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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 -
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 -
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 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Apr 2024This study aims to decipher the mechanism of sinomenine in inhibiting platelet-derived growth factor/platelet-derived growth factor receptor(PDGF/PDGFR) signaling...
This study aims to decipher the mechanism of sinomenine in inhibiting platelet-derived growth factor/platelet-derived growth factor receptor(PDGF/PDGFR) signaling pathway in rheumatoid arthritis-fibroblast-like synoviocyte(RA-FLS) migration induced by neutrophil extracellular traps(NETs). RA-FLS was isolated from the synovial tissue of 3 RA patients and cultured. NETs were extracted from the peripheral venous blood of 4 RA patients and 4 healthy control(HC). RA-FLS was classified into control group, HC-NETs group, RA-NETs group, RA-NETs+sinomenine group and RA-NETs+sinomenine+CP-673451 group. RNA-sequencing(RNA-seq) was conducted to identify the differentially expressed genes between HC-NETs and RA-NETs groups. Sangerbox was used to perform the Gene Ontology(GO) function and the Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment. Cytoscape was employed to build the protein-protein interaction(PPI) network. AutoDock Vina and PyMOL were used for molecular docking of sinomenine with PDGFβ and PDGFRβ. The cell proliferation and migration were determined by the cell counting kit-8(CCK-8) and cell scratch assay, respectively. Western blot was employed to determine the protein level of PDGFRβ. Real-time quantitative polymerase chain reaction(RT-qPCR) was carried out to determine the mRNA levels of matrix metalloproteinases(MMPs). The results revealed that neutrophils in RA patients were more likely to produce NETs. Compared with HC-NETs group, RA-NETs group showed up-regulated expression of PDGFβ and PDGFRβ. Compared with control group, RA-NETs group showed increased cell proliferation and migration and up-regulated protein level of PDGFRβ and mRNA levels of PDGFβ, PDGFRβ, MMP1, MMP3, and MMP9(P<0.05). Compared with RA-NETs group, RA-NETs+sinomenine group presented decreased cell proliferation and migration and down-regulated protein and mRNA level of PDGFRβ and mRNA levels of MMP1, MMP3, and MMP9(P<0.05). Compared with RA-NETs+sinomenine group, the proliferation ability of RA-NETs+sinomenine+CP-673451 group decreased(P<0.05). The findings prove that sinomenine reduces the RA-NETs-induced RA-FLS migration by inhibiting PDGF/PDGFR signaling pathway, thus mitigating RA.
Topics: Humans; Arthritis, Rheumatoid; Cell Movement; Signal Transduction; Morphinans; Synoviocytes; Platelet-Derived Growth Factor; Receptors, Platelet-Derived Growth Factor; Neutrophils; Male; Female; Fibroblasts
PubMed: 38812207
DOI: 10.19540/j.cnki.cjcmm.20240110.502 -
Journal of Medicinal Chemistry Jun 2024While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we...
While in the process of designing more effective synthetic opioid rescue agents, we serendipitously identified a new chemotype of potent synthetic opioid. Here, we report that conformational constraint of a piperazine ring converts a mu opioid receptor (MOR) antagonist into a potent MOR agonist. The prototype of the series, which we have termed atoxifent (), possesses potent in vitro agonist activity. In mice, atoxifent displayed long-lasting antinociception that was reversible with naltrexone. Repeated dosing of atoxifent produced antinociceptive tolerance and a level of withdrawal like that of fentanyl. In rats, while atoxifent produced complete loss of locomotor activity like fentanyl, it failed to produce deep respiratory depression associated with fentanyl-induced lethality. Assessment of brain biodistribution demonstrated ample distribution of atoxifent into the brain with a of approximately 0.25 h. These results indicate enhanced safety for atoxifent-like molecules compared to fentanyl.
Topics: Animals; Mice; Receptors, Opioid, mu; Respiratory Insufficiency; Analgesics, Opioid; Rats; Male; Fentanyl; Structure-Activity Relationship; Piperazines; Humans; Rats, Sprague-Dawley; Tissue Distribution; Brain; Naltrexone
PubMed: 38810170
DOI: 10.1021/acs.jmedchem.4c00333 -
Addiction (Abingdon, England) Aug 2024The aim of this study was to characterize the circumstances of drug overdose deaths and determine whether naloxone administration differed by overdose decedent race and...
AIMS
The aim of this study was to characterize the circumstances of drug overdose deaths and determine whether naloxone administration differed by overdose decedent race and ethnicity.
DESIGN AND SETTING
Analysis of data on unintentional and undetermined intent drug overdose deaths in Pennsylvania (2019-21) was collected from death certificates and the State Unintentional Drug Overdose Reporting System. Multivariable logistic regression models were adjusted for overdose death circumstances and the odds of naloxone administration were estimated by race/ethnicity and year.
CASES
The analytical sample included 3386 fatal overdose decedents in 2019, 3864 in 2020 and 3816 in 2021.
MEASUREMENTS
Evidence of naloxone administration (yes/no) was defined using scene evidence and toxicology reports from coroner and medical examiner records, while race/ethnicity (Hispanic, non-Hispanic Black, non-Hispanic White) was based on the death certificate.
