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Revue Medicale Suisse Feb 2021
Topics: Analgesics, Opioid; Humans; Morphine; Morphine Dependence; Probiotics
PubMed: 33586379
DOI: No ID Found -
Journal of Ethnopharmacology Nov 2022Papaveris 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...
ETHNOPHARMACOLOGICAL RELEVANCE
Papaveris 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 STUDY
Because 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 METHODS
Ultrahigh-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 AUC/AUC and AUC/AUC was used to represent the metabolic biotransformation ratio and the drug from blood-to-tissue transfer ratio, respectively.
RESULTS
The 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 AUC/AUC, AUC/AUC and AUC/AUC 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 (AUC/AUC) 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).
CONCLUSION
Based 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.
Topics: Animals; Codeine; Female; Humans; Morphine; Morphine Derivatives; Papaver; Placenta; Pregnancy; Rats; Tandem Mass Spectrometry
PubMed: 36007718
DOI: 10.1016/j.jep.2022.115623 -
Huan Jing Ke Xue= Huanjing Kexue May 2024It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are...
It is a new approach to identify legal or illegal use of morphine through information on municipal wastewater. However, the sources of morphine in wastewater are complex, and distinguishing the contribution of different sources has become a key issue. A total of 262 influent samples from 61 representative wastewater treatment plants in a typical city were collected from October 2022 to March 2023. The concentrations of morphine, codeine, thebaine, papaverine, noscapine, and monoacetylmorphine were analyzed in wastewater and poppy straws. Combined with the proportion of alkaloids in poppy straws, the source analysis of alkaloids in wastewater was analyzed using the ratio method and positive matrix factorization model (PMF). Only five alkaloids were detected in wastewater, and monoacetylmorphine, a metabolite of heroin, was not detected. The concentrations of morphine and codeine were significantly higher than those of noscapine, papaverine, and thebaine. By constructing the ratios of codeine/(morphine + codeine) and noscapine/(noscapine + codeine), the source of poppy straw could be qualitatively distinguished. The PMF results showed that three sources of morphine for medical use, poppy straw, and codeine contributed 44.9%, 43.7%, and 9.4%, respectively. The different sources varied in these months due to the COVID-19 and influenza A outbreaks, in which the use of drugs containing poppy straws and codeine was the main source, whereas the use of morphine analgesics remained relatively stable. Inventory analysis further demonstrated the reliability of the source contributions from the PMF model, and morphine was not abused in this city.
Topics: Morphine; Wastewater; Papaverine; Thebaine; Noscapine; Reproducibility of Results; Codeine; Morphine Derivatives; Alkaloids; Papaver
PubMed: 38629538
DOI: 10.13227/j.hjkx.202306005 -
Harm Reduction Journal Sep 2023The French Addictovigilance network has observed the existence of the intravenous use of oral morphine capsules among people suffering from opioid use disorders....
BACKGROUND
The French Addictovigilance network has observed the existence of the intravenous use of oral morphine capsules among people suffering from opioid use disorders. According to persons who inject morphine, these capsules are easy to dissolve and then inject, giving them the image of an "injectable" opioid substitution treatment (OST). In France, validated OSTs are only available orally, so dissolving morphine capsules represents the only alternative for patients who are not sufficiently relieved by oral forms. This practice presents risks related to the potential persistence of particles of the oral galenic in the injectable solution, despite its filtration, but also risks-notably of overdose-related to the pharmacological effects of opioids and to variations of the quantities of morphine extracted during the dissolution of the capsules. We conducted an online survey among the people concerned to collect data on their needs and expectations regarding a possible injectable substitution.
METHOD
An anonymous online survey including all voluntary respondents residing in France and using oral morphine intravenously was conducted in partnership with the Psychoactif harm reduction organization, from 23/03/2020 to 01/04/2021.
