RÉSUMÉ
The escalating incidence of opioid-related issues among pregnant women in the United States underscores the critical necessity to understand the effects of opioid use and Medication for Opioid Use Disorders (MOUDs) during pregnancy. This research employed a translational rodent model to examine the impact of gestational exposure to buprenorphine (BUP) or morphine on maternal behaviors and offspring well-being. Female rats received BUP or morphine before conception, representing established use, with exposure continuing until postnatal day 2 or discontinued on gestational day 19 to mimic treatment cessation before birth. Maternal behaviors - including care, pup retrieval, and preference - as well as hunting behaviors and brain neurotransmitter levels were assessed. Offspring were evaluated for mortality, weight, length, milk bands, surface righting latency, withdrawal symptoms, and brain neurotransmitter levels. Our results reveal that regardless of exposure length (i.e., continued or discontinued), BUP resulted in reduced maternal care in contrast to morphine-exposed and control dams. Opioid exposure altered brain monoamine levels in the dams and offspring, and was associated with increased neonatal mortality, reduced offspring weight, and elevated withdrawal symptoms compared to controls. These findings underscore BUP's potential disruption of maternal care, contributing to increased pup mortality and altered neurodevelopmental outcomes in the offspring. This study calls for more comprehensive research into prenatal BUP exposure effects on the maternal brain and infant development with the aim to mitigate adverse outcomes in humans exposed to opioids during pregnancy.
Sujet(s)
Analgésiques morphiniques , Encéphale , Buprénorphine , Comportement maternel , Morphine , Effets différés de l'exposition prénatale à des facteurs de risque , Grossesse , Animaux , Femelle , Morphine/effets indésirables , Morphine/toxicité , Effets différés de l'exposition prénatale à des facteurs de risque/induit chimiquement , Encéphale/effets des médicaments et des substances chimiques , Encéphale/croissance et développement , Encéphale/métabolisme , Analgésiques morphiniques/toxicité , Analgésiques morphiniques/effets indésirables , Rats , Comportement maternel/effets des médicaments et des substances chimiques , Rat Sprague-Dawley , Animaux nouveau-nés , Comportement animal/effets des médicaments et des substances chimiques , Mâle , Syndrome de sevrage , Troubles liés aux opiacésRÉSUMÉ
BACKGROUND: Cesarean deliveries (CD) are commonly performed using neuraxial anesthesia. The use of neuraxial morphine has proven beneficial in terms of postoperative pain management; however, its effect on postoperative urine retention remains unclear. OBJECTIVES: To determine whether morphine injection into the neuraxis during CD influences postoperative urinary retention rate. METHODS: We conducted a retrospective case-control observational study of patients undergoing CD. We compared patients using morphine injected into the intrathecal or epidural spaces (November 2020 to October 2021) to a historical cohort of patients undergoing CD without morphine (November 2019 to October 2020). The primary outcome was the rate of postoperative overt urinary retention necessitating bladder catheterization. RESULTS: The study group comprised 283 patients, and 313 patients in the control group were eligible for analysis. No differences were found with respect to the baseline demographic and indication for CD. The number of postpartum urinary bladder catheterizations due to urine retention was higher in the study group (5% vs. 1%, P-value = 0.003). No cases of 30-day readmission were recorded. Moreover, patients treated with neuraxial morphine required fewer repeat doses of postoperative anesthesia (oral analgesia 7.4 vs. 10.1, intravenous analgesia 0.29 vs. 0.31, oral opioids 0.06 vs. 3.70, intravenous opioids 0.01 vs. 0.45, P-value < 0.001 for all). CONCLUSIONS: While neuraxial morphine used during CD appears to be safe and effective, the risk of postoperative urinary retention seems to be increased due to its use. Cases of overt urinary retention treated by bladder catheterization does not lead to short-term complications.
