Treatment Of Opioid Addiction Research Articles

Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction

Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction

Development of fentanyl-specific monoclonal antibody (mAb) to antagonize the pharmacological effects of fentanyl

Fentanyl, a critical component of opioid analgesics, poses a severe threat to public health, exacerbating the drug problem due to its potential fatality. Herein, we present two novel haptens designed with different attachment sites conjugated to keyhole limpet hemocyanin (KLH), aiming to develop an efficacious vaccine against fentanyl. KLH-Fent-1 demonstrated superior performance over KLH-Fent-2 in antibody titer, blood-brain distribution, and antinociceptive tests. Consequently, we immunized mice with KLH-Fent-1 to generate fentanyl-specific monoclonal antibodies (mAbs) using the hybridoma technique to compensate for the defects of active immunization in the treatment of opioid overdose and addiction. The mAb produced by hybridoma 9D5 exhibited the ability to recognize fentanyl and its analogs with a binding affinity of 10−10 M. Subsequently, we developed a human IgG1 chimeric mAb to improve the degree of humanization. Pre-treatment with murine and chimeric mAb significantly reduced the analgesic effect of fentanyl and altered its blood-brain biodistribution in vivo. Furthermore, in a mouse model of fentanyl-induced respiratory depression, the chimeric mAb effectively reversed respiratory depression promptly and maintained a certain level during the week. The development of high-affinity chimeric mAb gives support to combat the challenges of fentanyl misuse and its detrimental consequences. In conclusion, mAb passive immunization represents a viable strategy for addressing fentanyl addiction and overdose.

White House proposed FY 2025 budget would increase MH BG $35 million, keep SUPTRS BG level

On March 11, the White House released the proposed budget for fiscal year (FY) 2025, which begins Oct. 1, 2024. The proposal includes a 10% set‐aside in the Substance Use Prevention, Treatment, and Recovery Services (SUPTRS) Block Grant, which is funded at just over $2 billion, level with FY 2023, the most recent year for which final numbers are available. The Community Mental Health Services Block Grant would receive $1.043 billion in the proposed budget, a $35 million increase compared to FY 2023. The budget request (the White House asks Congress to fund programs) includes a proposal in which the Substance Abuse and Mental Health Services Administration would use HIV instead of AIDS to calculate the set‐aside in the SUPTRS BG. The State Opioid Response (SOR) grant would receive $1.595 billion, an increase of more than $20 million compared to FY 2023. Among other programs included in the White House request: Strategic Prevention Framework–Partnerships for Success at $135.5 million, level compared to FY 2023; Medication‐Assisted Treatment for Prescription Drug and Opioid Addiction at $111 million, level compared to FY 2023; Drug Courts at $74 million, level compared to FY 2023; Screening, Brief Intervention, and Referral to Treatment grants at $33.8 million, level compared to FY 2023; and Pregnant and Postpartum Women care at $43,931,000, an additional $39 million compared to FY 2023).

Methadone Maintenance Therapy (MMT) and Alternatives in Opioid Use Disorder: Reviewing the latest advancements, outcomes, and challenges in substitutional therapy for opioid addiction - literature review

Introduction and Purpose: Opioid addiction is a serious challenge for public health worldwide, and methadone maintenance therapy (MMT) is a key therapeutic approach. This review intends to provide an up-to-date summary of the pathophysiology, clinical manifestation, diagnostic techniques, and treatment options for Opioid Use Disorder. Materials and methods: The literature available in PubMed, Scopus, and Google Scholar databases was reviewed using the following keywords: "MMT," "methadone maintenance therapy", “maintenance therapy”, "opioid use disorder", "opioid addiction," "methadone”, ”naloxone” “naltrexone”, and “buprenorphine”. State of Knowledge: This review examines current approaches in maintenance therapy for Opioid Use Disorder (OUD). In the study, we focus on treatments using methadone, buprenorphine, naloxone, and naltrexone. It focuses on recent advancements, comparing the effectiveness, safety, and patient outcomes of these therapies. Key challenges in treatment accessibility and implementation are also discussed, providing an updated overview of the field and identifying areas for future research in opioid addiction therapy. Conclusion: There is a series of studies researching the psychological and behavioral problems associated with opioid addiction. This research has given medical practitioners valuable guidance on effective management techniques. According to the authors, compared to other alternative treatment methods, methadone maintenance therapy (MMT) is still considered the most effective pharmacotherapeutic method in the treatment of opioid addiction. Nevertheless, ongoing research is essential to improve diagnostic processes, develop innovative therapies, and enhance the overall quality of care for those affected by these challenges.