RESULTS
The analysis of the 157 exploitable questionnaires showed that 41% of the respondents obtained their drugs only from illegal markets. The others received, regularly or occasionally, medical prescriptions, reimbursed in 84% of cases. For 78% of the respondents, injection was the most frequent route of morphine administration, with 3.8 ± 2 injections per day. 56% of the respondents were receiving an OST, on prescription (79%), monthly (86%), in addition to morphine. Skenan® capsules were the most frequently used (81%) and 47.2% of the respondents had already experienced injection-related complications. 95% of the respondents were in favor of experimenting with an injectable morphine substitution. Those who never received medical prescriptions were the youngest (< 25 years) respondents, they reported only occasional use of morphine, and always intravenously.
CONCLUSION
Oral morphine capsules dissolved and injected intravenously are not a safe and sustainable injectable substitution. Respondents wish to be able to benefit from an injectable substitution with a formulation adapted to the intravenous route. The availability of an injectable substitution would facilitate harm reduction and entry into care for the people concerned, particularly the youngest who have never received morphine prescriptions.
Topics: Humans; Analgesics, Opioid; Capsules; Morphine; Drug Overdose; Injections, Intravenous
PubMed: 37700290
DOI: 10.1186/s12954-023-00866-y -
Journal of Opioid Management 2020Opioid therapy in pediatrics may be particularly prone to error, yet the incidence of opioid-related medication error and harm has not yet been described in the... (Review)
Review
BACKGROUND
Opioid therapy in pediatrics may be particularly prone to error, yet the incidence of opioid-related medication error and harm has not yet been described in the pediatric inpatient setting.
METHODS
We reviewed a prospectively compiled medication safety database from November 1, 2012 to October 31, 2017. Reports originated from voluntary reporting, hospital code events, naloxone administrations, and reports of unexpected experiences of patient pain. Time, location, error characteristics, drug, route, prescription, error phase, mechanisms, harm, and outcome were collected for all reports. Error and harm were classified by the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) system.
RESULTS
Over 697 opioid medication safety reports were included during the study period. Opioids were administered at a rate of 79.26 administrations per 100 patient bed days, with morphine and hydromorphone administered at 62 versus 15 administrations per 100 bed days, respectively. Overall error rate was 0.94 errors per 10 patient days. Although the absolute rate of error reporting was greater for morphine (0.65 errors reported per 10 opioid administrations) than for hydromorphone, the adjusted incidence of harm was 0.211 per 10 hydromorphone administrations compared to 0.086 per 10 morphine administrations. 47 opioid errors resulted in harm, and administration errors (29) were almost twice as common as prescribing errors (15).
CONCLUSIONS
We report and aim to establish a comparative reference point for incidence of opioid-related error and harm adjusted for both hospital bed days and total opioid administrations within the pediatric hospital inpatient setting based on the above findings.
Topics: Analgesics, Opioid; Child; Hospitals, Pediatric; Humans; Medication Errors; Morphine; Time
PubMed: 33226094
DOI: 10.5055/jom.2020.0592 -
Journal of Neural Transmission (Vienna,... Aug 2022Opioid abuse during pregnancy may have noteworthy effects on the child's behavioral, emotional and cognitive progression. In this study, we assessed the effect of...
Opioid abuse during pregnancy may have noteworthy effects on the child's behavioral, emotional and cognitive progression. In this study, we assessed the effect of prenatal exposure to morphine on electrophysiological features of locus coeruleus (LC) noradrenergic neurons which is involved in modulating cognitive performance. Pregnant dams were randomly divided into two groups, that is a prenatal saline treated and prenatal morphine-treated group. To this end, on gestational days 11-18, either morphine or saline (twice daily, s.c.) was administered to pregnant dams. Whole-cell patch-clamp recordings were conducted on LC neurons of male offspring. The evoked firing rate, instantaneous frequency and action potentials half-width, and also input resistance of LC neurons significantly increased in the prenatal morphine group compared to the saline group. Moreover, action potentials decay slope, after hyperpolarization amplitude, rheobase current, and first spike latency were diminished in LC neurons following prenatal exposure to morphine. In addition, resting membrane potential, rise slope, and amplitude of action potentials were not changed by prenatal morphine exposure. Together, the current findings show a significant enhancement in excitability of the LC neurons following prenatal morphine exposure, which may affect the release of norepinephrine to other brain regions and/or cognitive performances of the offspring.