Sujet(s)
Analgésiques morphiniques , Césarienne , Morphine , Douleur postopératoire , Rétention d'urine , Humains , Rétention d'urine/étiologie , Rétention d'urine/épidémiologie , Femelle , Morphine/administration et posologie , Morphine/effets indésirables , Études rétrospectives , Césarienne/effets indésirables , Césarienne/méthodes , Grossesse , Adulte , Analgésiques morphiniques/administration et posologie , Analgésiques morphiniques/effets indésirables , Études cas-témoins , Douleur postopératoire/traitement médicamenteux , Douleur postopératoire/prévention et contrôle , Douleur postopératoire/étiologie , Rachianesthésie/effets indésirables , Rachianesthésie/méthodes , Anesthésie obstétricale/méthodes , Anesthésie obstétricale/effets indésirables , Anesthésie péridurale/effets indésirables , Anesthésie péridurale/méthodes , Injections rachidiennes , Cathétérisme urinaire/effets indésirables , Cathétérisme urinaire/méthodes , Complications postopératoires/épidémiologie , Complications postopératoires/étiologieRÉSUMÉ
The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide concentration-response relationships in 506 cancer patients receiving controlled-release oral morphine. Morphine-3-glucuronide concentrations (standardised to 11 h post-dose) were higher in patients without pain control (median (interquartile range) 1.2 (0.7-2.3) versus 1.0 (0.5-1.9) µM, P = 0.006), whereas morphine concentrations were higher in patients with cognitive dysfunction (40 (20-81) versus 29 (14-60) nM, P = 0.02). TLR2 rs3804100 variant carriers had reduced odds (adjusted odds ratio (95% confidence interval) 0.42 (0.22-0.82), P = 0.01) of opioid adverse events. IL2 rs2069762 G/G (0.20 (0.06-0.52)), BDNF rs6265 A/A (0.15 (0.02-0.63)) and IL6R rs8192284 carrier (0.55 (0.34-0.90)) genotypes had decreased, and IL6 rs10499563 C/C increased (3.3 (1.2-9.3)), odds of sickness response (P ≤ 0.02). The study has limitations in heterogeneity in doses, sampling times and diagnoses but still suggests that pharmacokinetics and immune genetics co-contribute to morphine pain control and adverse effects in cancer patients.
Sujet(s)
Analgésiques morphiniques , Douleur cancéreuse , Préparations à action retardée , Morphine , Pharmacogénétique , Humains , Morphine/effets indésirables , Morphine/pharmacocinétique , Morphine/administration et posologie , Mâle , Femelle , Douleur cancéreuse/traitement médicamenteux , Douleur cancéreuse/génétique , Adulte d'âge moyen , Analgésiques morphiniques/pharmacocinétique , Analgésiques morphiniques/effets indésirables , Analgésiques morphiniques/administration et posologie , Préparations à action retardée/pharmacocinétique , Sujet âgé , Pharmacogénétique/méthodes , Polymorphisme de nucléotide simple/génétique , Dérivés de la morphine/pharmacocinétique , Dérivés de la morphine/effets indésirables , Adulte , Variants pharmacogénomiques , Récepteur de type Toll-2/génétiqueRÉSUMÉ
Purpose: Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Patients and Methods: Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Results: Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. Conclusion: The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.