Multiscale topology in interactomic network: from transcriptome to antiaddiction drug repurposing.

The escalating drug addiction crisis in the United States underscores the urgent need for innovative therapeutic strategies. This study embarked on an innovative and rigorous strategy to unearth potential drug repurposing candidates for opioid and cocaine addiction treatment, bridging the gap between transcriptomic data analysis and drug discovery. We initiated our approach by conducting differential gene expression analysis on addiction-related transcriptomic data to identify key genes. We propose a novel topological differentiation to identify key genes from a protein-protein interaction network derived from DEGs. This method utilizes persistent Laplacians to accurately single out pivotal nodes within the network, conducting this analysis in a multiscale manner to ensure high reliability. Through rigorous literature validation, pathway analysis and data-availability scrutiny, we identified three pivotal molecular targets, mTOR, mGluR5 and NMDAR, for drug repurposing from DrugBank. We crafted machine learning models employing two natural language processing (NLP)-based embeddings and a traditional 2D fingerprint, which demonstrated robust predictive ability in gauging binding affinities of DrugBank compounds to selected targets. Furthermore, we elucidated the interactions of promising drugs with the targets and evaluated their drug-likeness. This study delineates a multi-faceted and comprehensive analytical framework, amalgamating bioinformatics, topological data analysis and machine learning, for drug repurposing in addiction treatment, setting the stage for subsequent experimental validation. The versatility of the methods we developed allows for applications across a range of diseases and transcriptomic datasets.

Behandeling van opioïdverslaafde zwangere vrouwen met buprenorfine: invloed op de foetus en de pasgeborene

Treatment of opioid addiction in pregnancy with buprenorphine: implications for the fetus and newborn The aim of this article is to summarize the actual knowledge on the use of buprenorphine for the treatment of opioid addiction in pregnancy. Buprenorphine is a semisynthetic thebaine derivative, increasingly used instead of methadone for the treatment of opioid-dependent pregnant women. Fetuses exposed to buprenorphine have a more favorable biophysical profile compared to methadone. The neonatal abstinence syndrome (NAS) occurs less in comparison to methadone-exposed neonates. Treatment is not always indicated and, if necessary, morphine is administered. Buprenorphine is a promising alternative to methadone in the treatment of pregnant women with opioid addiction.

Deaddicta® for maintenance treatment of Opioid-dependence: A six-month follow-up.

Opioid dependence, is one of the world's most critical health problems. Deaddicta is a herbal product considered an effective treatment for opioid addiction. Deaddicta's efficacy in the maintenance treatment of patients with opioid use disorder has recently been demonstrated through a double-blind randomized controlled trial (RCT). This study aimed to evaluate the permanence of Deaddicta's efficacy six months after the end of the maintenance treatment for opioid dependence. This study was performed following the previous RCT on the maintenance treatment of opioid addicts. Out of 41 participants who completed the study for three months in the previous research, 15 from the intervention group (Deaddicta capsules, 1500 mg/day) returned for follow-up. They all previously fulfilled the DSM-IV criteria for addiction, were aged 18 to 65, and had discontinued Deaddicta for six months. The outcome measures included addiction severity, depression and anxiety levels, and craving score. The scores of each parameter were compared in three phases: before intervention; after three months of intervention; and six months after the end of the study. Depression, anxiety, and craving scores decreased six months after the end of the previous study. This decrease was significant in the craving score (P = 0.011). No significant increase was observed in the frequency of use. The regression analysis showed a negative relationship between craving and the progression of phases. The Deaddicta product may have desirable and effective properties in decreasing temptation and, as a result, the maintenance treatment of opioid dependence.

Police Knowledge, Attitudes, and Beliefs About Opioid Addiction Treatment and Harm Reduction: A Survey of Illinois Officers

Police officers encounter individuals with opioid use disorder (OUD) during their routine work and are often called to the scene of overdoses. Despite this frequency, officer knowledge and attitudes about addiction, treatment, and harm reduction vary. Views held by officers, and the extent of their knowledge, can impact the decisions they make regarding people with OUD, yet our understanding of these factors is limited. Using stratified random sampling, we surveyed 248 officers from 27 Illinois police departments on their knowledge of addiction and the means to address it. We performed descriptive and regression analyses to examine differences based on officer characteristics. We found a high proportion of officers lacked knowledge of addiction, treatment, and harm reduction. Our findings suggest the need for police training to improve understanding of addiction. Community collaboration and coordination of resources may give officers the tools to better address OUD, reduce harm, and decrease overdose.