Topics: Action Potentials; Child; Female; Humans; Locus Coeruleus; Male; Morphine; Neurons; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 35674919
DOI: 10.1007/s00702-022-02515-3 -
Psychopharmacology Jan 2022The treatment of opiate addiction is an unmet medical need. Repeated exposure to opiates disrupts cognitive performance. Opioid substitution therapy, with, e.g.,...
RATIONALE
The treatment of opiate addiction is an unmet medical need. Repeated exposure to opiates disrupts cognitive performance. Opioid substitution therapy, with, e.g., methadone, may further exacerbate the cognitive deficits. Growing evidence suggests that mitragynine, the primary alkaloid from the Kratom (Mitragyna speciosa) leaves, may serve as a promising alternative therapy for opiate addiction. However, the knowledge of its health consequences is still limited.
OBJECTIVES
We aimed to examine the cognitive effects of mitragynine substitution in morphine-withdrawn rats. Furthermore, we asked whether neuronal addiction markers like the brain-derived neurotrophic factor (BDNF) and Ca/calmodulin-dependent kinase II alpha (αCaMKII) might mediate the observed effects.
METHODS
Male Sprague-Dawley rats were given morphine at escalating doses before treatment was discontinued to induce a spontaneous morphine withdrawal. Then, vehicle or mitragynine (5 mg/kg, 15 mg/kg, or 30 mg/kg) substitution was given for 3 days. A vehicle-treated group was used as a control. Withdrawal signs were scored after 24 h, 48 h, and 72 h, while novel object recognition (NOR) and attentional set-shifting (ASST) were tested during the substitution period.
RESULTS
Discontinuation of morphine significantly induced morphine withdrawal signs and cognitive deficit in the ASST. The substitution with mitragynine was able to alleviate the withdrawal signs. Mitragynine did not affect the recognition memory in the NOR but significantly improved the reversal learning deficit in the morphine-withdrawn rats.
CONCLUSIONS
These data support the idea that mitragynine could be used as safe medication therapy to treat opiate addiction with beneficial effects on cognitive deficits.
Topics: Animals; Cognition; Male; Mitragyna; Morphine; Rats; Rats, Sprague-Dawley; Secologanin Tryptamine Alkaloids
PubMed: 34693456
DOI: 10.1007/s00213-021-05996-4 -
British Journal of Pharmacology Apr 2020Autophagy is a critical cellular catabolic process in cell homoeostasis and brain function. Recent studies indicate that receptor for activated C kinase 1 (RACK1) is...
BACKGROUND AND PURPOSE
Autophagy is a critical cellular catabolic process in cell homoeostasis and brain function. Recent studies indicate that receptor for activated C kinase 1 (RACK1) is involved in autophagosome formation in Drosophila and mice, and that it plays an essential role in morphine-associated memory. However, the exact mechanism of the role of RACK1 in morphine-induced autophagy is not fully understood.
EXPERIMENTAL APPROACH
SH-SY5Y cells were cultured and morphine, rapamycin, 3-methyladenine and RACK1 siRNA were used to evaluate the regulation of RACK1 protein in autophagy. Western blotting and immunofluorescence were used to assess protein expression.
KEY RESULTS
Activation of autophagy (i.e. autophagosome accumulation and an increase in the LC3-II/LC3-I ratio) induced by morphine contributes to the maintenance of conditioned place preference (CPP) memory in mice. Moreover, morphine treatment significantly increased Beclin-1 expression and decreased the p-mTOR/mTOR and SQSTM1/p62 levels, whereas knockdown of RACK1 prevented morphine-induced autophagy in vitro. Furthermore, we found that in the mouse hippocampus, knockdown of RACK1 also markedly suppressed morphine-induced autophagy (decreased LC3-II/LC3-I ratio and increased p-mTOR/mTOR ratio). Importantly, morphine-induced autophagy in a RACK1-dependent manner. Conversely, morphine-induced RACK1 upregulation in vitro is partially inhibited by autophagy feedback.
CONCLUSIONS AND IMPLICATIONS
Our findings revealed a critical role for RACK1-dependent autophagy in morphine-promoted maintenance of CPP memory in mice and supported the notion that control of RACK1-dependent autophagic pathways may become an important target for novel therapeutics for morphine-associated memory.
Topics: Animals; Autophagy; Beclin-1; Cell Line; Mice; Morphine; Neurons; Receptors for Activated C Kinase
PubMed: 31747048
DOI: 10.1111/bph.14922 -
Journal of Analytical Toxicology May 2022Considering that the use of psychoactive substances (PSs) is a risk factor to either higher intensity or frequency of suicidal behavior, hair analysis was conducted to...
Considering that the use of psychoactive substances (PSs) is a risk factor to either higher intensity or frequency of suicidal behavior, hair analysis was conducted to investigate the most consumed PSs (opiates, amphetamine stimulants, marijuana, cocaine and heroin) in patients who attempted suicide and received urgent care at emergency service. Hair samples were extracted using methanol and sonicated under heating and then analyzed using liquid chromatography-tandem mass spectrometry. During validation, the method complied with international recommended criteria, with limits of detection between 0.0025 and 0.05 ng/mg and linearity between 0.1 and 4 ng/mg for methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), morphine, amphetamine, 6-acetylmorphine, 3,4-methylenedioxyamphetamine (MDA), fenproporex, diethylpropion and codeine; between 0.025 and 1 ng/mg for tetrahydrocannabinol (THC), benzoylecgonine and cocaethylene and between 0.25 and 10 ng/mg for cocaine and mazindol. A total of 109 hair samples were analyzed and segmented in 404 parts. Among all analyzed samples, 30.3% were positive for at least one PS (n = 33), such as cocaine (90.9%), codeine (12.1%), morphine (3.0%), MDMA (3.0%) and THC (3.0%). In segmental analysis of cocaine positive samples (n = 30), 76.7% of the samples indicated recent exposure to cocaine (<1 month). This same behavior was observed when analyzing codeine (n = 4) and morphine (n = 1). THC positive samples indicated exposure dated ∼4 months prior. In conclusion, the method was validated following international recommendations for the 12 most consumed PSs in Brazil, as well as two of the most common found metabolites.
Topics: Amphetamines; Chromatography, Liquid; Cocaine; Codeine; Dronabinol; Hair; Humans; Morphine; Morphine Derivatives; N-Methyl-3,4-methylenedioxyamphetamine; Substance Abuse Detection; Suicide, Attempted; Tandem Mass Spectrometry
PubMed: 34050658
DOI: 10.1093/jat/bkab058 -
Cannabis and Cannabinoid Research Jun 2021Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous... (Review)
Review
Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation. In addition to driving cytokine production, morphine drives changes in proinflammatory lipid signaling. The alteration of both cytokine and lipid signaling systems by morphine suggests that its chronic use leads to a pathological immune response that would benefit from targeted therapy. Engaging the endogenous cannabinoid system has shown therapeutic benefit, particularly regarding its anti-inflammatory and immunosuppressive effects. Promising preclinical and clinical investigations suggest that cannabidiol (CBD) is an effective adjuvant for treatment of symptoms of opioid use disorders; however, the mechanism through which CBD drives this outcome is unclear. One potential source of insight into this mechanism is in how CBD regulates immune regulators such as cytokines and lipid signaling systems, including endocannabinoids and related immune-responsive lipids. In this review, we outline the immune response to chronic opioid use as well as CBD in the context of a lipopolysaccharide-induced immune response and speculate on the mechanism of CBD as a modulator of chronic opioid-induced immune system dysregulation.
Topics: Analgesics, Opioid; Animals; Cannabidiol; Cytokines; Endocannabinoids; Humans; Inflammasomes; Inflammation; Lipid Metabolism; Lipopolysaccharides; Morphine; Toll-Like Receptor 4
PubMed: 34115948
DOI: 10.1089/can.2020.0181