Sujet(s)
Syndrome coronarien aigu , Morphine , Antagonistes des récepteurs purinergiques P2Y , Humains , Morphine/effets indésirables , Morphine/administration et posologie , Antagonistes des récepteurs purinergiques P2Y/effets indésirables , Antagonistes des récepteurs purinergiques P2Y/administration et posologie , Syndrome coronarien aigu/traitement médicamenteux , Mâle , Femelle , Adulte d'âge moyen , Sujet âgé , Antiagrégants plaquettaires/effets indésirables , Antiagrégants plaquettaires/administration et posologie , Analgésiques morphiniques/effets indésirables , Analgésiques morphiniques/administration et posologieRÉSUMÉ
INTRODUCTION: Opioid analgesics are often used to manage moderate to severe pain. A significant proportion of patients taking opioids have compromised kidney function. This systematic review aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease. METHODS: We searched eight electronic databases from inception to January 26, 2023. Published original research articles in English reporting on opioid use and pharmacokinetic data among adults with reduced renal function were included. Article screening, data extraction, and quality assessment were conducted by at least two investigators independently. This review was registered prospectively on PROSPERO (ID: CRD42020159091). RESULTS: There were 32 observational studies included, 14 of which reported on morphine use, three involved fentanyl use, two involved hydromorphone use, and 13 articles reported on other opioids including codeine, dihydrocodeine, and buprenorphine. CONCLUSION: There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Morphine remains the opioid for which there is the most evidence available on safety and analgesic effect in the context of renal disease. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.
Sujet(s)
Analgésiques morphiniques , Maladies du rein , Humains , Analgésiques morphiniques/usage thérapeutique , Analgésiques morphiniques/effets indésirables , Morphine/usage thérapeutique , Morphine/effets indésirables , Douleur/traitement médicamenteuxSujet(s)
Tolérance aux médicaments , Hyperalgésie , Morphine , Morphine/pharmacologie , Morphine/effets indésirables , Hyperalgésie/induit chimiquement , Hyperalgésie/physiopathologie , Animaux , Tolérance aux médicaments/physiologie , Facteurs d'échange de nucléotides guanyliques/métabolisme , Facteurs d'échange de nucléotides guanyliques/génétique , Souris , Analgésiques morphiniques/pharmacologie , HumainsRÉSUMÉ
Opioid use disorder (OUD) is a chronic relapsing disorder that is a major burden for the lives of affected individuals, and society as a whole. Opioid withdrawal is characterized by strong physical symptoms, along with signs of negative affect. Negative affect due to opioid withdrawal is a major obstacle to recovery and relapse prevention. The mechanisms behind negative affect due to either spontaneous or antagonist-precipitated opioid withdrawal are not well known, and more animal models need be developed. Here, we present behavioral models of negative affect upon naloxone-precipitated morphine withdrawal in adult male mice. Social, anxiety, and despair-like deficits were investigated following naloxone administration in mice receiving morphine under three dosing regimens; acute, chronic constant dose and chronic escalating doses. Social behaviour in the three-chamber social preference test was decreased following withdrawal from chronic and escalating but not acute morphine. Anxiety-like behaviour in the open field was increased for all three treatments. Despair-like behaviour was increased following withdrawal from chronic and escalating but not acute morphine. Altogether, these animal models will contribute to study behavioural and neuronal circuitries involved in the several negative affective signs characterizing OUD.
Sujet(s)
Modèles animaux de maladie humaine , Morphine , Naloxone , Syndrome de sevrage , Animaux , Mâle , Morphine/effets indésirables , Morphine/administration et posologie , Souris , Naloxone/administration et posologie , Naloxone/pharmacologie , Anxiété , Comportement animal/effets des médicaments et des substances chimiques , Antagonistes narcotiques/administration et posologie , Antagonistes narcotiques/pharmacologie , Analgésiques morphiniques/administration et posologie , Analgésiques morphiniques/effets indésirables , Comportement social , Dépendance à la morphine/psychologie , Troubles liés aux opiacésRÉSUMÉ
Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research.