FINDINGS
In the analytic sample, overdose death rates were the highest among Black people and increased over time (rate per 10 000 population, 2019: 4.3; 2020: 6.1; 2021: 6.5); rates were lowest among White people and remained constant over time (rate per 10 000 population, 2019: 2.6; 2020: 2.7; 2021: 2.6). Throughout all years, Black decedents had approximately 40-50% lower odds of naloxone administration compared with White decedents as referent [2019: odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.5-0.9; 2020: OR = 0.5, 95% CI = 0.4-0.7; 2021: OR = 0.6, 95% CI = 0.5-0.8], while Hispanic decedents had similar odds of naloxone administration to that of White decedents.
CONCLUSION
After controlling for overdose circumstances in drug overdose deaths in Pennsylvania, USA, from 2019 to 2021, Black people had lower odds of naloxone administration compared with White people, while there were no differences between Hispanic and White people.
Topics: Humans; Naloxone; Pennsylvania; Drug Overdose; Male; Female; Adult; Narcotic Antagonists; Middle Aged; White People; Young Adult; Black or African American; Ethnicity; Healthcare Disparities; Hispanic or Latino; Adolescent; Aged; Racial Groups
PubMed: 38808397
DOI: 10.1111/add.16478 -
Harm Reduction Journal May 2024People in Connecticut are now more likely to die of a drug-related overdose than a traffic accident. While Connecticut has had some success in slowing the rise in...
BACKGROUND
People in Connecticut are now more likely to die of a drug-related overdose than a traffic accident. While Connecticut has had some success in slowing the rise in overdose death rates, substantial additional progress is necessary.
METHODS
We developed, verified, and calibrated a mechanistic simulation of alternative overdose prevention policy options, including scaling up naloxone (NLX) distribution in the community and medications for opioid use disorder (OUD) among people who are incarcerated (MOUD-INC) and in the community (MOUD-COM) in a simulated cohort of people with OUD in Connecticut. We estimated how maximally scaling up each option individually and in combinations would impact 5-year overdose deaths, life-years, and quality-adjusted life-years. All costs were assessed in 2021 USD, employing a health sector perspective in base-case analyses and a societal perspective in sensitivity analyses, using a 3% discount rate and 5-year and lifetime time horizons.
RESULTS
Maximally scaling NLX alone reduces overdose deaths 20% in the next 5 years at a favorable incremental cost-effectiveness ratio (ICER); if injectable rather than intranasal NLX was distributed, 240 additional overdose deaths could be prevented. Maximally scaling MOUD-COM and MOUD-INC alone reduce overdose deaths by 14% and 6% respectively at favorable ICERS. Considering all permutations of scaling up policies, scaling NLX and MOUD-COM together is the cost-effective choice, reducing overdose deaths 32% at ICER $19,000/QALY. In sensitivity analyses using a societal perspective, all policy options were cost saving and overdose deaths reduced 33% over 5 years while saving society $338,000 per capita over the simulated cohort lifetime.
CONCLUSIONS
Maximally scaling access to naloxone and MOUD in the community can reduce 5-year overdose deaths by 32% among people with OUD in Connecticut under realistic budget scenarios. If societal cost savings due to increased productivity and reduced crime costs are considered, one-third of overdose deaths can be reduced by maximally scaling all three policy options, while saving money.
Topics: Humans; Connecticut; Naloxone; Opioid-Related Disorders; Narcotic Antagonists; Cost-Benefit Analysis; Drug Overdose; Opiate Overdose; Harm Reduction; Adult; Male; Quality-Adjusted Life Years; Female; Prisoners
PubMed: 38807226
DOI: 10.1186/s12954-024-01026-6 -
American Family Physician May 2024
Topics: Humans; Adult; Alcohol Deterrents; Alcoholism; Naltrexone; Alcohol-Related Disorders
PubMed: 38804761
DOI: No ID Found -
Scientific Reports May 2024Deep learning neural networks are often described as black boxes, as it is difficult to trace model outputs back to model inputs due to a lack of clarity over the...
Deep learning neural networks are often described as black boxes, as it is difficult to trace model outputs back to model inputs due to a lack of clarity over the internal mechanisms. This is even true for those neural networks designed to emulate mechanistic models, which simply learn a mapping between the inputs and outputs of mechanistic models, ignoring the underlying processes. Using a mechanistic model studying the pharmacological interaction between opioids and naloxone as a proof-of-concept example, we demonstrated that by reorganizing the neural networks' layers to mimic the structure of the mechanistic model, it is possible to achieve better training rates and prediction accuracy relative to the previously proposed black-box neural networks, while maintaining the interpretability of the mechanistic simulations. Our framework can be used to emulate mechanistic models in a large parameter space and offers an example on the utility of increasing the interpretability of deep learning networks.
Topics: Systems Biology; Neural Networks, Computer; Deep Learning; Naloxone; Humans; Pharmacology; Analgesics, Opioid; Computer Simulation
PubMed: 38802422
DOI: 10.1038/s41598-024-59378-9