dose. Moreover, methadone, but not morphine, reduced μ receptor (the main morphine receptor) binding, which can be of relevance for opioid tolerance. The present study is the first to report the brain distribution of morphine, which can be described by standard pharmacokinetic processes, and methadone in the developing chicken embryo. The present findings supplement the already established model and support the use of this chicken model to study NAS.

The effect of morphine on rat microglial phagocytic activity: An in vitro study of brain region-, plating density-, sex-, morphine concentration-, and receptor-dependency

Opioids have long been used for clinical pain management, but also have addictive properties that have contributed to the ongoing opioid epidemic. While opioid activation of opioid receptors is well known to contribute to reward and reinforcement, data now also suggest that opioid activation of immune signaling via toll-like receptor 4 (TLR4) may also play a role in addiction-like processes. TLR4 expression is enriched in immune cells, and in the nervous system is primarily expressed in microglia. Microglial phagocytosis is important for developmental, homeostatic, and pathological processes. To examine how morphine impacts microglial phagocytosis, we isolated microglia from adult male and female rat cortex and striatum and plated them in vitro at 10,000 (10K) or 50,000 cells/well densities. Microglia were incubated with neutral fluorescent microbeads to stimulate phagocytosis in the presence of one of four morphine concentrations. We found that the brain region from which microglia are isolated and plating density, but not morphine concentration, impacts cell survival in vitro. We found that 10−12 M morphine, but not higher concentrations, increases phagocytosis in striatal microglia in vitro independent of sex and plating density, while 10−12 M morphine increased phagocytosis in cortical microglia in vitro independent of sex, but contingent on a plating density. Finally, we demonstrate that the effect of 10−12 M morphine in striatal microglia plated at 10 K density is mediated via TLR4, and not μORs. Overall, our data suggest that in rats, a morphine-TLR4 signaling pathway increases phagocytic activity in microglia independent of sex. This may is useful information for better understanding the possible neural outcomes associated with morphine exposures.

Pharmacogenetics and Personalized Medicines

Personalized or precision medicine has been used to describe the right drug to the right person at the right dose at the right time. One important aspect of personalized medicines is the genetic makeup of the individual. Pharmacogenetics investigates the role of individual genes in drug disposition. The use of pharmacogenetics will increase drug efficacy with minimum side effects. Several tables have been published by the FDA that list the pharmacogenetic associations with certain drugs. These tables suggest that certain subgroups of patients with certain genetic variants are likely to have “altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events” (https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations#about).These tables include: Section 1: Pharmacogenetic associations for which the data support therapeutic management recommendations such as celecoxib and CYP2C9 polymorphisms. Section 2: Pharmacogenetic associations for which the data indicate a potential impact on safety or response such as codeine in CYP2D6 poor metabolizers will result in a lower concentration of the active form morphine. Section 3: Pharmacogenetic associations for which the data demonstrate a potential impact on pharmacokinetic properties only. In this list, the implications of the genotypes have not been well established for example atorvastatin and SLCO1B1 phenotypes may result in a higher systemic concentration of the drug. In the US pharmacogenetic tests are available as direct-to-consumer (DTC) tests. With DTC tests, individuals can send in a saliva sample and get results directly at their homes (Drelles et al 2021). Although the evidence on the effects of such tests and pharmacogenetic counseling is available and mounting in many clinical practices all around the world but is still to be implemented in the clinical practice in Jordan.

Functionalization of metal-organic frameworks with metallic nanoclusters for ultra-sensitive monitoring of morphine in biological fluids