Sujet(s)
Douleur aigüe , Kétamine , Douleur musculosquelettique , Humains , Sujet âgé , Kétamine/effets indésirables , Kétamine/administration et posologie , Morphine/administration et posologie , Morphine/effets indésirables , Gestion de la douleur/effets indésirables , Douleur aigüe/diagnostic , Douleur aigüe/traitement médicamenteux , Douleur aigüe/induit chimiquement , Douleur musculosquelettique/induit chimiquement , Douleur musculosquelettique/traitement médicamenteux , Analgésiques/effets indésirables , Analgésiques morphiniques/effets indésirables , Service hospitalier d'urgencesRÉSUMÉ
BACKGROUND: Multimodal postoperative analgesia following total hip arthroplasty is recommended, but the optimal combination of drugs remains uncertain. The aim of the RECIPE trial was to investigate the relative benefit and harm of the different combinations of paracetamol, ibuprofen, and the analgesic adjuvant dexamethasone for treatment of postoperative pain following total hip arthroplasty. METHODS: The RECIPE trial was a randomised, blinded, placebo-controlled trial conducted at nine Danish hospitals. Adults scheduled for total hip arthroplasty were randomly assigned (1:1:1:1) using a computer-generated list with stratification by site to receive combinations of oral paracetamol 1000 mg every 6 h, oral ibuprofen 400 mg every 6 h, or a single-dose of intravenous dexamethasone 24 mg in the following groups: paracetamol plus ibuprofen, ibuprofen plus dexamethasone, paracetamol plus dexamethasone, and paracetamol plus ibuprofen plus dexamethasone. The primary outcome was 24 h intravenous morphine consumption, analysed in a modified intention-to-treat population, defined as all randomly assigned participants who underwent total hip arthroplasty. The predefined minimal important difference was 8 mg. Safety outcomes included serious and non-serious adverse events within 90 days and 24 h. The trial was registered with ClinicalTrials.gov, NCT04123873. FINDINGS: Between March 5, 2020, and Nov 15, 2022, we randomly assigned 1060 participants, of whom 1043 (589 [56%] women and 454 [44%] men) were included in the modified intention-to-treat population. 261 were assigned to paracetamol plus ibuprofen, 262 to ibuprofen plus dexamethasone, 262 to paracetamol plus dexamethasone, and 258 to paracetamol plus ibuprofen plus dexamethasone. Median 24 h morphine consumption was 24 mg (IQR 12-38) in the paracetamol plus ibuprofen group, 20 mg (12-32) in the paracetamol plus dexamethasone group, 16 mg (10-30) in the ibuprofen plus dexamethasone group, and 15 mg (8-26) in the paracetamol plus ibuprofen plus dexamethasone group. The paracetamol plus ibuprofen plus dexamethasone group had a significantly reduced 24 h morphine consumption compared with paracetamol plus ibuprofen (Hodges-Lehmann median difference -6 mg [99% CI -10 to -3]; p<0·0001) and paracetamol plus dexamethasone (-4 mg [-8 to -1]; p=0·0013), however, none of the comparisons showed differences reaching the minimal important threshold of 8 mg. 91 (35%) of 258 participants in the paracetamol plus ibuprofen plus dexamethasone group had one or more adverse events, compared with 99 (38%) of 262 in the ibuprofen plus dexamethasone group, 103 (39%) of 262 in the paracetamol plus dexamethasone group, and 165 (63%) of 261 in the paracetamol plus ibuprofen group. INTERPRETATION: In adults undergoing total hip arthroplasty, a combination of paracetamol, ibuprofen, and dexamethasone had the lowest morphine consumption within 24 h following surgery and the most favourable adverse event profile, with a lower incidence of serious and non-serious adverse events (primarily driven by differences in nausea, vomiting, and dizziness) compared with paracetamol plus ibuprofen. FUNDING: The Novo Nordisk Foundation and Næstved-Slagelse-Ringsted Hospitals' Research Fund.
