-
Drug Design, Development and Therapy 2024Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an...
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- =3.55*10). 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.
Topics: Humans; Morphine; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Male; Female; Middle Aged; Aged; Platelet Aggregation Inhibitors; Analgesics, Opioid
PubMed: 38828024
DOI: 10.2147/DDDT.S458299 -
Drug Design, Development and Therapy 2024This study was designed to investigate the effects of preadministration of nalmefene before general anesthesia induction on sufentanil-induced cough (SIC) in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Preadministration of Nalmefene on Sufentanil-Induced Cough During Induction of General Anesthesia in Patients Undergoing Breast Surgery: A Double-Blind Randomized Controlled Trial.
PURPOSE
This study was designed to investigate the effects of preadministration of nalmefene before general anesthesia induction on sufentanil-induced cough (SIC) in patients undergoing breast surgery.
PATIENTS AND METHODS
A total of 105 patients scheduled for elective breast surgery under general anesthesia were selected and randomly assigned into three groups: normal saline (Group C), low-dose nalmefene 0.1 μg·kg (Group LN), and high-dose nalmefene 0.25 μg·kg (Group HN). Sufentanil 0.5 μg·kg was injected intravenously within 2 s after 5 min of intervention. The count and severity of cough within 2 min after sufentanil injection, as well as the time to first cough, were recorded. In addition, we also collected intraoperative hemodynamic data, postoperative pain scores, the incidence of receiving rescue analgesics, and side effects up to 24 h after surgery.
RESULTS
Compared to Group C, the incidence of SIC was significantly lower in Group LN and HN (64.7% vs 30.3% and 14.7%, respectively; < 0.001), but no significant difference was observed between the two groups (=0.126). Compared to Group C, the risk factors decreased by 53.4% (95% confidence interval [CI] =0.181-0.735, =0.008) in Group LN and by 75.9% (95% CI=0.432-0.898, =0.001) in Group HN. Of the patients with SIC, less frequent SIC within 2 min after induction and a lower proportion of severe coughs were observed than Group C ( < 0.05), and no difference was detected between Group LN and HN. Additionally, the onset time to the first SIC did not differ significantly between the groups. Intraoperative hemodynamic data, postoperative pain scores, and side effects in the first 24 h did not differ among the groups.
CONCLUSION
Preadministration of nalmefene prior to induction of general anesthesia effectively suppressed SIC in patients undergoing breast surgery, without affecting intraoperative hemodynamic fluctuation and postoperative pain intensity.
Topics: Humans; Sufentanil; Anesthesia, General; Cough; Female; Naltrexone; Double-Blind Method; Middle Aged; Adult; Breast; Analgesics, Opioid; Dose-Response Relationship, Drug
PubMed: 38828019
DOI: 10.2147/DDDT.S462710 -
Cureus May 2024Perioperative neurocognitive disorders (PNDs) affect a large percentage of people who undergo surgeries that need general anesthesia. There is an increased risk of... (Review)
Review
Perioperative neurocognitive disorders (PNDs) affect a large percentage of people who undergo surgeries that need general anesthesia. There is an increased risk of death and a major disruption to postoperative self-care as a result of this. This study compiles all the relevant materials that the authors have found to investigate postnatal depression and its causes, as well as the methods used to determine the probability and severity of PNDs and how to reduce their risk before surgery. Postnatal depression can have many causes, and this text explores some of them. These include a history of alcohol or opiate use, immunological dysregulation, advanced age, educational background, infections, neurocognitive impairment, and pre-existing chronic inflammatory disorders. It also delves into various methods used to gauge the likelihood and severity of postpartum depression. The following assessment tools were covered: the Clock Drawing Test, Domain-Specific Tests, the Mini-Mental State Examination, and the Montreal Cognitive Assessment. In addition to biochemical markers, neuroimaging techniques play an important role in diagnosis. The Frailty Fried assessment, which measures inertia, sluggishness, lack of physical activity, fatigue, and unintentional weight loss, is a key prognostic sign that is highlighted. There is strong evidence that the index, which is derived from these five characteristics, may accurately predict the likelihood of PNDs. Risk mitigation strategies are also covered in this research. Preoperative brain plasticity-based therapies, such as physical exercise and intensive cognitive training, can significantly reduce the incidence and severity of postoperative neurocognitive disorders. A peripheral nerve block, monitoring cerebral oxygen saturation, dexmedetomidine, and a reduction in anesthesia depth are all ways to improve anesthetic procedures. Methods that lower blood pressure should be avoided, the body temperature should be kept down during surgery, or the time without liquids should be lengthened; all of these raise the risk of postoperative nausea and vomiting and make it worse. Potential approaches include a Mediterranean diet, physical activity, cognitive stimulation, smoking cessation, alcohol reduction, avoidance of anticholinergic medications, and non-steroidal anti-inflammatory drug stewardship, although there is no definitive evidence for successful postoperative neurocognitive rehabilitation procedures. More standardized diagnostic criteria, evaluation methods, and PND classification are urgently needed, according to this study. Different cases of PNDs are characterized by different combinations of tests, cutoff values, and methods because there is a broad variety of diagnostic tests used to make the diagnosis. Until now, PNDs and pre-existing neurocognitive disorders have been diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). With an aging population comes an increase in the occurrence and prevalence of PNDs, which calls for a specific way to classify and describe the condition.