A reliable, fast, and cost-effective method of monitoring morphine (MO) concentration in biological fluids is highly desired in clinical and modern medicine. Nanotechnology has opened up new possibilities for developing morphine biosensors, but the most advanced electrodes available offer a detection limit (LOD) of ≥10 nM. This work introduces a new, ultrasensitive electrochemical biosensor based on microporous metal-organic frameworks (∼1100 cm2 g−1 surface area) modified by Ag clusters (∼2 nm) and functionalized by Au nanoparticles (∼180 nm). Electrochemical studies show that functionalizing the microporous crystalline particles (620 ± 45 nm) with metal nanoclusters enhances charge transfer kinetics and electrochemical surface area by about 50 and 10 folds, respectively, resulting in high sensitivity (0.127 µA µM−1), broad linear dynamic range (0.05–600 µM), and low LOD (3 ± 0.2 nM). The differential pulse voltammetry confirms the stability (over 6 weeks), repeatability (RSD=3.0%), and reproducibility (RSD=4.0%) of the hybrid biosensor. The decent selectivity and specificity (RSD=7.4%) of the biosensor against various analogs co-existing with MO in urine have also been determined. Therefore, the hybrid metal-inorganic biosensor presents a promising prospect for simple, low-cost, and precise monitoring of biomolecules, including morphine, in biological fluids and clinical medicine.

Morphine pharmacokinetics and opioid transporter expression at the blood-retina barrier of male and female mice.

Opioids are effective analgesics for treating moderate to severe pain, however, their use must be weighed against their dangerous side effects. Investigations into opioid pharmacokinetics provide crucial information regarding both on- and off-target drug effects. Our recent work showed that morphine deposits and accumulates in the mouse retina at higher concentrations than in the brain upon chronic systemic exposure. We also found reduced retinal expression of P-glycoprotein (P-gp), a major opioid extruder at the blood-brain barrier (BBB). Here, we systematically interrogated the expression of three putative opioid transporters at the blood-retina barrier (BRB): P-gp, breast cancer resistance protein (Bcrp) and multidrug resistance protein 2 (Mrp2). Using immunohistochemistry, we found robust expression of P-gp and Bcrp, but not Mrp2, at the inner BRB of the mouse retina. Previous studies have suggested that P-gp expression may be regulated by sex hormones. However, upon acute morphine treatment we found no sex differences in morphine deposition levels in the retina or brain, nor on transporter expression in the retinas of males and females with a high or low estrogen:progesterone ratio. Importantly, we found that P-gp, but not Bcrp, expression significantly correlated with morphine concentration in the retina, suggesting P-gp is the predominant opioid transporter at the BRB. In addition, fluorescence extravasation studies revealed that chronic morphine treatment did not alter the permeability of either the BBB or BRB. Together, these data suggest that reduced P-gp expression mediates retinal morphine accumulation upon systemic delivery, and in turn, potential effects on circadian photoentrainment.

Oxycodone, Morphine, and Fentanyl in Patients With Chronic Pain: Proposal of Dose-Specific Concentration Ranges.

Interpreting opioid concentrations is challenging because of the lack of reference ranges. Therefore, the authors aimed to propose dose-specific concentration ranges in serum for oxycodone, morphine, and fentanyl in patients with chronic pain, based on concentration measurements from a large number of patients and supported by theoretical pharmacokinetic calculations and previously published concentrations. The opioid concentrations in patients undergoing therapeutic drug monitoring (TDM) for various indications (TDM group) and patients with cancer (cancer group) were investigated. Patients were divided based on the daily opioid doses, and the 10th and 90th percentiles of the concentrations in each dose interval were evaluated. In addition, the expected average serum concentrations were calculated for each dose interval based on published pharmacokinetic data, and a targeted literature search for previously reported dose-specific concentrations was performed. The opioid concentrations in 1054 patient samples were included: 1004 in the TDM group and 50 in the cancer group. In total, 607 oxycodone, 246 morphine, and 248 fentanyl samples were evaluated. The authors proposed dose-specific concentration ranges based mainly on 10th-90th percentiles of the concentrations measured in patient samples, whereas the calculated average concentrations and previously published concentrations were used to adjust the ranges. In general, results from calculations and concentrations retrieved from previous literature were within the 10th-90th percentiles of concentrations from patient samples. However, the lowest calculated average concentrations of fentanyl and morphine were below the 10th percentiles of patient samples in all dose groups. The proposed dose-specific ranges may be useful for interpreting steady-state opioid serum concentrations in clinical and forensic settings.

Does nonlinear blood-brain barrier transport matter for (lower) morphine dosing strategies?

