Opioid Drugs Research Articles

A systematic review and network meta-analysis of pharmaceutical interventions used to manage chronic pain.

It is estimated 1.5 billion of the global population suffer from chronic pain with prevalence increasing with demographics including age. It is suggested long-term exposure to chronic could cause further health challenges reducing people's quality of life. Therefore, it is imperative to use effective treatment options. We explored the current pharmaceutical treatments available for chronic pain management to better understand drug efficacy and pain reduction. A systematic methodology was developed and published in PROSPERO (CRD42021235384). Keywords of opioids, acute pain, pain management, chronic pain, opiods, NSAIDs, and analgesics were used across PubMed, Science direct, ProQuest, Web of science, Ovid Psych INFO, PROSPERO, EBSCOhost, MEDLINE, ClinicalTrials.gov and EMBASE. All randomised controlled clinical trials (RCTs), epidemiology and mixed-methods studies published in English between the 1st of January 1990 and 30th of April 2022 were included. A total of 119 studies were included. The data was synthesised using a tri-partied statistical methodology of a meta-analysis (24), pairwise meta-analysis (24) and network meta-analysis (34). Mean, median, standard deviation and confidence intervals for various pain assessments were used as the main outcomes for pre-treatment pain scores at baseline, post-treatment pain scores and pain score changes of each group. Our meta-analysis revealed the significant reduction in chronic pain scores of patients taking NSAID versus non-steroidal opioid drugs was comparative to patients given placebo under a random effects model. Pooled evidence also indicated significant drug efficiency with Botulinum Toxin Type-A (BTX-A) and Ketamine. Chronic pain is a public health problem that requires far more effective pharmaceutical interventions with minimal better side-effect profiles which will aid to develop better clinical guidelines. The importance of understanding ubiquity of pain by clinicians, policy makers, researchers and academic scholars is vital to prevent social determinant which aggravates issue.

Medication safety, privacy, and stigma: A qualitative study of pharmacy opioid agonist treatment disruptions and adaptations in the 2022 Northern Rivers floods, Australia

BackgroundOpioid agonist treatment (OAT) involves the daily consumption of long-acting opioid medications to assist in managing health and wellbeing issues related to illicit or high-strength opioid drug use. Flooding events disrupted OAT service systems in the Northern Rivers region (Australia) in 2022. This study describes the experiences of OAT consumers and pharmacists during this time, including how structural stigma may have limited clinician behaviours and influenced consumer experiences. MethodsInterview transcripts from eleven pharmacists and thirteen consumers were collated and thematically analysed. ResultsOpioid agonist treatment consumers experienced disruptions when their prescribing and pharmacy treatment sites were destroyed by flood or where roads were cut off, and faced long delays if they attended the primary public clinic for emergency dosing or prescription re-issuing. Absent prescriptions were the main barrier to enabling emergency dosing. Pharmacists’ efforts in providing advance takeaways or discretionary doses reduced consumer hardships and distress. The treatment access difficulties that consumers experienced were found to be constrained by stigma, and this intensified risks related to medication safety and privacy. ConclusionsTreatment access was enabled when pharmacists operated outside of the restrictive medication safety protocols that opioid agonist treatment is uniquely subject to, and that is informed by structural stigma towards OAT consumers. Potential distress was averted where pharmacists took responsive approaches to protecting and maintaining OAT access. Future emergency planning should aim to protect and transmit OAT dose authorisation records more effectively, while striving to minimise adverse impacts including decreased privacy and accessibility.

Ultrasound-guided erector spinae plane block for perioperative analgesia in patients undergoing laparoscopic nephrectomies surgery: a randomized controlled trial