Nalmefene attenuates reinstatement of methamphetamine-seeking behavior in rats through group II metabotropic glutamate receptors (mGluR2/3)

Nalmefene, an analog to naltrexone, is an antagonist at the μ opioid receptor and a partial agonist at the κ opioid receptor. Both agents are approved for the treatment of alcohol use disorder and opioid addiction. Here, we evaluated the potential of nalmefene for treating psychostimulant dependence using a methamphetamine (METH) self-administration rat model. Rats were trained to press a lever for 0.02-mg intravenous METH infusions paired with drug-associated cues (light and tone) under a fixed ratio 1 schedule. After a 10-day METH self-administration acquisition phase, rats underwent extinction training. A reinstatement test was conducted after fulfilment of the extinction criterion under saline infusions. Re-exposure to METH-associated cues or a priming injection of METH (1.0 mg/kg, i.p.) significantly reinstated METH-seeking behaviors. Pretreatment with nalmefene (10 mg/kg, i.p.) immediately before reinstatement tests significantly attenuated the METH-seeking behaviors induced by both cues and METH priming injection. To investigate the mechanism of effect of nalmefene, we also tested the ability of a group II metabotropic glutamate receptors (mGluR2/3) antagonist, LY341495, to the ameliorating effects of nalmefene. Pretreatment with LY341495 (1.0 mg/kg, i.p.) before nalmefene administration antagonized the effect of nalmefene on reinstatement. LY341495 alone did not affect the reinstatement of lever pressing. We found that nalmefene attenuates METH-seeking behaviors during withdrawal, and this attenuation of reinstatement is mediated by the activation of mGluR2/3. The present findings suggest that nalmefene could decrease incentive motivation for drug use in psychostimulant dependence.

Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens

Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)—key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24-h cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes associated with vesicle-mediated transport and membrane trafficking in the NAc and platelet-derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.

De Novo Design of κ-Opioid Receptor Antagonists Using a Generative Deep-Learning Framework.

Likely effective pharmacological interventions for the treatment of opioid addiction include attempts to attenuate brain reward deficits during periods of abstinence. Pharmacological blockade of the κ-opioid receptor (KOR) has been shown to abolish brain reward deficits in rodents during withdrawal, as well as to reduce the escalation of opioid use in rats with extended access to opioids. Although KOR antagonists represent promising candidates for the treatment of opioid addiction, very few potent selective KOR antagonists are known to date and most of them exhibit significant safety concerns. Here, we used a generative deep-learning framework for the de novo design of chemotypes with putative KOR antagonistic activity. Molecules generated by models trained with this framework were prioritized for chemical synthesis based on their predicted optimal interactions with the receptor. Our models and proposed training protocol were experimentally validated by binding and functional assays.

The potential protective effect of melatonin and N-acetylcysteine alone and in combination on opioid-induced testicular dysfunction and degeneration in rat

Methadone (Met) is the most common treatment for opioid addiction. Although Met is effective for treatment of opioid dependence, sexual dysfunctions and infertility have been reported as a major problem in patients under Met treatment. The present study aimed to evaluate the effect of melatonin and N-acetylcysteine (N) on morphine and Met-induced oxidative stress, apoptosis, suppression of blood sexual hormones, impairment in sperm parameters, and sexual dysfunction. Adult male Wistar rats (n = 66) were randomly divided into 11 equal groups (n = 6) as follows: control, sham, morphine, Met, Met+N, Met+ melatonin, Met+melatonin+N, morphine+ Met, morphine+Met+ melatonin, morphine+Met+N, and morphine+Met+ melatonin+N groups. On day 56 post-treatment, the blood was collected from the tail and the serum levels of sex hormones were evaluated, then the rats were sacrificed, and their bilateral testes and epididymis were retrieved for histological, immunohistochemical, molecular, testicular tissue stress oxidative status, and sperm parameters assays. Exposure to morphine, Met, and shift of morphine to Met resulted in testicular degeneration that can be attributed to generating the stress oxidative-induced- apoptotic testicular cell death and impairing spermatogenesis. Melatonin and N alone and particularly, in combination with each other improved testicular degeneration, sex hormone suppression, and testicular function mediated by increasing the testicular antioxidant capacity and inhibition of the apoptosis pathway. It’s suggested that oral administration of antioxidants may be an effective treatment for attenuating some opioid-related testicular dysfunction and degeneration.