Sujet(s)
Analgésiques non narcotiques , Arthroplastie prothétique de hanche , Mâle , Adulte , Humains , Femelle , Analgésiques non narcotiques/usage thérapeutique , Acétaminophène/usage thérapeutique , Ibuprofène/effets indésirables , Arthroplastie prothétique de hanche/effets indésirables , Association de médicaments , Morphine/effets indésirables , Dexaméthasone/effets indésirablesRÉSUMÉ
Prescription opioids are the gold standard for treating moderate to severe pain despite their well-documented adverse effects. Of all prescription medications, opioids are abused most widely, and fatal overdoses have reached epidemic levels. One strategy for improving the margin of safety of opioids is combining them with non-opioid drugs to decrease the opioid dose needed for pain relief, thereby reducing adverse effects that occur with larger doses. The N-methyl-D-aspartate receptor antagonist ketamine has been used safely as an analgesic but only under a very limited range of conditions. The current studies characterized the antinociceptive, behavioral suppressant, and gastrointestinal effects of morphine and ketamine alone and in mixtures to determine their interaction in 24 adult male Sprague-Dawley rats (nâ =â 8 per assay). Given alone, both morphine and ketamine produced antinociception, decreased responding for food, and reduced gastrointestinal transit (i.e. produced constipation). The effects of morphine:ketamine mixtures generally were additive, except for the antinociceptive effects of 1:1 mixtures for which the difference in slope (i.e. non-parallel shift) between the observed and predicted effects suggested synergy at smaller doses and additivity at larger doses. The potency of morphine to produce constipation was not enhanced by administration of morphine:ketamine mixtures with antinociceptive effects. The nature of the interaction between morphine and ketamine for adverse effects such as dependence, withdrawal, abuse, or respiratory depression remains unknown but also might be related to the ratio of each drug in mixtures. It will be important to identify conditions that produce the largest potential therapeutic window in humans.
Sujet(s)
Effets secondaires indésirables des médicaments , Kétamine , Adulte , Humains , Mâle , Rats , Animaux , Morphine/effets indésirables , Kétamine/effets indésirables , Rat Sprague-Dawley , Analgésiques morphiniques/effets indésirables , Douleur/traitement médicamenteuxRÉSUMÉ
BACKGROUND: Morphine-sparing effects are often used to evaluate non-opioid analgesic interventions. The exact effect that would warrant the implementation of these interventions in clinical practice (a minimally important difference) remains unclear. We aimed to determine this with anchor-based methods. METHODS: This was a post hoc analysis of three studies investigating pain management after hip or knee arthroplasty (PANSAID [NCT02571361], DEX-2-TKA [NCT03506789] and Pain Map [NCT02340052]). The overall population was median aged 70, median ASA 2, 54% female. We examined the correlation between 0 and 24 h postoperative iv morphine equivalent consumption and the severity of nausea, vomiting, sedation and dizziness. The anchor was different severity degrees of these opioid-related adverse events. The primary outcome was the difference in morphine consumption between patients experiencing no versus only mild events. Secondary outcomes included the difference in morphine consumption between patients with mild versus moderate and moderate versus severe events. We used Hodges-Lehmann median differences, exact Wilcoxon-Mann-Whitney tests and quantile regression. RESULTS: The difference in iv morphine consumption was 6 mg (95% confidence interval: 4-8) between patients with no versus only mild events, 5 mg (2-8) between patients with mild versus moderate events and 0 mg (-4 to 4) between patients with moderate versus severe events. CONCLUSIONS: In populations comparable to this post-hoc analysis (orthopaedic surgery, median age 70 and ASA 2), we suggest a minimally important difference of 5 mg for 0-24 h postoperative iv morphine consumption.
Sujet(s)
Arthroplastie prothétique de genou , Morphine , Humains , Femelle , Sujet âgé , Mâle , Morphine/effets indésirables , Arthroplastie prothétique de genou/effets indésirables , Sensation vertigineuse/induit chimiquement , Douleur postopératoire/étiologie , Analgésiques morphiniques/effets indésirables , Nausée/induit chimiquement , Vomissement/induit chimiquement , Méthode en double aveugleRÉSUMÉ
DNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underlying opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied in the context of addiction. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (m5C) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring. We identified dynamic changes in glycine tRNA (tRNAGlyGCC) cytosine methylation, corresponding to altered expression levels of this tRNA at multiple timepoints following 15 days of daily morphine. Additionally, a robust increase in methylation, coupled with decreased expression, was present after 30 days of withdrawal, suggesting that repeated opioid administration produces changes to the tRNA regulome long after discontinuation. Furthermore, forebrain-wide knockout of neuronal Nsun2, a tRNA methyltransferase, was associated with disruption of opioid conditioned place preference, and this effect was recapitulated by regional mPFC Nsun2 knockout. Taken together, these studies provide a foundational link between the regulation of tRNA cytosine methylation and opioid reward and highlight the tRNA machinery as a potential therapeutic target in addiction.