BackgroundLaparoscopic nephrectomy is a commonly utilized surgical approach for the management of renal cancer. Despite its widespread acceptance, postoperative pain management remains a significant challenge for many patients undergoing this procedure. Traditional pain management techniques, including opioid and nonsteroidal anti-inflammatory drug administration, may not provide adequate pain relief and may result in adverse effects. In recent years, erector spinae plane block (ESPB) has emerged as a promising regional anesthesia technique due to its simplicity, safety, and potential efficacy in reducing postoperative pain. ESPB has demonstrated effectiveness in reducing postoperative pain in various surgical procedures. However, the efficacy of ESPB in laparoscopic nephrectomy for renal cancer has not been extensively studied. As such, further investigation is necessary to determine the potential benefits of ESPB in this context. The addition of adjuvants such as dexmedetomidine and dexamethasone to nerve blocks has been shown to improve both the duration and quality of the block. Multiple studies have demonstrated the safety and efficacy of these adjuvants in reducing postoperative pain and opioid consumption and improving patient satisfaction. The use of dexmedetomidine and dexamethasone as adjuvants for nerve blocks represents a promising approach for enhancing regional anesthesia and analgesia. In light of these findings, we have incorporated dexmedetomidine and dexamethasone into our nerve block protocol.MethodsThis study is a randomized controlled trial conducted at a single center, with 50 participants being randomized in a 1:1 ratio to either the ESPB group or the control group. The trial aims to investigate the efficacy of ESPB in patients diagnosed with kidney cancer who are scheduled for laparoscopic nephrectomy. The primary outcome measure is the total consumption of intraoperative sufentanil. Secondary outcomes include the VAS score at rest and during coughing at 1 h, 6 h, 12 h, 24 h, and 48 h after surgery; total intraoperative remifentanil consumption; the number of times rescue analgesia is required; and the incidence of nausea and vomiting in the first 24 h after surgery. This study is registered for a duration of 1 year and is being conducted in China.DiscussionThe objective of our study is to evaluate the potential benefits of erector spinae plane block (ESPB) in patients undergoing laparoscopic nephrectomy, with a focus on the impact of dexmedetomidine and dexamethasone as adjuvants on the quality and duration of the block, as well as postoperative pain and opioid consumption. By investigating the effects of these adjuvants in the context of ESPB, we hope to contribute to the growing body of literature on the use of adjuvants in nerve blocks and provide further insight into the potential benefits of this approach for improving patient outcomes following laparoscopic nephrectomy. This trial was approved by the Ethics Committee of the Second Affiliated Hospital of Army Medical University.Trial registrationChina Clinical Trial Register ChiCTR2300068578. Registered on 20 February 2023.

Deletion of arrestin-3 does not reduce drug-seeking behavior in a longitudinal paradigm of oral morphine self-administration.

Opioid drugs are potent analgesics that mimic the endogenous opioid peptides, endorphins and enkephalins, by activating the µ-opioid receptor. Opioid use is limited by side effects, including significant risk of opioid use disorder. Improvement of the effect/side effect profile of opioid medications is a key pursuit of opioid research, yet there is no consensus on how to achieve this goal. One hypothesis is that the degree of arrestin-3 recruitment to the µ-opioid receptor impacts therapeutic utility. However, it is not clear whether increased or decreased interaction of the µ-opioid receptor with arrestin-3 would reduce compulsive drug-seeking. We utilized three genotypes of mice with varying abilities to recruit arrestin-3 to the µ-opioid receptor in response to morphine in a novel longitudinal operant self-administration model. We also created a quantitative method to define compulsivity in drug-seeking based on a multi-variate analysis of several operant response variables. We demonstrate that arrestin-3 knockout and wild type mice have highly variable drug-seeking behavior with few genotype differences. In contrast, in mice where the µ-opioid receptor strongly recruits arrestin-3, drug-seeking behavior is much less varied. We found that mice lacking arrestin-3 were more likely to meet the criteria for compulsivity whereas mice with enhanced arrestin-3 recruitment did not develop a compulsive phenotype. These experiments show that a lack of arrestin-3 is not protective against the abuse liability of morphine in an operant self-administration context. Our data also suggest that opioids that engage both G protein and arrestin-3, recapitulating the endogenous signaling pattern, will reduce abuse liability.

Sex differences in opioid response: a role for the gut microbiome?

Opioid drugs have been long known to induce different responses in males compared to females, however, the molecular mechanisms underlying these effects are yet to be fully characterized. Recent studies have established a link between the gut microbiome and behavioral responses to opioids. Chronic opioid use is associated with gut dysbiosis, or microbiome disruptions, which is thought to contribute to altered opioid analgesia and reward processing. Gut microbiome composition and functioning have also been demonstrated to be influenced by sex hormones. Despite this, there is currently very little work investigating whether sex differences in the gut microbiome mediate sex-dependent responses to opioids, highlighting a critical gap in the literature. Here, we briefly review the supporting evidence implicating a potential role for the gut microbiome in regulating sexually dimorphic opioid response and identify areas for future research.