PubMed: 38826940
DOI: 10.7759/cureus.59436 -
The Journal of Toxicological Sciences 2024Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited....
Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through I inhibition in vivo, but its potential to develop torsade de pointes will be small.
Topics: Animals; Dogs; Halothane; Morphine; Heart Rate; Anesthetics, Inhalation; Male; Toxicokinetics; Dose-Response Relationship, Drug; Analgesics, Opioid; Blood Pressure; Electrocardiography; Female; Infusions, Intravenous; Vasodilation; Electrophysiological Phenomena
PubMed: 38825486
DOI: 10.2131/jts.49.269 -
The Pharmacogenomics Journal Jun 2024The aim was to determine if opioid neuroimmunopharmacology pathway gene polymorphisms alter serum morphine, morphine-3-glucuronide and morphine-6-glucuronide...
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.
Topics: Humans; Morphine; Male; Female; Cancer Pain; Middle Aged; Analgesics, Opioid; Delayed-Action Preparations; Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Morphine Derivatives; Adult; Pharmacogenomic Variants; Toll-Like Receptor 2
PubMed: 38824169
DOI: 10.1038/s41397-024-00339-w -
Annals of Medicine Dec 2024Racial and ethnic disparities are evident in the accessibility of treatment for opioid use disorder (OUD). Even when medications for OUD (MOUD) are accessible, racially...
BACKGROUND
Racial and ethnic disparities are evident in the accessibility of treatment for opioid use disorder (OUD). Even when medications for OUD (MOUD) are accessible, racially and ethnically minoritized groups have higher attrition rates from treatment. Existing literature has primarily identified the specific racial and ethnic groups affected by these disparities, but has not thoroughly examined interventions to address this gap. Recovery peer navigators (RPNs) have been shown to improve access and overall retention on MOUD.
PATIENTS AND METHODS
In this retrospective cohort study, we evaluate the role of RPNs on patient retention in clinical care at an outpatient program in a racially and ethnically diverse urban community. Charts were reviewed of new patients seen from January 1, 2019 through December 31, 2019. Sociodemographic and clinical visit data, including which providers and services were utilized, were collected, and the primary outcome of interest was continuous retention in care. Bivariate analysis was done to test for statistically significant associations between variables by racial/ethnic group and continuous retention in care using Student's t-test or Pearson's chi-square test. Variables with p value ≤0.10 were included in a multivariable regression model.
RESULTS
A total of 131 new patients were included in the study. RPNs improved continuous retention in all-group analysis (27.6% pre-RPN compared to 80.2% post-RPN). Improvements in continuous retention were observed in all racial/ethnic subgroups but were statistically significant in the non-Hispanic Black (NHB) group ( < 0.001). Among NHB, increases in continuous retention were observed post-RPN in patients with male sex ( < 0.001), public health insurance ( < 0.001), additional substance use ( < 0.001), medical comorbidities ( < 0.001), psychiatric comorbidities ( = 0.001), and unstable housing ( = 0.005). Multivariate logistic regression demonstrated that patients who lacked insurance had lower odds of continuous retention compared to patients with public insurance (aOR = 0.17, 95% CI 0.039-0.70, = 0.015).
CONCLUSIONS
RPNs can improve clinical retention for patients with OUD, particularly for individuals experiencing several sociodemographic and clinical factors that are typically correlated with discontinuation of care.
Topics: Humans; Retrospective Studies; Male; Female; Opioid-Related Disorders; Buprenorphine; Adult; Opiate Substitution Treatment; Patient Navigation; Middle Aged; Retention in Care; Peer Group; Ambulatory Care; Healthcare Disparities; Ethnicity; Outpatients
PubMed: 38823420
DOI: 10.1080/07853890.2024.2355566 -
Harm Reduction Journal May 2024Efforts to distribute naloxone have equipped more people with the ability to reverse opioid overdoses but people who use drugs are often reluctant to call 911 due to...
BACKGROUND
Efforts to distribute naloxone have equipped more people with the ability to reverse opioid overdoses but people who use drugs are often reluctant to call 911 due to concerns for legal repercussions. Rural communities face unique challenges in reducing overdose deaths compared to urban communities, including limited access to harm reduction services as well as greater concerns about stigma and privacy.
METHODS
The Rural Opioid Initiative was funded in 2017 to better understand the health-related harms associated with the opioid crisis in rural US communities and consists of eight studies spanning ten states and 65 counties. Each study conducted semi-structured qualitative interviews with people who use drugs to understand contextual factors influencing drug use and health behaviors. We analyzed qualitative data from seven studies with data available at the time of analysis to understand peer response to overdose.