Sujet(s)
Souris de lignée C57BL , Morphine , Cortex préfrontal , ARN de transfert , Récompense , Syndrome de sevrage , Animaux , Mâle , Souris , Morphine/pharmacologie , Morphine/administration et posologie , Morphine/effets indésirables , Syndrome de sevrage/génétique , Cortex préfrontal/métabolisme , Cortex préfrontal/effets des médicaments et des substances chimiques , ARN de transfert/génétique , Épigenèse génétique/effets des médicaments et des substances chimiques , Analgésiques morphiniques/pharmacologie , Analgésiques morphiniques/administration et posologie , Souris knockout , Comportement de recherche de substances/effets des médicaments et des substances chimiques , Comportement de recherche de substances/physiologieRÉSUMÉ
Opioids, such as morphine and oxycodone, are widely used for pain management associated with chronic pancreatitis (CP); however, their impact on the progression and pain sensitivity of CP has never been evaluated. This report investigates the impact of opioid use on the severity of CP, pain sensitivity, and the gut microbiome. C57BL/6 mice were divided into control, CP, CP with morphine/oxycodone, and either morphine or oxycodone alone groups. CP was induced by administration of caerulein (50ug/kg/h, i.p. hourly x7, twice a week for 10 weeks). The mouse-to-pancreas weight ratio, histology, and Sirius red staining were performed to measure CP severity. Tail flick and paw pressure assays were used to measure thermal and mechanical pain. DNA was extracted from the fecal samples and subjected to whole-genome shotgun sequencing. Germ-free mice were used to validate the role of gut microbiome in sensitizing acute pancreatic inflammation. Opioid treatment exacerbates CP by increasing pancreatic necrosis, fibrosis, and immune-cell infiltration. Opioid-treated CP mice exhibited enhanced pain hypersensitivity and showed distinct clustering of the gut microbiome compared to untreated CP mice, with severely compromised gut barrier integrity. Fecal microbiota transplantation (FMT) from opioid-treated CP mice into germ-free mice resulted in pancreatic inflammation in response to a suboptimal caerulein dose. Together, these analyses revealed that opioids worsen the severity of CP and induce significant alterations in pain sensitivity and the gut microbiome in a caerulein CP mouse model. Microbial dysbiosis plays an important role in sensitizing the host to pancreatic inflammation.
Sujet(s)
Microbiome gastro-intestinal , Pancréatite chronique , Animaux , Souris , Analgésiques morphiniques/effets indésirables , Oxycodone/effets indésirables , Dysbiose/induit chimiquement , Dysbiose/traitement médicamenteux , Céruléine/effets indésirables , Microbiome gastro-intestinal/physiologie , Souris de lignée C57BL , Pancréatite chronique/induit chimiquement , Pancréatite chronique/traitement médicamenteux , Pancréatite chronique/anatomopathologie , Morphine/effets indésirables , Douleur/traitement médicamenteux , InflammationRÉSUMÉ
Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individuals, leading to chronic pain and reduced quality of life. Even with antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16S rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain pathways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine- and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mouse model to be a relevant system that can help elucidate the pathogenic mechanisms of the opioid- and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate interplay between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies.