Development and clinical feasibility study of a brief version of an addiction-focused phenotyping battery in females receiving buprenorphine for opioid use disorder.

We aimed to streamline the NIDA Phenotyping Assessment Battery (PhAB), a package of self-report scales and neurobehavioral tasks used in substance use disorder (SUD) clinical trials, for clinical administration ease. Tailoring the PhAB to shorten administration time for a treatment setting is critical to expanding its acceptability in SUD clinical trials. This study's primary objectives were to develop a brief version of PhAB (PhAB-B) and assess its operational feasibility and acceptability in a female clinical treatment sample. Assessments of the original PhAB were evaluated along several criteria to identify a subset for the PhAB-B. Non-pregnant females (N=55) between ages 18-65, stabilized on buprenorphine for opioid use disorder (OUD) at an outpatient addiction clinic, completed this abbreviated battery remotely or after a provider visit in clinic. Participant satisfaction questions were administered. REDCap recorded the time to complete PhAB-B measures. The PhAB-B included 11 measures that probed reward, cognition, negative emotionality, interoception, metacognition, and sleep. Participants who completed the PhAB-B (N=55) were 36.1±8.9 years of age, White (54.5%), Black (34.5%), and non-Latinx (96.0%). Most participants completed the PhAB-B remotely (n = 42, 76.4%). Some participants completed it in-person (n = 13, 23.6%). PhAB-B mean completion time was 23.0±12.0 min. Participant experiences were positive, and 96% of whom reported that they would participate in the study again. Our findings support the clinical feasibility and acceptability of the PhAB-B among a female opioid use disorder outpatient addiction treatment sample. Future studies should assess the PhAB-B psychometric properties among broader treatment samples.

Strain and sex-related behavioral variability of oxycodone dependence in rats

Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting public health, social dynamics, and economic stability. The urgent need for improved treatments for opioid addiction necessitates a deeper understanding of its biological underpinnings, with genetic variations playing a crucial role in individual susceptibility to opioid use disorder (OUD) and influencing clinical practices.In this study, we leverage the genetic diversity of four rat strains (ACI/N, BN/NHsd, WKY/N, and F344/N) to examine the contribution of genetic factors to oxycodone metabolism and addiction-like behaviors. We used the extended access to intravenous oxycodone self-administration procedure (12 h/day, 0.15 mg/kg/injection) to comprehensively characterize oxycodone-related behaviors and pharmacokinetics. We measured escalation of oxycodone self-administration, motivation for drug consumption, tolerance to the analgesic effects of oxycodone, withdrawal-induced hyperalgesia, and oxycodone-induced respiratory depression. Additionally, we examined oxycodone-seeking behavior after four weeks of withdrawal by reintroducing the animals to environmental and cue stimuli previously associated with oxycodone self-administration.The findings revealed notable strain differences in several behavioral measures, including oxycodone metabolism. Intriguingly, BN/NHsd and WKY/N strains exhibited similar drug intake and escalation patterns but displayed significant disparities in oxycodone and oxymorphone metabolism. Minimal sex differences were observed within strains, primarily relating to oxycodone metabolism.In conclusion, this study identifies strain differences in the behavioral responses and pharmacokinetics associated with oxycodone self-administration in rats, providing a robust foundation for identifying genetic and molecular variants associated with various facets of the opioid addiction process.

Prescription psychostimulants as a harm reduction and treatment intervention for methamphetamine use disorder and the implications for nursing clinical practice: A scoping review of the literature.