RESULTS
Of the 304 participants interviewed, 55% were men, 70% were white, 80% reported current injection drug use, and 60% reported methamphetamine use. Similar to what has been found in studies focused on urban settings, people who use drugs in rural communities use a range of strategies to reverse overdoses, including non-evidence-based approaches. Several reported that multiple doses of naloxone are needed to reverse overdose. Three themes emerged around the willingness to call 911, including (1) hesitancy to call 911 for fear of legal consequences, (2) negative perceptions or experiences with law enforcement officers, and (3) efforts to obtain medical intervention while avoiding identification/law enforcement involvement.
CONCLUSION
People who use drugs employ multiple strategies to attempt overdose reversal, including non-evidence-based approaches. Greater education about the most effective and least harmful strategies is needed. Reluctance to call 911 is rooted in concerns about potential legal consequences as well as perceptions about law enforcement officers, which may be heightened in rural communities where people who use drugs are more easily identified by law enforcement. People who use drugs will go to great strides to connect their peers to needed medical services, suggesting that comprehensive interventions to reduce interactions with law enforcement officers and eliminate legal consequences for reporting overdoses are critical.
Topics: Humans; Female; Male; Rural Population; Adult; Drug Overdose; Harm Reduction; Narcotic Antagonists; Naloxone; Middle Aged; Qualitative Research; United States; Young Adult; Drug Users
PubMed: 38822387
DOI: 10.1186/s12954-024-01007-9 -
JAMA Network Open May 2024Many US states are substantially increasing community-based naloxone distribution, supported in part through settlements from opioid manufacturers and distributors.
IMPORTANCE
Many US states are substantially increasing community-based naloxone distribution, supported in part through settlements from opioid manufacturers and distributors.
OBJECTIVES
To evaluate the potential impact of increased naloxone availability on opioid overdose deaths (OODs) and explore strategies to enhance this impact by integrating interventions to address solitary drug use.
DESIGN, SETTING, AND PARTICIPANTS
This decision analytical modeling study used PROFOUND (Prevention and Rescue of Fentanyl and Other Opioid Overdoses Using Optimized Naloxone Distribution Strategies), a previously published simulation model, to forecast annual OODs between January 2023 and December 2025. The simulated study population included individuals from Rhode Island who misused opioids and stimulants and were at risk for opioid overdose.
EXPOSURES
The study modeled expanded naloxone distribution supported by the state's opioid settlement (50 000 naloxone nasal spray kits each year). Two approaches to expanding naloxone distribution were evaluated: one based on historical spatial patterns of naloxone distribution (supply-based approach) and one based on the spatial distribution of individuals at risk (demand-based approach). In addition, hypothetical interventions to enhance the likelihood of witnessed overdoses in private or semiprivate settings were considered.
MAIN OUTCOMES AND MEASURES
Annual number of OODs and ratio of fatal to nonfatal opioid overdoses.
RESULTS
Modeling results indicated that distributing more naloxone supported by the state's opioid settlement could reduce OODs by 6.3% (95% simulation interval [SI], 0.3%-13.7%) and 8.8% (95% SI, 1.8%-17.5%) in 2025 with the supply-based and demand-based approaches, respectively. However, increasing witnessed overdoses by 20% to 60% demonstrated greater potential for reducing OODs, ranging from 8.5% (95% SI, 0.0%-20.3%) to 24.1% (95% SI, 8.6%-39.3%). Notably, synergistic associations were observed when combining both interventions: increased naloxone distribution with the 2 approaches and a 60% increase in witnessed overdoses could reduce OODs in 2025 by 33.5% (95% SI, 17.1%-50.4%) and 37.4% (95% SI, 19.6%-56.3%), respectively.
CONCLUSIONS AND RELEVANCE
These findings suggest that interventions to address solitary drug use are needed to maximize the impact of continued efforts to increase community-based naloxone distribution, which may be particularly important for jurisdictions that have strong community-based naloxone distribution programs.
Topics: Naloxone; Humans; Narcotic Antagonists; Rhode Island; Opiate Overdose; Analgesics, Opioid; Opioid-Related Disorders; Drug Overdose
PubMed: 38814644
DOI: 10.1001/jamanetworkopen.2024.13861 -
Drugs & Aging Jun 2024Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate... (Review)
Review
Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.
Topics: Humans; Aged; Central Nervous System Agents; Aging
PubMed: 38814377
DOI: 10.1007/s40266-024-01117-w -
Journal of Medicinal Chemistry Jun 2024Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain...
Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and characterization of 24 analogues. Two analogues, and , showed longer durations of action than NLF in a warm-water tail immersion assay, produced effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.
Topics: Structure-Activity Relationship; Spiro Compounds; Animals; Morphinans; Mice; Male; Humans; Receptors, Opioid, kappa; Pain Management; Pain; Analgesics
PubMed: 38814086
DOI: 10.1021/acs.jmedchem.4c00646