Sujet(s)
Douleur chronique , Infections à VIH , Neuropathies périphériques , Souris , Animaux , Morphine/effets indésirables , Infections à VIH/complications , Infections à VIH/traitement médicamenteux , Analgésiques morphiniques/effets indésirables , Dysbiose , ARN ribosomique 16S/génétique , Qualité de vieRÉSUMÉ
One-third of cancer pain patients do not experience adequate pain relief using analgesic ladder by the World Health Organization. Interventional procedures, such as epidural morphine, have been considered. This study aimed to review the literature comparing the effects of epidural administration of morphine with the oral route. This systematic review included randomized controlled trials (RCTs) conducted with patients with gastrointestinal neoplasm. A search was conducted on PubMed, EMBASE, Web of Science, Scopus, Cochrane Library, and CINAHL databases to identify studies published up to May 2023. The retrieved study was evaluated using the Risk of Bias 2 (RoB 2) tool and qualitatively synthesized. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (Prospero: CRD42021264728). Only one RCT, a crossover trial, was included in this systematic review. The study was conducted with ten participants (one withdrawal) and reported a statistically significant difference between both subcutaneous and epidural morphine solutions and oral morphine. The adverse events were not described. The included study presents some concerns of bias and low certainty of evidence on the effectiveness and security of epidural morphine administration. The available literature does not suffice to elucidate whether morphine administration via the epidural route is more effective than other routes. Further RCTs are necessary to improve the level of evidence on the effectiveness and risk-benefit of epidural morphine in the management of cancer pain in gastrointestinal neoplasm patients.
Sujet(s)
Analgésie péridurale , Analgésiques morphiniques , Douleur cancéreuse , Tumeurs gastro-intestinales , Morphine , Essais contrôlés randomisés comme sujet , Humains , Administration par voie orale , Analgésie péridurale/méthodes , Analgésiques morphiniques/administration et posologie , Analgésiques morphiniques/effets indésirables , Analgésiques morphiniques/usage thérapeutique , Douleur cancéreuse/traitement médicamenteux , Tumeurs gastro-intestinales/traitement médicamenteux , Tumeurs gastro-intestinales/complications , Morphine/administration et posologie , Morphine/usage thérapeutique , Morphine/effets indésirables , Résultat thérapeutiqueRÉSUMÉ
OBJECTIVE: Our study aimed to investigate the analgesic efficacy of nebulized ketamine in managing acute moderate-to-severe musculoskeletal pain in older emergency department (ED) patients compared with intravenous (IV) morphine. METHODS: This was a non-inferiority, double-blind, randomized controlled trial conducted at a single medical centre. The patients aged 65 and older, who presented at the ED musculoskeletal pain within 7 days and had a pain score of 5 or more on an 11-point numeric rating scale (NRS), were included in the study. The outcomes were a comparison of the NRS reduction between nebulized ketamine and IV morphine 30 minutes after treatment, incidence of adverse events and rate of rescue therapy. RESULTS: The final study included 92 individuals, divided equally into two groups. At 30 minutes, the difference in mean NRS between the nebulized ketamine and IV morphine groups was insignificant (5.2 versus 5.7). The comparative mean difference in the NRS change from baseline between nebulized ketamine and IV morphine [-1.96 (95% confidence interval-CI: -2.45 to -1.46) and -2.15 (95% CI: -2.64 to -1.66) = 0.2 (95% CI: -0.49 to 0.89)] did not exceed the non-inferiority margin of 1.3. The rate of rescue therapy did not differ between the groups. The morphine group had considerably higher incidence of nausea than the control group (zero patients in the ketamine group versus eight patients (17.4%) in the morphine group; P = 0.006). CONCLUSIONS: Nebulized ketamine has non-inferior analgesic efficacy compared with IV morphine for acute musculoskeletal pain in older persons, with fewer adverse effects.