Use of Opioids and Epidural Anaesthesia in Labor Analgesia as Important Risk Factors for Apparent Postpartum Urinary Retention: A Case-Control Study.

Labor analgesic interventions, particularly the use of opioids and epidural anaesthesia, have raised concerns regarding their potential impact on postpartum urinary retention (PUR), necessitating a comprehensive investigation into their association with this clinical outcome. This retrospective case-control study analysed clinical data from postpartum patients at our hospital from January 2023 to December 2023. Anaesthetic methods, including opioid and non-opioid drug usage, epidural analgesia and non-use of analgesia, were assessed. Logistic regression analysis was also performed to determine important associations with apparent PUR. This study included clinical data from 54 postpartum patients with PUR and 54 without urinary retention. A higher percentage of women with apparent PUR received opioids during labour compared with those without PUR (p = 0.033). Conversely, a lower percentage of women with apparent PUR received non-opioid analgesics compared with those without PUR (p = 0.026). In addition, a higher percentage of women with apparent PUR received epidural analgesia compared with those without PUR (p = 0.041). Logistic regression analysis demonstrated that opioid consumption during labour was significantly associated with apparent PUR (odds ratio (OR) = 2.469, p = 0.022). By contrast, non-opioid consumption during labour was inversely associated with apparent PUR (OR = 0.297, 95% CI = 0.123-0.681, p = 0.005). In addition, the use of epidural analgesia during labour showed a remarkable association with apparent PUR (OR = 2.857, 95% CI = 1.289-6.552, p = 0.011). Opioid use during labour and the use of epidural analgesia were identified as important risk factors for apparent PUR. These findings emphasise the need for a thoughtful and balanced approach to analgesic management during labour to minimise the risk of PUR in obstetric patients.

Developing a cube-like nanocomposite integrated into a polymer network as a highly porous and effective electrospun nanofiber for extracting trace quantities of opioid and analgesic drugs in biological fluids

The incorporation of the synthesized MOF Zn–Ni–Co OH/MWCNT into a polymer network of PAN using an electrospun device for the extraction of analgesic drugs in biological fluids prior to identification by a HPLC-UV device.

Effectiveness of Ultrasound-guided Adductor Canal Block for Postoperative Pain Management in below Knee Orthopaedic Surgeries: A Randomised Controlled Study

Introduction: The sensory innervation below the knee is provided by the saphenous nerve and sciatic nerve. Drugs deposited in the Adductor Canal (AC) at the Adductor Hiatus (AH) level spread both proximally up to the mid-canal and distally to the popliteal fossa through the perivascular space. The Adductor Canal Block (ACB) is a newer technique by which both nerves can be blocked in a single procedure. Aim: To evaluate the efficacy of ACB for postoperative pain management in below knee surgeries. Materials and Methods: This randomised controlled study was conducted in a tertiary care hospital. A total of 81 patients with American Society of Anaesthesiologists (ASA) I and II physical status were randomly allocated to either group A (ACB) or group B (Control), scheduled for below knee orthopaedic surgery. Group A patients received a mixture of 40 mL of 0.125% bupivacaine and 8 mg dexamethasone in the AC at the hiatus level under ultrasound guidance. Group B patients received standard care for pain management. The duration of sensory and motor block, mean Visual Analogue Scale (VAS) scores, amount of opioid drug requirement, drug-related side-effects, and satisfaction scores were compared between the two groups. Data were presented as mean±Standard Deviation (SD) for continuous variables and frequency (%) for categorical data and were analysed using t-tests and Chi-square tests. Results: The mean age in group A was 42.9±13.5 years and in group B was 46.3±13.1 years. In group A, there were 30 males and 11 females, while in group B, there were 32 males and 8 females. The mean Body Mass Index (BMI) between group A and B was 27.4±3.2 kg/m2 and 26.3±3.1 kg/m2 , respectively. The mean duration of sensory block was longer in group A (12.3±4.6 hours) compared to group B (4.7±0.7 hours). The mean VAS scores (1.351±0.659 vs 3.240±0.590) were significantly lower in group A. The total opioid requirement was 42.9±73.6 mg vs 205.9±26.0 mg between the two groups, which was significantly lower in group A. Conclusion: In distal ACB, a single procedure with 40 mL of 0.125% bupivacaine significantly reduces postoperative VAS scores and analgesic requirements while increasing patient satisfaction levels. Therefore, this block is safe and recommended for postoperative pain management in below knee surgeries.

An Entropy Based Observational Study to Assess the Dosage of Propofol Required for Induction of Anaesthesia by Varying the Time Intervals between Fentanyl and Propofol Administration

Background: Propofol is the preferred drug for the induction of anesthesia in many centers. However, its ubiquitous use is hampered by adverse effects. The rationale behind our study is to prove that whether the administration of an opioid drug before propofol induction, lowers the amount of propofol requirement for balanced anesthesia, and enhances hemodynamic stability. Aim: The present study intends to know the consequence of the differing time intervals between the administration of fentanyl and propofol on the dosage of propofol required to achieve induction of general anesthesia. Methods: In this observational study, 84 patients were included in the study. Patients who received propofol immediately after fentanyl injection were included in Group 1, whereas patients who received propofol at 3 min and 6 min after fentanyl injection, respectively, were grouped as Group 2 and Group 3. The total propofol required, the hemodynamic variations and the entropy values were recorded. SSPS version 25.09 (IBM) was used for statistical analysis. Results: In this study, it was observed that there was a significant reduction in propofol requirement in Group 2 and Group 3 compared with Group 1. The incidence of hypotension was seen in about 42.9% of Group 1 when compared to Group 2 and 3, which was 28.6% and 17.8%, respectively. Furthermore, the entropy values in Group 3 were initially higher and later were comparable in all the groups. Conclusion: Our study concluded that as the duration between the administration of propofol and fentanyl increases, the hemodynamic stability also increases and there is no variation in the depth of anesthesia attained in the distinct study population.

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

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

Comparative Effects of Cognitive Rehabilitation and Photobiomodulation on Drug Craving in Treatment-Seeking Opioid Addicts.

Background: Drug addiction refers to a maladaptive pattern of drug use that frequently leads to substance abuse problems and accompanying cognitive and behavioral symptoms. Among the crucial criteria of drug addiction, craving stands out as a potent factor contributing to ongoing drug abuse and relapse following period of abstinence. To date, there is no definitive method for eradicating opioid cravings. The introduction of novel neurocognitive interventions, such as cognitive rehabilitation and photobiomodulation (PBM), into the realm of psychiatric treatments holds promise due to the parallels between drug addiction and other psychiatric disorders. These innovative techniques offer potential value in addressing drug addiction. Objective: This study aimed to assess and compare the efficacy of cognitive rehabilitation and PBM in alleviating drug cravings among individuals undergoing addiction treatment in clinical settings. Methods: The research used randomized clinical trial as the chosen research method. The statistical population encompassed all clients receiving treatment for addiction at clinics, selected through the convenience sampling method, with α = 0.05 significance level and an effect size of 85%. Gpower software was utilized to determine three equal groups. Sixty-three participants, each having a mean total score higher than 3 out of 5 on the Desire for Drug Questionnaire (DDQ), were randomly assigned to two experimental groups (n = 21 each) and a control group (n = 21). For the assessment of immediate and periodic opioid craving, the DDQ and the Obsessive Compulsive Drug Use Scale were used. In the low-level laser group, an 810 nm wavelength with continuous irradiation was applied twice a week at a distance of 1 cm by 1 cm to the prefrontal part of the brain for duration of 6 weeks (12 sessions). In the brain rehabilitation group, the stop signal and n-back tasks software were used twice a week for period of 6 weeks (comprising 12 sessions, each lasting 30 min). Results: The results demonstrated that each intervention significantly reduced drug craving in both the post-test and follow-up phases compared to the control group. The Bonferroni post hoc test indicated that PBM was more effective than cognitive rehabilitation in terms of working memory (WM) and inhibitory control for reducing drug craving (p < 0.05). Conclusions: While both PBM and cognitive rehabilitation targeting WM and inhibitory control effectively reduced opioid drug craving, low-level laser therapy proved to be more effective than cognitive rehabilitation in this regard.

Environmental Enrichment during Abstinence Reduces Oxycodone Seeking and c-Fos Expression in a Subpopulation of Medial Prefrontal Cortex Neurons

BackgroundSeveral preclinical studies have demonstrated that environmental enrichment (EE) during abstinence reduces drug seeking for psychostimulant and opioid drugs. Drug seeking is dependent on activity within the dorsomedial prefrontal cortex, and enrichment has been able to reduce drug seeking-associated increases in c-Fos in this region. In this study, we tested the hypothesis that EE during abstinence from oxycodone self-administration would reduce drug seeking and c-Fos immunoreactivity within the prefrontal cortex in a cell-type specific manner. MethodsMale rats self-administered oxycodone in two-hours sessions for three weeks, then underwent an initial drug seeking test under extinction conditions after one week of forced abstinence. Following this test, rats received either EE or remained individually housed in their home cage, then a second drug seeking test, with tissue collection immediately afterward. ResultsCompared to rats in standard housing, environmentally enriched rats had lower oxycodone seeking. In the prelimbic and infralimbic prefrontal cortices, the number of c-Fos+ cells was reduced, and this reduction was predominantly in inhibitory cells neurons, as evidenced by a reduction in the proportion of c-Fos+ cells in GAD+, but not CamKII+ cells. There was also a robust positive relationship between the number of c-Fos+ cells and persistence of oxycodone seeking in both the PrL and IL. ConclusionsThese findings further support the effectiveness of enriched environments to reduce reactivity to drug-associated stimuli and contexts and provide a potential mechanism by which this occurs.

A systematic analysis and data mining of opioid-related adverse events submitted to the FAERS database.

The opioid epidemic has become a serious national crisis in the United States. An indepth systematic analysis of opioid-related adverse events (AEs) can clarify the risks presented by opioid exposure, as well as the individual risk profiles of specific opioid drugs and the potential relationships among the opioids. In this study, 92 opioids were identified from the list of all Food and Drug Administration (FDA)-approved drugs, annotated by RxNorm and were classified into 13 opioid groups: buprenorphine, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol. A total of 14,970,399 AE reports were retrieved and downloaded from the FDA Adverse Events Reporting System (FAERS) from 2004, Quarter 1 to 2020, Quarter 3. After data processing, Empirical Bayes Geometric Mean (EBGM) was then applied which identified 3317 pairs of potential risk signals within the 13 opioid groups. Based on these potential safety signals, a comparative analysis was pursued to provide a global overview of opioid-related AEs for all 13 groups of FDA-approved prescription opioids. The top 10 most reported AEs for each opioid class were then presented. Both network analysis and hierarchical clustering analysis were conducted to further explore the relationship between opioids. Results from the network analysis revealed a close association among fentanyl, oxycodone, hydrocodone, and hydromorphone, which shared more than 22 AEs. In addition, much less commonly reported AEs were shared among dihydrocodeine, meperidine, oxymorphone, and tapentadol. On the contrary, the hierarchical clustering analysis further categorized the 13 opioid classes into two groups by comparing the full profiles of presence/absence of AEs. The results of network analysis and hierarchical clustering analysis were not only consistent and cross-validated each other but also provided a better and deeper understanding of the associations and relationships between the 13 opioid groups with respect to their adverse effect profiles.

Effects of remifentanil combined with propofol on hemodynamics and oxidative stress in patients undergoing resection of rectal carcinoma.

Rectal carcinoma (RC) treatment primarily involves laparoscopic surgery, which may induce significant hemodynamic changes and weaken immune function. Certain anesthetic approaches using opioid drugs (including remifentanil and sufentanil) pose risks, such as hypotension. To determine the effects of remifentanil combined with propofol on hemodynamics and oxidative stress in patients undergoing RC resection. A total of 211 patients one hundred and four patients with RC treated at the First Affiliated Hospital of Dalian Medical University between November 2018 and November 2022 were retrospectively analyzed. Among them, the remifentanil group included 45 patients receiving remifentanil with propofol anesthesia and the sufentanil group included 59 patients receiving sufentanil with propofol anesthesia. Changes in the hemodynamic index, oxidative stress index, general data, consumption of remifentanil, and use of vasoactive drugs were compared. The incidences of adverse reactions were calculated. The two groups did not significantly differ in terms of operation, anesthesia, and extubation times (P > 0.05). At 1 min after intubation, the sufentanil group showed a notably higher heart rate, systolic blood pressure (SBP), diastolic blood pressure, and mean arterial pressure (MAP) compared with the remifentanil group (P < 0.05), whereas the sufentanil group showed a notably higher SBP and MAP compared with the remifentanil group at 5 min after pneumoperitoneum (P < 0.05). Thirty minutes after surgery, the remifentanil group showed significantly lower plasma cortisol, noradrenaline, and glucose levels than the sufentanil group (P < 0.001). The remifentanil group consumed significantly less remifentanil than the sufentanil group (P < 0.05), and the adoption frequency of ephedrine was lower in the remifentanil group than that in the sufentanil group (P < 0.05). The incidence of hypotension was notably higher in the sufentanil group than that in the remifentanil group (P < 0.05). Remifentanil combined with propofol can improve hemodynamics and relieve oxidative stress in patients undergoing RC resection.