The global rise in methamphetamine use and its negative effects warrants the need for research exploring harm reduction and treatment interventions for individuals with methamphetamine use disorder. Agonist medications have been utilized for years for the treatment of heroin and opioid addiction, but have yet to be incorporated into mainstream Canadian practice for methamphetamine dependence. This review aims to provide an overview of the current trends of prescription psychostimulant usage for individuals with methamphetamine use disorder from a Canadian perspective, identifies the barriers to accessing prescription psychostimulants for methamphetamine use disorder and highlights the nursing clinical practice implications in caring for individuals with the disorder. Discourse on the sustained abstinence and harm reduction debate is presented from the perspective of methamphetamine abuse is provided along with the neuropsychiatric complications of chronic methamphetamine use. The impacts of specific prescription psychostimulants on cognition are discussed as is the use of neuroimaging techniques to assess neuronal damage in methamphetamine users. Sign of toxicity, overdose and the contraindications for use of these prescription psychostimulants is also presented. The implications to nursing clinical practice in caring for this population is provided, touching on the clinical presentation of methamphetamine use, completing thorough assessment and screening and patient education. The findings of this review indicate the need for further research in this area exploring the benefits of prescription psychostimulants as a harm reduction and treatment intervention for the global problem of methamphetamine dependence.

Stimulant use among patients in opioid treatment settings: Provider perspectives

IntroductionMethadone maintenance therapy (MMT) has been a pillar of opioid addiction treatment. Opioid treatment programs (OTPs) have been faced with an escalating threat of stimulant use and related overdose deaths among patients. We know little about how providers currently address stimulant use while maintaining treatment for opioid use disorder. MethodsWe conducted 5 focus groups with 36 providers (n = 11 prescribers; 25 behavioral health staff), and collected an additional 46 surveys (n = 7 prescribers; 12 administrators; 27 behavioral health staff). Questions focused on perceptions of patient stimulant use and interventions. We applied inductive analysis to identify themes relevant to identification of stimulant use, use trends, intervention approaches, and perceived needs to improve care. ResultsProviders indicated a trend of rising stimulant use among patients, especially those experiencing homelessness or comorbid health conditions. They reported a range of approaches to patient screening and intervention, including medication and harm reduction, improving treatment engagement, increasing level of care, and providing incentives. Providers expressed less agreement as to which of these interventions were effective, and though providers saw stimulant use as a common and severe problem, they reported little problem recognition and interest in treatment from their patients. A particular concern of providers was the prevalence and danger of synthetic opioids, such as fentanyl. They sought more research and resources to identify effective interventions and medications to address these issues. Also notable was an interest in contingency management (CM) and use of reinforcements/rewards to encourage stimulant use reduction. ConclusionProviders face challenges in treating patients who use both opioids and stimulants. Although methadone is available to treat opioid use, no such “silver bullet” exists for stimulant use disorder. The rise in stimulant and synthetic opioid (e.g., fentanyl) combination products is presenting an extraordinary challenge for providers whose patients are at unprecedented risk for overdose. Providing OTPs with more resources to address polysubstance use is critical. Existing research indicates strong support for CM in OTPs, but providers reported regulatory and financial barriers to implementation. Further research should develop effective interventions that are accessible to providers in OTPs.

Machine-learning analysis of opioid use disorder informed by MOR, DOR, KOR, NOR and ZOR-based interactome networks

Opioid use disorder (OUD) continuously poses major public health challenges and social implications worldwide with dramatic rise of opioid dependence leading to potential abuse. Despite that a few pharmacological agents have been approved for OUD treatment, the efficacy of said agents for OUD requires further improvement in order to provide safer and more effective pharmacological and psychosocial treatments. Proteins including mu, delta, kappa, nociceptin, and zeta opioid receptors are the direct targets of opioids and play critical roles in therapeutic treatments. The protein–protein interaction (PPI) networks of the these receptors increase the complexity in the drug development process for an effective opioid addiction treatment. The report below presents a PPI-network informed machine-learning study of OUD. We have examined more than 500 proteins in the five opioid receptor networks and subsequently collected 74 inhibitor datasets. Machine learning models were constructed by pairing gradient boosting decision tree (GBDT) algorithm with two advanced natural language processing (NLP)-based autoencoder and Transformer fingerprints for molecules. With these models, we systematically carried out evaluations of screening and repurposing potential of more than 120,000 drug candidates for four opioid receptors. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were also considered in the screening of potential drug candidates. Our machine-learning tools determined a few inhibitor compounds with desired potency and ADMET properties for nociceptin opioid receptors. Our approach offers a valuable and promising tool for the pharmacological development of OUD treatments.

