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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 -
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 -
International Journal of Pharmaceutics Jun 2024Opioids are powerful analgesics; however, their significant systemic adverse effects and the need for frequent administration restrict their use. Nalbuphine (NA) is a...
Opioids are powerful analgesics; however, their significant systemic adverse effects and the need for frequent administration restrict their use. Nalbuphine (NA) is a κ-agonist narcotic with limited adverse effects, but needs to be frequently administrated due to its short elimination half-life. Whereas sebacoyl dinalbuphine ester (SDE) is a NA prodrug, which can effectively prolong the analgesic effect, but lacks immediate pain relief. Therefore, in this study, a rapid and sustained local delivery formulation to introduce NA and SDE directly into surgical sites was developed. An amphiphilic nanostructured lipid carrier (NLC) poloxamer 407 (P407) gel (NLC-Gel) was developed to permit concurrent delivery of hydrophobic SDE from the NLC core and hydrophilic NA from P407, offering a dual rapid and prolonged analgesic effect. Benefiting from the thermal-sensitive characteristic of P407, the formulation can be injected in liquid phase and instantly transit into gel at wound site. NLC-Gel properties, including particle size, drug release, rheology, and stability, were assessed. In vivo evaluation using a rat spinal surgery model highlighted the effect of the formulation through pain behavior test and hematology analysis. NLC-Gels demonstrated an analgesic effect comparable with that of commercial intramuscular injected SDE formulation (IM SDE), with only 15 % of the drug dosage. The inclusion of supplemental NA in the exterior gel (PA12-Gel + NA) provided rapid drug onset owing to swift NA dispersion, addressing acute pain within hours along with prolonged analgesic effects. Our findings suggest that this amphiphilic formulation significantly enhanced postoperative pain management in terms of safety and efficacy.
Topics: Nalbuphine; Pain, Postoperative; Animals; Gels; Male; Poloxamer; Rats, Sprague-Dawley; Analgesics, Opioid; Drug Liberation; Drug Carriers; Rats; Lipids; Particle Size; Nanostructures; Esters
PubMed: 38823469
DOI: 10.1016/j.ijpharm.2024.124295 -
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 -
Neuroscience Letters Jun 2024OPRM1 gene encoding mu-opioid receptor (MOR) is the primary candidate gene for buprenorphine (BUP) pharmacogenetics. OPRM1 undergoes alternative splicing leading to...
OPRM1 gene encoding mu-opioid receptor (MOR) is the primary candidate gene for buprenorphine (BUP) pharmacogenetics. OPRM1 undergoes alternative splicing leading to multiple MOR subtypes. Thus, in the current study 2 SNPs (rs1799972 and rs562859) were selected due to evidence for their contribution to alternative splicing of OPRM1. The effects of 2 SNPs of OPRM1 gene on plasma buprenorphine and norbuprenorphine levels in a sample of 233 OUD patients receiving BUP/naloxone were examined. Polymorphisms were analyzed by PCR and RFLP. BUP and norbuprenorphine concentrations in plasma were measured by LC-MS/MS. OPRM1 rs2075572 GC + CC (0.12 ng/ml) had significantly higher plasma BUP level compared to GG (0.084 ng/ml) (p = 0.043). Although there was not a statistically significant difference between OPRM1 rs562859 genotypes (p = 0.46), patients with OPRM1 rs562859 CT + TT had higher plasma BUP and BUP-related values as compared to those with CC. In conclusion, the effect of OPRM1 rs2075572 on BUP levels in opioid users' plasma was shown in a Caucasian population for the first time. On the other hand, OPRM1 rs562859 seems not to influence the BUP pharmacology.
Topics: Humans; Receptors, Opioid, mu; Male; Female; Adult; Buprenorphine; Polymorphism, Single Nucleotide; Opioid-Related Disorders; Middle Aged; Analgesics, Opioid; Genotype
PubMed: 38821204
DOI: 10.1016/j.neulet.2024.137846 -
Early Human Development Jul 2024Naltrexone is a medication used to treat both opioid and alcohol use disorder with limited experience in pregnant individuals, particularly in comparison to more... (Comparative Study)
Comparative Study
BACKGROUND
Naltrexone is a medication used to treat both opioid and alcohol use disorder with limited experience in pregnant individuals, particularly in comparison to more commonly utilized treatments such as buprenorphine-naloxone. The long-term outcomes of infants exposed to naltrexone has not been previously examined.
AIMS
To compare the neurobehavioral outcomes of naltrexone versus buprenorphine-naloxone exposed infants.
STUDY DESIGN
Multi-centered prospective cohort study.
SUBJECTS
Pregnant people on prescribed buprenorphine-naloxone or naltrexone were enrolled during pregnancy and the dyad followed until 12 months after delivery.
OUTCOME MEASURES
Infants were evaluated at 4-6 weeks corrected gestational age (CGA) using the NICU Neonatal Neurobehavioral Scale (NNNS) and at the 12-month CGA visit using the Ages and Stages Questionnaire, Third Edition (ASQ-3).
RESULTS
There were 7 dyads in the naltrexone group and 34 in the buprenorphine-naloxone group. On the NNNS, infants exposed to naltrexone had higher median scores for arousal and excitability, and lower median scores for attention and regulation at 4-6 weeks CGA compared to the buprenorphine-naloxone group. None of the infants in the naltrexone group were monitored for NOWS and had shorter length of hospital stay compared with the buprenorphine-naloxone group. Although no statistically significant differences were observed, more infants in the buprenorphine-naloxone group were identified as at risk for development delays in the communication, problem solving, and personal social domains of the ASQ-3 at 12 months CGA. Results should be interpreted with caution given this study's small sample size and lack of a prospective comparison cohort.
CONCLUSIONS
In this small cohort, there are differences noted in infant neurobehavior by NNNS at 4-6 weeks of age when comparing the buprenorphine-naloxone and naltrexone groups. At 12 months, ASQ-3 scores were similar but with percentage differences in potential development delay risk observed between the two groups. Larger cohort studies are needed to determine the long-term child outcomes after naltrexone exposure in pregnancy.
Topics: Humans; Female; Pregnancy; Infant, Newborn; Adult; Naltrexone; Narcotic Antagonists; Buprenorphine; Prenatal Exposure Delayed Effects; Male; Buprenorphine, Naloxone Drug Combination; Child Development; Infant; Infant Behavior; Prospective Studies; Opioid-Related Disorders; Naloxone; Pregnancy Complications
PubMed: 38815498
DOI: 10.1016/j.earlhumdev.2024.106051 -
NEJM Evidence May 2024AbstractA growing number of patients are prescribed buprenorphine for opioid use disorder (OUD). Consequently, clinicians are likely to encounter hospitalized patients... (Review)
Review
AbstractA growing number of patients are prescribed buprenorphine for opioid use disorder (OUD). Consequently, clinicians are likely to encounter hospitalized patients with acute surgical or nonsurgical pain who are also prescribed buprenorphine for OUD. This scenario evokes the clinical question of how to adequately manage acute pain among hospitalized patients receiving buprenorphine for OUD. This article reviews buprenorphine's pharmacology, describes various buprenorphine products used to treat pain and OUD, and provides pain management recommendations for patients prescribed buprenorphine in the setting of acute surgical and nonsurgical pain.
Topics: Buprenorphine; Humans; Opioid-Related Disorders; Acute Pain; Analgesics, Opioid; Pain Management; Opiate Substitution Treatment
PubMed: 38815158
DOI: 10.1056/EVIDccon2300275