Differences in perceptions of community stigma towards opioid use disorder between community substance use coalition members and the general public

IntroductionTo examine differences in perceptions about community stigma towards individuals with opioid use disorder (OUD) between community members involved in the opioid response (i.e., coalition members) and the general public, and how community geography may moderate this relationship. MethodsThis study administered identical cross-sectional surveys about perceived community opioid-related stigma to two distinct populations in 66 communities participating in the HEALing Communities Study prior to the intervention period (i.e., coalition members, November 2019–January 2020; residents, March–April 2020). Linear-mixed models compared survey responses of populations, including the moderating effect of community rural/urban location. ResultsA total of 826 coalition members and 1131 residents completed the surveys. The study found no differences between the coalition members and residents for general perceived community opioid-related stigma. In both urban and rural communities, coalition members reported greater perceived community stigma than residents reported towards medication for opioid use disorder (MOUD), naloxone, and drug treatment as an alternative to incarceration. ConclusionOur findings suggest similar perceived community opioid-related stigma between coalition members and residents, yet differences emerge related to evidence-based practices (i.e., MOUD, naloxone, and drug treatment as an alternative to incarceration) to reduce opioid overdose deaths. Trial registrationClinicalTrials.gov Identifier: NCT04111939.

Fast Screening of Fentanyl Illicit Drug By the Electrochemical Enhancement of Raman Intensity

Fentanyl is a potent opioid drug used as an analgesic and anesthetic because it is approximately 100 times more potent than morphine and 50 times more potent than heroin as an analgesic. However, the overdose of fentanyl requires small dose and can cause stupor, changes in pupil size, clammy skin, cyanosis, coma, and respiratory failure leading to death. During the last years the illicit fentanyl and its analogues have been responsible for most drug overdose deaths in different countries and for that reason, the development of identification and detection methods is mandatory.Spectroelectrochemical methods are currently proposed for the screening of this drug [1]. For instance, the combination of electrochemistry (EC) and surface-enhanced Raman scattering (SERS) has received growing attention due to the enhancement of Raman intensity associated with EC-SERS effect. However, the generation of reproducible SERS substrates is a traditional limitation of this effect. In that way, activation of metallic screen-printed electrodes (SPEs) by electrochemical routes allows to obtain reproducible nanostructures with excellent SERS properties [2], opening new gates for analytical applications.In this work, the development of a fentanyl detection method based on EC-SERS effect is achieved. Spectroelectrochemical screening of this drug with metallic SPEs consists of two consecutive steps performed in a single experiment: (1) electrochemical generation of metallic NPs with SERS effect and (2) Raman detection of fentanyl present in solution.Metallic SPEs provide interesting results being not only useful in the characterization of fentanyl, but also for analytical purposes. The proposed EC-SERS method with gold SPEs allows the detection of 0.33 ug/ml fentanyl and offers a rapid, efficient, and accurate approach for the detection of this drug.

Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model.

Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 μg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.

Advancement in Opioid Abuse-deterrent Formulation Technologies and Regulatory Expectation.

Chronic pain is a byproduct of many diseases and conditions. Along with long-term opioid medication use in chronic pain management, misuse of this vital medication has been a topic of much debate over the last two decades. Abuse-deterrent formulations play a critical role in comprehensive opioid risk management strategies, limiting the attractiveness and drug-liking qualities of an opioid drug by limiting their bioavailability, making abuse of the tampered opioid medication less appealing or rewarding, or impeding the extraction of the opioid drug and thus impeding the administration of the opioid formulation via alternative routes. The present article covers various regulatory actions, expectations in abuse-deterrent formulation approval, and emerging opioid abuse-deterrent formulation strategies, such as incorporating physical barriers, chemical barriers, aversion agents, pH modulating release properties, novel delivery systems, agonist/antagonist combinations, and prodrugs, as potential approaches to encountering the crisis of the opioid abuse epidemic. Looking at the severity of the opioid crisis across the globe now is the right time for various regulatory agencies to come under one roof to save society from the opioid epidemic, define the policy on how and when to prescribe opioid formulations to patients, perform abuse risk assessments, and make more efforts to approve only abusedeterrent opioid medication.

Opioid, methamphetamine, and polysubstance use: perinatal outcomes for the mother and infant.

The escalation in opioid pain relief (OPR) medications, heroin and fentanyl, has led to an increased use during pregnancy and a public health crisis. Methamphetamine use in women of childbearing age has now eclipsed the use of cocaine and other stimulants globally. Recent reports have shown increases in methamphetamine are selective to opioid use, particularly in rural regions in the US. This report compares the extent of our knowledge of the perinatal outcomes of OPRs, heroin, fentanyl, two long-acting substances used in the treatment of opioid use disorders (buprenorphine and methadone), and methamphetamine. The methodological limitations of the current research are examined, and two important initiatives that will address these limitations are reviewed. Current knowledge of the perinatal effects of short-acting opioids, OPRs, heroin, and fentanyl, is scarce. Most of what we know about the perinatal effects of opioids comes from research on the long-acting opioid agonist drugs used in the treatment of OUDs, methadone and buprenorphine. Both have better perinatal outcomes for the mother and newborn than heroin, but the uptake of these opioid substitution programs is poor (<50%). Current research on perinatal outcomes of methamphetamine is limited to retrospective epidemiological studies, chart reviews, one study from a treatment center in Hawaii, and the US and NZ cross-cultural infant Development, Environment And Lifestyle IDEAL studies. Characteristics of pregnant individuals in both opioid and MA studies were associated with poor maternal health, higher rates of mental illness, trauma, and poverty. Infant outcomes that differed between opioid and MA exposure included variations in neurobehavior at birth which could complicate the diagnosis and treatment of neonatal opioid withdrawal (NOWs). Given the complexity of OUDs in pregnant individuals and the increasing co-use of these opioids with MA, large studies are needed. These studies need to address the many confounders to perinatal outcomes and employ neurodevelopmental markers at birth that can help predict long-term neurodevelopmental outcomes. Two US initiatives that can provide critical research and treatment answers to this public health crisis are the US Environmental influences on Child Health Outcomes (ECHO) program and the Medication for Opioid Use Disorder During Pregnancy Network (MAT-LINK).

The role of neuroinflammation in the transition of acute to chronic pain and the opioid-induced hyperalgesia and tolerance.

Current evidence suggests that activation of glial and immune cells leads to increased production of proinflammatory mediators, creating a neuroinflammatory state. Neuroinflammation has been proven to be a fundamental mechanism in the genesis of acute pain and its transition to neuropathic and chronic pain. A noxious event that stimulates peripheral afferent nerve fibers may also activate pronociceptive receptors situated at the dorsal root ganglion and dorsal horn of the spinal cord, as well as peripheral glial cells, setting off the so-called peripheral sensitization and spreading neuroinflammation to the brain. Once activated, microglia produce cytokines, chemokines, and neuropeptides that can increase the sensitivity and firing properties of second-order neurons, upregulating the signaling of nociceptive information to the cerebral cortex. This process, known as central sensitization, is crucial for chronification of acute pain. Immune-neuronal interactions are also implicated in the lesser-known complex regulatory relationship between pain and opioids. Current evidence suggests that activated immune and glial cells can alter neuronal function, induce, and maintain pathological pain, and disrupt the analgesic effects of opioid drugs by contributing to the development of tolerance and dependence, even causing paradoxical hyperalgesia. Such alterations may occur when the neuronal environment is impacted by trauma, inflammation, and immune-derived molecules, or when opioids induce proinflammatory glial activation. Hence, understanding these intricate interactions may help in managing pain signaling and opioid efficacy beyond the classical pharmacological approach.