Morphine blood-brain barrier (BBB) transport is governed by passive diffusion, active efflux and saturable active influx. This may result in nonlinear plasma concentration-dependent brain extracellular fluid (brainECF) pharmacokinetics of morphine. In this study, we aim to evaluate the impact of nonlinear BBB transport on brainECF pharmacokinetics of morphine and its metabolites for different dosing strategies using a physiologically based pharmacokinetic simulation study. We extended the human physiologically based pharmacokinetic LeiCNS-PK3.0, model with equations for nonlinear BBB transport of morphine. Simulations for brainECF pharmacokinetics were performed for various dosing strategies: intravenous (IV), oral immediate (IR) and extended release (ER) with dose range of 0.25–150 mg and dosing frequencies of 1–6 times daily. The impact of nonlinear BBB transport on morphine CNS pharmacokinetics was evaluated by quantifying (i) the relative brainECF to plasma exposure (AUCu,brainECF/AUCu,plasma) and (ii) the impact on the peak-to-trough ratio (PTR) of concentration-time profiles in brainECF and plasma. We found that the relative morphine exposure and PTRs are dose dependent for the evaluated dose range. The highest relative morphine exposure value of 1.4 was found for once daily 0.25 mg ER and lowest of 0.1 for 6-daily 150 mg IV dosing. At lower doses the PTRs were smaller and increased with increasing dose and stabilized at higher doses independent of dosing frequency. Relative peak concentrations of morphine in relation to its metabolites changed with increasing dose. We conclude that nonlinearity of morphine BBB transport affects the relative brainECF exposure and the fluctuation of morphine and its metabolites mainly at lower dosing regimens.

Hypothermia versus normothermia after out-of-hospital cardiac arrest; the effect on post-intervention serum concentrations of sedatives and analgesics and time to awakening

BackgroundThis study investigated the association of two levels of targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) with administered doses of sedative and analgesic drugs, serum concentrations, and the effect on time to awakening. MethodsThis substudy of the TTM2-trial was conducted at three centers in Sweden, with patients randomized to either hypothermia or normothermia. Deep sedation was mandatory during the 40-hour intervention. Blood samples were collected at the end of TTM and end of protocolized fever prevention (72 hours). Samples were analysed for concentrations of propofol, midazolam, clonidine, dexmedetomidine, morphine, oxycodone, ketamine and esketamine. Cumulative doses of administered sedative and analgesic drugs were recorded. ResultsSeventy-one patients were alive at 40 hours and had received the TTM-intervention according to protocol. 33 patients were treated at hypothermia and 38 at normothermia. There were no differences between cumulative doses and concentration and of sedatives/analgesics between the intervention groups at any timepoint. Time until awakening was 53 hours in the hypothermia group compared to 46 hours in the normothermia group (p = 0.09). ConclusionThis study of OHCA patients treated at normothermia versus hypothermia found no significant differences in dosing or concentration of sedatives or analgesic drugs in blood samples drawn at the end of the TTM intervention, or at end of protocolized fever prevention, nor the time to awakening.

Estimation of the consumption level of four drugs in Beijing using wastewater-based epidemiology

Objective: To estimate the consumption level of four drugs in Beijing using wastewater-based epidemiology (WBE). Methods: The primary sludge from one large wastewater treatment plants (WWTPs) was collected in Beijing from July 2020 to February 2021. The concentrations of codeine, methadone, ketamine and morphine in the sludge were detected through solid-phase extraction-liquid chromatography-tandem mass spectrometry. The consumption, prevalence and number of users of four drugs were estimated by using the WBE approach. Results: Among 416 sludge samples, codeine had the highest detection rate (82.93%, n=345) with a concentration [M (Q1, Q3)] of 0.40 (0.22-0.8) ng·g-1, and morphine had the lowest detection rate (28.37%,n=118) with a concentration [M (Q1, Q3)] of 0.13 (0.09, 0.17) ng·g-1. There was no significant difference in the consumption of the four drugs on working days and weekends (all P values>0.05). Drug consumption was significantly higher in winter than that in summer and autumn (all P values <0.05). The consumption [M (Q1, Q3)] of codeine, methadone, ketamine and morphine in winter was 24.9 (15.58, 38.6), 9.39 (4.57, 26.72), 9.84 (5.18, 19.45) and 5.67 (3.57, 13.77) μg·inhabitant-1·day-1, respectively. For these drugs, there was an upward trend in the average drug consumption during summer, autumn and winter (the Z values of the trend test were 3.23, 3.16, 2.19, and 3.32, respectively and all P values<0.05). The prevalence [M (Q1, Q3)] of codeine, methadone, ketamine and morphine were 0.0056% (0.003 4%, 0.009 2%), 0.0148% (0.009 6%, 0.026 7%),0.0333% (0.0210%, 0.0710%) and 0.0072% (0.003 8%, 0.011 7%), respectively. The estimated number of drug users [M (Q1, Q3)] was 918 (549, 1 511), 2 429 (1 578, 4 383), 5 451 (3 444, 11 642) and 1 173 (626, 1 925),respectively. Conclusion: Codeine, methadone, ketamine and morphine have been detected in the sludge of WWTPs in Beijing, and the consumption level of these drugs varies in different seasons.

Optimization and analytical behavior of a morphine electrochemical sensor in environmental and biological samples based on graphite rod electrode using graphene/Co3O4 nanocomposite

In this research, a new sensor based on graphene/Co3O4 (Gr/Co3O4) nanocomposite was employed for electrochemically determination of morphine (MOR). The modifier was synthesized with a simple hydrothermal technique and well characterized using X-ray difraction (XRD), scanning electron microscope (SEM) and energy dispersive X-ray spectroscopy (EDS) tools. The modified graphite rod electrode (GRE) was revealed a high electrochemical catalytic activity for the MOR oxidation and employed for the electroanalysis of trace MOR concentration by means of differential pulse voltammetry (DPV) technique. At the optimum experimental factors, the resulting sensor offered a good response for MOR in the concentration range of 0.5–100.0 μM with a detection limit of 80 nM. In addition, the modified electrode demonstrated an acceptable selectivity, stability and reproducibility. This assay was also provided a valid platform for the detection of MOR in environmental and biological samples with acceptable recoveries and RSD in the range of 97.2–102.8% and 1.7–3.4%, respectively. Taking to the simplicity, low cost and short analysis time, this approach is suggested for clinical, environmental and forensic testing of MOR.

Concentrations, pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites following oral administration to horses.

The metabolism and pharmacokinetics of intravenous (i.v.) morphine in the horse have been described; however, administration of therapeutic doses has also been associated with neuroexcitation and adverse gastrointestinal effects. In this study, we hypothesized that oral administration would lead to comparable concentrations of morphine and its presumed active metabolite, morphine 6-glucuronide (M6G) without the adverse effects associated with i.v. administration. Eight horses were administered a single i.v. dose of 0.2mg/kg morphine and oral doses of 0.2, 0.6, and 0.8mg/kg of morphine in a four-way balanced crossover design, with a 2-week washout period between doses. Concentrations of morphine and metabolites were determined, and pharmacokinetic parameters determined. Physiologic and behavioral outcomes including the number of steps taken, changes in heart rate, and gastrointestinal borborygmi were assessed. Oral administration of morphine resulted in higher concentrations of morphine metabolites, including M6G (Cmax : 11.6-37.8ng/mL (0.6mg/kg); 15.8-42.6ng/mL (0.8mg/kg)), compared with i.v. Bioavailability was 36.5%, 27.6% and 28.0% for 0.2, 0.6 and 0.8mg/kg, respectively. Behavioral and physiologic changes were noted in all groups but were less prominent with oral compared with i.v. administration. Results of the current study are encouraging for further study, specifically anti-nociceptive effects of morphine following oral administration.