Sujet(s)
Kétamine , Douleur musculosquelettique , Sujet âgé , Sujet âgé de 80 ans ou plus , Humains , Analgésiques , Service hospitalier d'urgences , Kétamine/effets indésirables , Morphine/effets indésirables , Douleur musculosquelettique/diagnostic , Douleur musculosquelettique/traitement médicamenteux , Méthode en double aveugleRÉSUMÉ
The µ-opioid receptor-biased agonist theory holds that Gio protein signaling mediates the analgesic effect of opioids and the related side effects via the ß-arrestin2 signaling pathway. A series of µ-opioid-biased agonists have been developed in accordance with this theory, and the FDA has approved TRV130 (as a representative of biased agonists) for marketing. However, several reports have raised the issue of opioid side effects associated with the use of agonists. In this study, five permeable peptides were designed to emulate 11 S/T phosphorylation sites at the µ-opioid receptor (MOR) carboxyl-terminal. In vitro experiments were performed to detect the activation level of G proteins from the cAMP inhibition assay and the ß-arrestin2 recruitment by the BRET assay. Designed peptides might effectively interfere with the activation of the Gio and ß-arrestin2 pathways when combined with morphine. The resulting morphine-induced tolerance, respiratory inhibition, and constipation in mice showed that the ß-arrestin2 pathway was responsible for morphine tolerance while the Gio signaling pathway was involved with respiratory depression and constipation and that these side effects were significantly related to phosphorylation sites S363 and T370. This study may provide new directions for the development of safer and more effective opioid analgesics, and the designed peptides may be an effective tool for exploring the mechanism by which µ-opioid receptors function, with the potential of reducing the side effects that are associated with clinical opioid treatment.
Sujet(s)
Analgésiques morphiniques , Morphine , Souris , Animaux , Morphine/effets indésirables , Analgésiques morphiniques/effets indésirables , Analgésiques morphiniques/métabolisme , Récepteur mu/métabolisme , Transduction du signal , Constipation/induit chimiquement , Peptides/métabolisme , bêta-Arrestine 2/métabolismeRÉSUMÉ
Although nalbuphine, a semi-synthetic analgesic compound, is less potent than morphine in terms of alleviating severe pain, our recent findings have revealed that nalbuphine-6-glucuronide (N6G), one of the glucuronide metabolites of nalbuphine, promotes a significantly more robust analgesic effect than its parent drug. Nevertheless, despite these promising observations, the precise mechanisms underlying the analgesic effects of nalbuphine glucuronides have yet to be determined. In this study, we aim to elucidate the mechanisms associated with the analgesic effects of nalbuphine glucuronides. Pharmacokinetic and pharmacodynamic studies were conducted to investigate the relationship between the central and peripheral compartments of nalbuphine and its derivatives. The analgesic responses of these compounds were evaluated based on multiple behavioral tests involving thermal and mechanical stimuli. Radioligand binding assays were also performed to determine the binding affinity and selectivity of these compounds for different opioid receptors. The results of these tests consistently confirmed that the heightened analgesic effects of N6G are mediated through its enhanced binding affinity for both mu- and kappa-opioid receptors, even comparable to those of morphine. Notably, N6G exhibited fewer side effects and did not induce sudden death, thereby highlighting its superior safety profile. Additionally, pharmacokinetic studies indicated that N6G could cross the blood-brain barrier when administered peripherally, offering pain relief. Overall, N6G provides great analgesic efficacy and enhanced safety. These findings highlight the potential value of nalbuphine glucuronides, particularly N6G, as promising candidates for the development of novel analgesic drugs.
Sujet(s)
Nalbuphine , Récepteur kappa , Humains , Nalbuphine/effets indésirables , Récepteur mu , Glucuronides/usage thérapeutique , Analgésiques/pharmacologie , Analgésiques/usage thérapeutique , Récepteurs aux opioïdes/métabolisme , Morphine/effets indésirables , Douleur/traitement médicamenteux , Douleur/induit chimiquement , Analgésiques morphiniques/usage thérapeutiqueRÉSUMÉ
While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that low concentration (100 nM) of morphine reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors.