Cardiovascular Risk of Opioids: A Real-World Study Based on FAERS

Objective:This research utilizes the FAERS for data mining to identify heart-related side effects caused by opioids,ensuring the safe use of these medications.Methods:Data from 79 quarters(Q12004 to Q32023)involving adverse event(AE)reports for opioids like morphine and oxycodone was reviewed.We applied the MedDRA system to categorize events and used statistical tools,ROR and BCPNN,for signal detection.These findings were cross-checked with drug labels and SIDER 4.1 for accuracy.Identified risks were then categorized by severity using DME and IME classifications.Results:Analysis of adverse events(AEs)for the five examined drugs(35359,14367,144441,10592,and 28848)identified 33,6,12,37,and 34 cardiovascular AEs,and 16,5,7,25,and 21 instances of important medical events(IMEs)respectively.Each drug was linked to cases of cardiac and cardiopulmonary arrest.The cardiovascular AEs varied widely in occurrence and severity,with methadone notably presenting diverse and potent risks,including sudden cardiac death as a distinct medical event(DME).A comparison with SIDER 4.1 showed 11 opioid-related cardiovascular AEs in line with our findings.Standardized MedDRA Queries(SMQs)confirmed these results,indicating stronger signals for methadone and tramadol,while morphine,hydromorphone,and oxycodone exhibited fewer and weaker signals.Conclusion:The study revealed numerous heart-related adverse effects(AEs)not listed on drug labels and identified new AE patterns.Recognizing these differences in AE profiles and risks across different opioids is crucial for safer prescription practices to minimize cardiac complications.

Exploring the Contribution of Pharmacists in Addressing the Opioid Crisis through Naloxone Prescriptions and Pharmacist-Led Interventions

The opioid epidemic in the United States continues to take the lives of many individuals, with overdoses continuing to rise every year. Naloxone is an opioid antagonist that is efficacious in temporarily reversing opioid overdoses. Pharmacists play an important role in the accessibility and education of naloxone in both the community and health system settings. Recent efforts, such as co-dispensing naloxone with opioid prescriptions, naloxone training programs, and approval of naloxone to be over-the-counter, have been implemented in hopes to better control the opioid epidemic. Despite the efforts to make naloxone more accessible, there are still some barriers to overcome such as lack of training, cost, stigma, and patient refusal. This review aims to explore the contributions pharmacists have made thus far and define the barriers that still have to be resolved.

Fentanyl and xylazine crisis:Crafting coherent strategies for opioid overdose prevention

The United States is in the throes of a severe opioid overdose epidemic,primarily fueled by the pervasive use of fentanyl and the emerging threat of xylazine,a veterinary sedative often mixed with fentanyl.The high potency and long duration of fentanyl is compounded by the added risks from xylazine,heightening the lethal danger faced by opioid users.Measures such as enhanced surveillance,public awareness campaigns,and the distribution of fentanylxylazine test kits,and naloxone have been undertaken to mitigate this crisis.Fentanyl-related overdose deaths persist despite these efforts,partly due to inconsistent policies across states and resistance towards adopting harm reduction strategies.A multifaceted approach is imperative in effectively combating the opioid overdose epidemic.This approach should include expansion of treatment access,broadening the availability of medications for opioid use disorder,implementation of harm reduction strategies,and enaction of legislative reforms and diminishing stigma associated with opioid use disorder.

The Impact of Opioid Drugs on Memory and Other Cognitive Functions: A Review

Background and Purpose: Opioids, used for centuries to alleviate pain, have become a double-edged sword. While effective, they come with a host of adverse effects, including memory and cognition impairment. This review delves into the impact of opioid drugs on cognitive functions, explores underlying mechanisms, and investigates their prevalence in both medical care and illicit drug use. The ultimate goal is to find ways to mitigate their potential harm and address the ongoing opioid crisis. Methods: We sourced data from PubMed and Google Scholar, employing search combinations like “opioids,” “memory,” “cognition,” “amnesia,” “cognitive function,” “executive function,” and “inhibition.” Our focus was on English-language articles spanning from the inception of these databases up to the present. Results: The literature consistently reveals that opioid use, particularly at high doses, adversely affects memory and other cognitive functions. Longer deliberation times, impaired decision-making, impulsivity, and behavioral disorders are common consequences. Chronic high-dose opioid use is associated with conditions such as amnesiac syndrome (OAS), post-operative cognitive dysfunction (POCD), neonatal abstinence syndrome (NAS), depression, anxiety, sedation, and addiction. Alarming trends show increased opioid use over recent decades, amplifying the risk of these outcomes. Conclusion: Opioids cast a shadow over memory and cognitive function. These effects range from amnesiac effects, lessened cognitive function, depression, and more. Contributing factors include over-prescription, misuse, misinformation, and prohibition policies. Focusing on correct informational campaigns, removing punitive policies, and focusing on harm reduction strategies have been shown to lessen the abuse and use of opioids and thus helping to mitigate the adverse effects of these drugs. Further research into the impacts of opioids on cognitive abilities is also needed as they are well demonstrated in the literature, but the mechanism is not often completely understood.

Pain management in acute musculoskeletal injury: Effect of opioid vs nonopioid medications

BACKGROUND The use of opioids for pain is linked to an increased risk of developing opioid use disorder,and has resulted in the emergence of the opioid crisis over the last few years.AIM The systematic review question is“How does the use of opioid medications in pain management,compared with non-opioid medications,affect pain intensity over the short,intermediate,and long-term in adults with acute traumatic pain?”.METHODS The protocol was prospectively registered on the International Prospective Re-gister of Systematic Reviews:CRD42021279639.Medline and Google Scholar were electronically searched for controlled peer-reviewed studies published in full,with the PICO framework:P:Adult patients with traumatic injuries,I:Opioid medications,C:Non-opioid medi-cations,O:A minimum clinically important difference(MCID)in pain.RESULTS After full-text screening,we included 14 studies in the qualitative synthesis.Of these 14 studies,12 were rando-mized clinical trials(RCTs)and 2 were pseudo-RCTs with a total of 2347 patients enrolled.There was heteroge-neity in both medication utilized and outcome in these studies;only two studies were homogeneous regarding the type of study conducted,the opioid used,its comparator,and the outcome explored.The MCID was evaluated in 8 studies,while in 6 studies,any measured pain reduction was considered as an outcome.In 11 cases,the setting of care was the Emergency Department;in 2 cases,care occurred out-of-hospital;and in one case,the setting was not well-specified.The included studies were found to have a low-moderate risk of bias.CONCLUSION Non-opioids can be considered an alternative to opioids for short-term pain management of acute musculoskeletal injury.Intravenous ketamine may cause more adverse events than other routes of administration.

Adaptive Modeling of Monthly Depression Levels in Terms of Daily Assessments of Opioid Medications Taken and Pain Levels for Cancer Patients

A research study collected intensive longitudinal data from cancer patients on a daily basis as well as non-intensive longitudinal survey data on a monthly basis. Although the daily data need separate analysis, those data can also be utilized to generate predictors of monthly outcomes. Alternatives for generating daily data predictors of monthly outcomes are addressed in this work. Analyses are reported of depression measured by the Patient Health Questionnaire 8 as the monthly survey outcome. Daily measures include numbers of opioid medications taken, numbers of pain flares, least pain levels, and worst pain levels. Predictors are averages of recent non-missing values for each daily measure recorded on or prior to survey dates for depression values. Weights for recent non-missing values are based on days between measurement of a recent value and a survey date. Five alternative averages are considered: averages with unit weights, averages with reciprocal weights, weighted averages with reciprocal weights, averages with exponential weights, and weighted averages with exponential weights. Adaptive regression methods based on likelihood cross-validation (LCV) scores are used to generate fractional polynomial models for possible nonlinear dependence of depression on each average. For all four daily measures, the best LCV score over averages of all types is generated using the average of recent non-missing values with reciprocal weights. Generated models are nonlinear and monotonic. Results indicate that an appropriate choice would be to assume three recent non-missing values and use the average with reciprocal weights of the first three recent non-missing values.

Personalized medicine and opioid use disorder

Opioid use disorder(OUD)is a major public health problem affecting millions of people worldwide.Although OUD is a chronic and relapsing disorder,a variety of pharmacological and non-pharmacological interventions are available.Medication-assisted treatment of OUD generally relies on competition for opioid receptors against the addictive substance.The mechanisms of this competition are to block or inactivate the opioid receptor or activate the receptor with a substance that is intermittent or long acting.Methadone and buprenorphine are two United States Food and Drug Administration-approved medications that have long-term positive effects on the health of opioid-dependent individuals.Although clinical studies of drugs generally demonstrate efficacy in thousands of people and toxicity is excluded,it cannot be predicted whether the given drug will cause side effects in one of the patients at the treatment dose.Individual differences can be explained by many biological and environmental factors.Variations in genes encoding drug metabolism or cellular drug targets significantly explain the variability in drug response between individuals.Therefore,for the effects of candidate genes to be accepted and included in individual treatment protocols,it is important to repeat studies on individuals of different ethnic backgrounds and prove a similar effect.

Guidance on opioids prescribing for the management of persistent non-cancer pain in older adults

Many older adults suffer from persistent pain but prevalence studies consistently showed high levels of untreated or under-treated pain in old population.Both persistent pain and pain under-treatment adversely affect independence and quality of life in geriatric patients.Pain management is challenging in this age-group because of the declining organ function,the presence of concurrent diseases and polypharmacy.For all the above reasons,persistent pain in the elderly should be considered a geriatric syndrome per se and effective approaches are warranted.Current guidelines and consensus statements recommend opioid therapy for older adults with moderateto-severe persistent pain or functional impairment and diminished quality of life due to pain.However clinicians and patients themselves have some concerns about opioids use.Age-related decline in organs functions and warnings about risk of addiction and drug misuse/abuse also in geriatric patients need particular attention for safe prescribing.On the basis of clinical evidence,these practical recommendations will help to improve the competence on opioid role in persistent pain management and the likelihood of a successful analgesic trial in older patients.

Chronic opioids in gastroparesis: relationship with gastrointestinal symptoms, healthcare utilization and employment

AIM To examine the relationship of chronic scheduled opioid use on symptoms, healthcare utilization and employment in gastroparesis(Gp) patients. Methods Patients referred to our tertiary care academic center from May 2016 to July 2017, with established diagnosis or symptoms suggestive of Gp filled out the Patient Assessment of Upper GI Symptoms, abdominal pain and demographics questionnaires, and underwent gastric emptying and blood tests. They were asked about taking pain medicines and the types, doses, and duration. We used Mann Whitney U test, Analysis of Variance, Student's t test and χ2 tests where appropriate for data analyses.RESULTS Of 223 patients with delayed gastric emptying, 158(70.9%) patients were not taking opioids(Gp NO), 22(9.9%) were taking opioids only as needed, while 43(19.3%) were on chronic(> 1 mo) scheduled opioids(Gp CO), of which 18 were taking opioids forreasons that included gastroparesis and/or stomach pain. Median morphine equivalent use was 60 mg per day. Gp CO reported higher severities of many gastrointestinal symptoms compared to Gp NO including nausea(mean ± SE of mean of 4.09 ± 0.12 vs 3.41 ± 0.12, P = 0.011), retching(2.86 ± 0.25 vs 1.98 ± 0.14, P = 0.003), vomiting(2.93 ± 0.24 vs 2.07 ± 0.15, P = 0.011), early satiety(4.17 ± 0.19 vs 3.57 ± 0.12, P = 0.004), post-prandial fullness(4.14 ± 0.18 vs 3.63 ± 0.11, P = 0.022), loss of appetite(3.64 ± 0.21 vs 3.04 ± 0.13, P = 0.039), upper abdominal pain(3.86 ± 0.20 vs 2.93 ± 0.13, P = 0.001), upper abdominal discomfort(3.74 ± 0.19 vs 3.09 ± 0.13, P = 0.031), heartburn during day(2.55 ± 0.27 vs 1.89 ± 0.13, P = 0.032), heartburn on lying down(2.76 ± 0.28 vs 1.94 ± 0.14, P = 0.008), chest discomfort during day(2.42 ± 0.20 vs 1.83 ± 0.12, P = 0.018), chest discomfort at night(2.40 ± 0.23 vs 1.61 ± 0.13, P = 0.003), regurgitation/reflux during day(2.77 ± 0.25 vs 2.18 ± 0.13, P = 0.040) and bitter/acid/sour taste in the mouth(2.79 ± 0.27 vs 2.11 ± 0.14, P = 0.028). Gp CO had a longer duration of nausea per day(median of 7 h vs 4 h for Gp NO, P = 0.037), and a higher number of vomiting episodes per day(median of 3 vs 2 for Gp NO, P = 0.002). Their abdominal pain more frequently woke them up at night(78.1% vs 57.3%, P = 0.031). They had a lower employment rate(33.3% vs 54.2%, P = 0.016) and amongst those who were employed less number of working hours per week(median of 23 vs 40, P = 0.005). They reported higher number of hospitalizations in the last 1 year(mean ± SE of mean of 2.90 ± 0.77 vs 1.26 ± 0.23, P = 0.047). CONCLUSION Gp CO had a higher severity of many gastrointestinal symptoms, compared to Gp NO. Hospitalization rates were more than 2-fold higher in Gp CO than Gp NO.Gp CO also had lower employment rate and working hours, when compared to Gp NO.

Polysubstance Use and Overdose Visualized via Maps: Opioids

Polysubstance (combinations of substances) abuse and overdose deaths now surpass mono-substance abuse and overdose deaths. Several international and governmental organizations such as the WHO (World Health Organization), CDC (Centers for Disease Control and Prevention), several of the Institutes of the NIH (National Institutes of Health), Regulators, and Enforcement Agencies, among others, track and provide a valuable source of statistical information about drug (prescription and illicit) (mis)use and overdose. The information is disseminated free to stakeholders and the general public for use. Although the numeric presentations of the data are helpful and adequate for professionals, the non-expert and the visual learner often find visual representation more clear and more compelling. With this in mind, the aim of this study was to present polysubstance use and overdose using visual maps of the available data. This article considers the opioids.

Effects of propofol combined with different types of opioids on inflammatory stress response in painless gastroscopy

Objective:To study the effects of propofol combined with different types of opioids on inflammatory stress response in painless gastroscopy.Methods: Patients who underwent painless gastroscopy in our hospital between August 2014 and January 2018 were retrospectively analyzed, divided into those with nalbuphine hydrochloride, dezocine and sufentanil according to different choice of opioids and included in group A, group B and group C of the study respectively. The contents of inflammatory cytokines and oxidative stress products in serum as well as the expression levels of inflammatory pathway molecules and antioxidant pathway molecules in peripheral blood were measured before and 6 h after gastroscopy.Results: HMGB-1, TNF-α, IFN-γ, CRP, MDA, OH- and O2- contents in serum as well as RhoA, ROCK, Wnt3a,β-catenin, JNK, ERK1/2, Nrf2, ARE, HO-1,γ-GCS and Prx1 expression in peripheral blood of three groups of patients after gastroscopy were higher than those before gastroscopy, and HMGB-1, TNF-α, IFN-γ, CRP, MDA, OH- and O2- contents in serum as well as RhoA, ROCK, Wnt3a,β-catenin, JNK and ERK1/2 expression in peripheral blood of group A after gastroscopy were lower than those of group B and group C whereas Nrf2, ARE, HO-1,γ-GCS and Prx1 expression in peripheral blood were higher than those of group B and group C.Conclusion: Propofol combined with nalbuphine hydrochloride can be more effective than dezocine and sufentanil to reduce the inflammatory stress response in painless gastroscopy.

Research progress on the influence of opioids on fetal neurodevelopment during pregnancy

Women usually suffer from chronic pain due to pregnancy or have an increased level of chronic pain.In view of the definite curative effect of opioids on chronic pain and opioid use disorders,opioids have attracted much attention in the treatment of bone,joint,neuropathic and other chronic pain and opioid use disorders in pregnant women.Considering that the unreasonable use of opioids by pregnant women will lead to risks such as drug accumulation and increased neural sensitivity in the fetus,the correct and reasonable use of opioids is the key to the treatment.In recent years,it has been found that opioids can cross the blood fetal barrier into the fetal circulation,and damage fetal nerve development to varying degrees.However,the studies on the typical diseases such as neonatal neural tube defects and neonatal abstinence syndrome are not comprehensive.Therefore,this article has clarified the unreasonable use of opioids during pregnancy and its effect on fetal nerve development,and put forward relevant measures in order to provide reference for clinicians/pharmacists in obstetrics and gynecology.

Dimethyltyrosine, the Viagra of Opioids

Introduction The introduction of 2＇ ,6＇-dimethyl-L＇tyrosine （Dmt） at the N-terminus of Tyr-Tic （1,2,3,4-tetra-hydroisoquinoline-3-carboxylic acid ）-containing δ-opioid antagonists enhances receptor affinity and in vitro bioactivity to several orders of magnitude and its application in the formation of ligands with new properties, such as potent inverse agonism. For example, the δ2 agonist,

“New-Look” Opioids: Biased Ligands

Between the illicit use of opioids and attendant overdoses, and accidental overdoses with prescribed drugs, overuse of opioids has become a serious problem. At the same time, finding that fine balance between minimizing the risk of opioid misuse and abuse while at the same time providing access to treatment for patients who need pain control presents an ongoing challenge. Efforts to discover and develop better agents have led to what we term “new-look” opioids. We summarize here one such approach—known as biased ligands. By targeting a subset of GPCR signal transduction, this approach attempts to increase the separation between therapeutic and adverse effects.

REGULATION OF ANTI-SRBC ANTIBODY PRODUCTION BY OPIOIDS AND THEIR MECHANISMS

This study focused on the influences of opioids on the generation of antibody against sheep erythrocyte in vitro, It was found that morphine. a-CAO, DADLE, MENK were able to inhibit the capacity of murine spleen cells to generate antibody and leukotriene C4 and conversely. dynorphin was able to stimulate the capacity of murine spleen cells to generate antibody and leukotriene C4. Morphine, a-CAO, MENK, DADLE, dynorphin decreased intracellular cAMP level, increased [Ca(2+)]i and calmodulin activity. The effects were completely blocked by naloxone, the specific opioid antagonist. Our results showed that opioids regulate the production of antibody in murine spleen cells, and alter intracellular cAMP, [Ca(2+)]i calmodulin activity. and leukotriene C4 production by way of binding to different receptor types.

Impact of adding opioids to paravertebral blocks in breast cancer surgery patients:A systematic review and meta-analysis

BACKGROUND Several breast cancer studies have reported the use of adjuvant opioids with the paravertebral block(PVB)to improve outcomes.However,there is no level-1 evidence justifying its use.AIM To elucidate if the addition of opioids to PVB improves pain control in breast cancer surgery patients.METHODS We conducted an electronic literature search across PubMed,Embase,Scopus,and Google Scholar databases up to October 20,2020.Only randomized controlled trials(RCTs)comparing the addition of opioids to PVB with placebo for breast cancer surgery patients were included.RESULTS Six RCTs were included.Our meta-analysis indicated significantly reduced 24-h total analgesic consumption with the addition of opioids to PVB as compared to placebo[standardized mean difference(SMD)-1.57,95%confidence interval(CI):-2.93,-0.21,I2=94%].However,on subgroup analysis,the results were nonsignificant for studies using single PVB(SMD:-1.76,95%CI:-3.65,0.13 I2=95.09%)and studies using PVB infusion(SMD:-1.30,95%CI:-4.26,1.65,I2=95.49%).Analysis of single PVB studies indicated no significant difference in the time to first analgesic request between opioid and placebo groups(mean difference-11.28,95%CI:-42.00,19.43,I2=99.39%).Pain scores at 24 h were marginally lower in the opioid group(mean difference-1.10,95%CI:-2.20,0.00,I2=0%).There was no difference in the incidence of postoperative nausea and vomiting between the two groups.CONCLUSION Current evidence suggests a limited role of adjuvant opioids with PVB for breast cancer surgery patients.Further homogenous RCTs with a large sample size are needed to clarify the beneficial role of opioids with PVB.

The neuroimmunopharmacology of opioids and the CNS drug discovery

Opioids have been used for treated pain for thousands of years. Meanwhile, opioids induce drug addic- tion, which causes serious medical and social problems. Most opioids research have been concentrated on neurons in the central nerve system （CNS） , however, the action of glia, which accounts for 90% cells in CNS have been long neglected. Unlike the classical opioid-neuron stereoselective interaction opioids were found to non-stereose- lectively bind the accessory protein myeloid differentiation factor 2 （MD-2） of innate immune Toll- like receptor 4 （TLR4） , which induces glial activation and pro-inflammatory factors production, therefore contributing to opioid hyper-analgesia, drug tolerance, dependence and addiction. A series of TLR4 antagonists have been discovered by multiple drug discovery strategies for inhibiting the opioids＇ side effects and treating drug abuse, among which （ ＋ ）-naltrexone and T-5342126 have been transferred to Xalud and BioLineRx respectively, for further pre-clini- cal/clinical drug development.