Heroin-Related Fatalities in Jeddah, Saudi Arabia, between 2008 and 2018

To date, epidemiological studies have not evaluated heroin-related deaths in the Middle East and North African regions, especially Saudi Arabia. All heroin-related postmortem cases reported at the Jeddah Poison Control Center (JPCC) over a 10-year period (21 January 2008 to 31 July 2018) were reviewed. In addition, liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) was utilized to determine the 6-monoacetylmorphine (6-MAM), 6-acetylcodeine (6-AC), morphine (MOR), and codeine contents in unhydrolyzed postmortem specimens. Ninety-seven heroin-related deaths were assessed in this study, and they represented 2% of the total postmortem cases at the JPCC (median age, 38; 98% male). In the blood, urine, vitreous humor, and bile samples, the median morphine concentrations were 280 ng/mL, 1400 ng/mL, 90 ng/mL, and 2200 ng/mL, respectively; 6-MAM was detected in 60%, 100%, 99%, and 59% of the samples, respectively; and 6-AC was detected in 24%, 68%, 50%, and 30% of the samples, respectively. The highest number of deaths (33% of total cases) was observed in the 21-30 age group. In addition, 61% of cases were classified as "rapid deaths," while 24% were classified as "delayed deaths." The majority (76%) of deaths were accidental; 7% were from suicide; 5% were from homicide; and 11% were undetermined. This is the first epidemiological study to investigate heroin-related fatalities in Saudi Arabia and the Middle East and North African region. The rate of heroin-related deaths in Jeddah remained stable but increased slightly at the end of the study period. Most patients were heroin-dependent abusers and from the middle-aged group. The availability of urine, vitreous humor, and bile specimens provided valuable information regarding the opioids that were administered and the survival time following heroin injection.

Modeling the effects of drugs of abuse on within-host dynamics of two HIV species

Injection drug use is one of the most significant risk factors associated with contracting human immunodeficiency virus (HIV), and drug users infected with HIV suffer from a higher viral load and rapid disease progression. While replication of HIV may result in many mutant viruses that can escape recognition of the host’s immune response, the presence of morphine (a drug of abuse) can decrease the viral mutation rate and cellular immune responses. This study develops a mathematical model to explore the effects of morphine-altered mutation and cellular immune response on the within-host dynamics of two HIV species, a wild-type and a mutant. Our model predicts that the morphine-altered mutation rate and cellular immune response allow the wild-type virus to outcompete the mutant virus, resulting in a higher set point viral load and lower CD4 count. We also compute the basic reproduction numbers and show that the dominant species is determined by morphine concentration, with the mutant dominating below and the wild-type dominating above a threshold. Furthermore, we identified three biologically relevant equilibria, infection-free, mutant-only, and coexistence, which are completely characterized by the fitness cost of mutation, mutant escape rate, and morphine concentration.

Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide after a single intravenous and intramuscular administration in the cow.

Introduction: This study aimed to determine morphine pharmacokinetics and morphine-6-glucuronide production quantification following intravenous (IV) and intramuscular (IM) administration in cattle.

Preparation and characterization of morphine gelatine microspheres

ABSTRACTMorphine is a widely used opioid analgesic. However, standard morphine dosages and administration methods exhibit a short half-life and pose a risk of respiratory depression. Sustained-release microspheres can deliver prolonged efficacy and reduce side effects. We present a new controlled-release morphine gelatine microsphere (MGM) prepared using an emulsification-crosslinking strategy. The gelatine microsphere design improves the bioavailability of morphine. And it not only increases the clinical analgesic efficacy but also the safety of clinical medication through a gradual, sustained release. Besides, we describe MGMs’ preparation, release, pharmacodynamics, and pharmacokinetics. And the drug metabolism pathway. We calculate the release rate of morphine by measuring plasma morphine concentration over time and pharmacokinetic parameters. It optimized the manufacturing process of MGMs, which makes the analgesic effect have a longer duration. MGMs analgesic effect shows dose dependence. After they were administrated, MGMs were released more slowly. Peak concentration was reduced, and the relative bioavailability improved. It even reached 88.84%. Its pharmacokinetic process was consistent with the two-component first-order absorption model. MGMs deliver sustained-release and long-action pharmacokinetics. It shows design goals of improving drug bioavailability, prolonging drug residence time in vivo, and maintaining stable blood drug concentration.