Five years follow up of buprenorphine treatment in Clinical Center of Montenegro

IntroductionMontenegro is a country in Southeastern Europe. Podgorica, the capital and largest city covers 30 % of its total population of 621 000 and around 80 % of patients enrolled in buprenorphine treatment.Buprenorphine was registered in Montenegro in May 2017.Buprenorphine is an opioid partial agonist. It’s a safe and an effective option for the treatment of opioid addiction. Buprenorphine may be abusable. Its abuse potential, however, is lower in comparison with that of opioid full agonists.ObjectivesBenefits of buprenorphine treatment:Suppress symptoms of opioid withdrawal. Reduce illicit opioid use. Help patients stay in treatment.Buprenorphine maintenance keeps the person stable while they make positive changes in their lives.Health problems are reduced or avoided, especially those related to injecting, such as HIV, hepatitis B and hepatitis C viruses, skin infections and vein problems.Crime behavior reductionMethodsClinical study.ResultsWe followed the patients who were enrolled in the buprenorphine substitution treatment for a period of five years, to be more precise in the period from May 2017 August 2022.In May of 2017 only 33 patients were enrolled in program, the number of patients were gradually increased to 193 patients in December of 2017. Until the December of 2018 the number of patients was increased to 203. In December of 2019 numbers of patients were increased to 291. At the end of 2020 numbers of patients were 348. In December of 2021 numbers of patients were increased to384 and in August of 2022 numbers of patient were 426.ConclusionsHealth problems are reduced or avoided.Crime behavior was reduced for 65% over five year’s period.A total of 124 new cases of HCV infection were discovered from the beginning of study to the end of July of 2022.Doses are required only once a day.For most adults with opioid use disorder, maintenance therapy with buprenorphine is the most effective treatment approach.Disclosure of InterestNone Declared

AI-assisted de novo design of selective κ-opioid receptor antagonists for the treatment of opioid addiction.

Daunting estimates of overdose fatalities, costs of healthcare, lost productivity, and criminal justice involvement for the misuse of prescription opioids have converted opioid use disorders into a major national crisis in the United States. Among likely efficacious pharmacological interventions for the treatment of opioid dependence are those that can attenuate brain reward deficits experienced during periods of abstinence. Pharmacological blockade of κ-opioid receptors (KOR) has been shown to abolish brain reward deficits detected in rodents during withdrawal from opioids, as well as to reduce the escalation of opioid use in rats with extended access to opioids. Although KOR antagonists represent promising candidates for the treatment of opioid addiction, very few potent selective KOR antagonists are known to date and most of them exhibit significant safety concerns. Here, we used a deep learning framework for the de novo design of ligands with predefined molecular properties to predict new chemotypes with KOR antagonistic activity. Specifically, we pre-trained a deep generative tensorial model to learn a mapping of the chemical space from a ZINC subset of purchasable drug-like molecules, as well as sets of effective (IC50 < 1 µM) or less effective (IC50 ≥ 1 µM) known KOR inhibitors from the ChEMBL database, while simultaneously encoding the relationship between the molecules and their properties. Subsequently, we biased the resulting generative model towards the development of putative KOR antagonists with a reinforcement learning algorithm that rewarded similarity to the antagonist binding mode revealed by the JDTic-bound KOR crystal structure, as well as novelty, synthetic accessibility, absence of unstable and reactive moieties, drug-like solubility, and blood-brain barrier permeability. The generated molecules were prioritized for chemical synthesis and functional evaluation based on their predicted optimal interactions with the receptor.

Changes and trends in medication-assisted treatment in Israel

BackgroundAs opioid prescription in Israel is increasing, there is a growing need for monitoring opioid use disorder and providing opioid agonist therapy. Our goal is to describe, sub-analyze, and identify obstacles in the treatment of opioid misuse in the Israeli medication assisted treatment centers.MethodsData on methadone, buprenorphine, and buprenorphine combined with naloxone for the indication of opioid addiction treatment for the period 2013–2020 were obtained from pharmaceutical companies that distribute them in Israel. Data on utilization of these drugs were also extracted from the database maintained by the Israel Ministry of Health's Pharmaceutical Administration Division. The data were converted to defined daily doses (DDD)/1000 inhabitants/day.ResultsThe number of patients receiving medication assisted treatment increased by 10% since 2013, with a shift from buprenorphine alone to buprenorphine/naloxone in government-run centers. Methadone remains the most popular maintenance drug.ConclusionsThe change in opioid maintenance prescription does not match the significant increase in opioid consumption. Optimization of treatment can be achieved by the creation of a comprehensive database, cooperation between healthcare organizations and the government and further development of non-stigmatic and accessible services.