Study on Opioids Diffusion Based on Improved SIR Model

The abuse of opioids is harmful to the national economy and health.The U.S.government has spent a lot of time,energy and money to deal with this phenomenon.Based on the topic background and team discussion,we deeply excavated the data and information provided in the topic,determined the current use of opioids,and constructed an improved SIR model to determine the source of drug abuse,the mechanism of drug abuse diffusion and the origin of each state through reverse derivation,which provided guidance for the government in the context of opioid abuse.Based on the above results,we simulated and analyzed the improved SIR model and determined the accuracy and stability of the model in the data set.

Connectome-based predictive modelling can predict follow-up craving after abstinence in individuals with opioid use disorders

Background Individual differences have been detected in individuals with opioid use disorders(OUD)in rehabilitation following protracted abstinence.Recent studies suggested that prediction models were effective for individual-level prognosis based on neuroimage data in substance use disorders(SUD).Aims This prospective cohort study aimed to assess neuroimaging biomarkers for individual response to protracted abstinence in opioid users using connectome-based predictive modelling(CPM).Methods One hundred and eight inpatients with OUD underwent structural and functional magnetic resonance imaging(fMRI)scans at baseline.The Heroin Craving Questionnaire(HCQ)was used to assess craving levels at baseline and at the 8-month follow-up of abstinence.CPM with leave-one-out cross-validation was used to identify baseline networks that could predict follow-up HCQ scores and changes in HCQ(HCQtolow V-up-HCQpa baseline).Then,the follow-up aseline predictive ability of identified networks was tested in a separate,heterogeneous sample of methamphetamine individuals who underwent MRI scanning before abstinence for SUD.Results CPM could predict craving changes induced by long-term abstinence,as shown by a significant correlation between predicted and actual HCQ fllow-up(r=0.417,p<0.001)and changes in HCQ(negative:r=0.334,p=0.002;positive:r=0.233,p=0.038).Identified craving-related prediction networks included the somato-motor network(SMN),salience network(SALN),default mode network(DMN),medial frontal network,visual network and auditory network.In addition,decreased connectivity of frontal-parietal network(FPN)-SMN,FPN-DMN and FPN-SALN and increased connectivity of subcortical network(SCN)-DMN,SCN-SALNandSCN-SMN were positively correlated with craving levels.Conclusions These findings highlight the potential applications of CPM to predict the craving level of individuals after protracted abstinence,as well as the generalisation ability;the identified brain networks might be the focus of innovative therapies in the future.

A Randomized Controlled Clinical Trial on Efficacy and Safety of Electroacupuncture on Oral Oxycodone Hydrochloride Prolonged-Release Tablets Related Constipation

Objective:To observe the efficacy and safety of electroacupuncture on oral oxycodone hydrochloride prolonged-release tablets related constipation in Qi(气)deficiency syndrome.Methods:A randomized control trial was conducted in 44 participants,who were divided into the treatment group(electroacupuncture group)and the control group(western medicine group).Two groups were treated by electroacupuncture at Zusanli(ST36),Tianshu(ST25),Zhigou(SJ6)and Shangjuxu(ST37)acupoints every day for 20 mins for 14 consecutive days and lactulose oral solution 30 ml every day for 14 consecutive days respectively.The constipation symptoms,traditional Chinese medicine(TCM)symptoms,quality of life,physical condition before and after the treatments were observed,and the safety indicators were monitored.Results:The treatment group was better than the control group in improving constipation symptom score,improving TCM symptom score and improving quality of life score,and the difference was statistically significant.There was no significant difference between the two groups in improving physical condition score.No acupuncture related adverse events were observed in the treatment group.Two patients in the control group withdrew from the study due to taking emergency defecation therapy and mild diarrhea respectively.Conclusion:Electroacupuncture is better than lactulose in the treatment of Qi deficiency constipation related to oxycodone hydrochloride prolonged-release tablets.It can significantly improve the symptoms of constipation,improve the symptoms of TCM,improve the quality of life.It is safe and effective.