Pulsed ultrasound-assisted extraction followed by purification with SBA-15 for the control of opium alkaloids in biscuits and sponge cakes

Food products containing poppy seeds are increasingly consumed. These seeds may be contaminated with opium alkaloids (OAs) from the latex of the plant (Papaver somniferum L.), which may present a health hazard to the consumer. Therefore, the aim of this work was to develop an efficient, fast and environmentally friendly methodology to control OAs in biscuits and sponge cake products by analysis with liquid chromatography coupled to a triple quadrupole tandem mass detector (HPLC-MS/MS). For this purpose, the ultrasound-assisted extraction (UAE) step was optimised using a 5-variable full factorial design at two levels, obtaining lower solvent volume and time than with other classical methods. Then, a solid phase extraction (SPE) was used to remove matrix effects. A commercial material (HLB) and two silica synthesised materials (HMS and SBA-15) were evaluated and optimised, selecting SBA-15 (50 mg). Finally, the method was validated and applied to real samples, showing morphine concentrations in 5 of 7 products but below the maximum permitted limit.

An Unusual Case of High 6-Monoacetylmorphine and Low Morphine in Urine: Heroin Abuse or Analytical Error?

A 59-year-old male with a past medical history of chronic low back pain, opioid use disorder, and type 2 diabetes mellitus presented to an outpatient clinic for pain contract–related urine drug screen testing. Current medications included metformin, oxycodone, and Suboxone® (buprenorphine and naloxone combination). The patient stated that 5 days prior to the visit, he stopped taking Suboxone due to complaints of nausea and vomiting. Urine toxicology test results are summarized in Table 1. ... ... Suboxone is an opioid abuse management medication that is formulated with buprenorphine and naloxone. Naloxone has limited bioavailability when administered sublingually and should be barely detectable in urine. However, when Suboxone is taken parenterally, naloxone enters the blood stream and is largely excreted in urine. In this case, the presence of a high concentration of naloxone in urine with a high ratio to buprenorphine suggested parenteral administration (1). Heroin is readily metabolized into 6-MAM and then to morphine. Typically, the 6-MAM-to-morphine ratio is <0.26, so it is uncommon to see a high positive 6-MAM with very low morphine concentrations (2). The calculated 6-MAM-to-morphine ratio in this sample was 7.27. Conversion from morphine to 6-MAM due to contaminants in enzyme hydrolysis or acid hydrolysis used during sample preparation in urine samples with extremely high morphine (>100 000 μg/L) has been reported (3). In our case, morphine was very low, so this was unlikely, but to rule out any analytical cause, the positive urine sample was sent to a reference laboratory, which confirmed our findings. The fact that 2 laboratories using different mass spectrometry–based methods showed detectable 6-MAM supported heroin use, instead of a false positive due to an interference. The unusually low morphine result in some heroin users has been reported elsewhere and may be mostly attributed to inhibitors of carboxylesterases from the heroin synthesis process (2) or explained by polymorphism in the esterase enzymes metabolizing 6-MAM to morphine (4). The physician also requested serum fentanyl testing by mass spectrometry 5 days after the original urine sample collection (fentanyl was not part of our general urine drug screen), which came back positive for fentanyl and norfentanyl. In addition to the unexpected positive amphetamine result, all of this confirmed that this patient suffered from polysubstance abuse.

Investigation of the Extraction of Natural Alkaloids in Karr Reciprocating Plate Columns: Mass Transfer Study

ABSTRACT Solvent extraction plays a vital role in manufacturing high purity alkaloids from natural poppies. Cyanex® 923, which has been widely used in hydrometallurgical processes, is shown to be an effective extractant for natural alkaloid extraction. In this work, 0.2 M Cyanex® 923 in xylene (dispersed phase) was used to investigate the equilibrium isotherm of morphine at pH 9 and morphine extraction in two different reciprocating Karr columns. Two sources of morphine solution (continuous phase), including technical morphine with few impurities and industrial upstream morphine rich extract containing more impurities and other alkaloids, were studied to investigate morphine mass transfer efficiencies in the Karr columns based on different dispersed phase velocities and reciprocating frequencies. The mass transfer coefficients of technical morphine solution were calculated using a backflow model associated with axial dispersion, and the mass transfer coefficients were further used to regress a mass transfer correlation. The regressed correlation was further validated, and the process model was shown to be reliable to predict the extraction efficiency, and outlet morphine concentration of both aqueous phase and organic phase. This work provides insights to scale-up the process design in a short time, bridging the gap between bench scale research and pilot industry scale testing using a simple correlation method.