Nalmefene Hydrochloride: Potential Implications for Treating Alcohol and Opioid Use Disorder.

Nalmefene hydrochloride was first discovered as an opioid antagonist derivative of naltrexone in 1975. It is among the most potent opioid antagonists currently on the market and is differentiated from naloxone and naltrexone by its partial agonist activity at the kappa-opioid receptor which may benefit in the treatment of alcohol use disorder. Oral nalmefene has been approved in the European Union for treatment of alcohol use disorder since 2013. As of 2023, nalmefene is available in the United States as an intranasal spray for reversal of opioid overdose but is not approved for alcohol or opioid use disorder as a maintenance treatment. The substantially longer half-life of nalmefene and 5-fold higher binding affinity to opioid receptors makes it a superior agent over naloxone in the reversal of high potency synthetic opioids like fentanyl and the emerging nitazenes. Nalmefene presents with a comparable side effect profile to other opioid antagonists and should be considered for further development as a maintenance treatment for opioid and other substance use disorders.

Aticaprant: (a κ-opioid receptor antagonist) for major depressive disorder.

INTRODUCTION: Major depression is a common, disabling mental health condition associated with the highest disease burden for any neuropsychiatric disorder worldwide, according to the WHO. Due to the imperfect efficacy and tolerability profiles of existing treatments, investigational compounds in novel treatment classes are needed. Opioid-receptor antagonists are a potential new class of treatments currently under investigation. AREAS COVERED: Major depressive disorder is first overviewed. Existing treatments, both their mechanisms of action and their place within the antidepressant space, are discussed herein. Then, the profile of Aticaprant and the wider context of kappa-opioid antagonism for depression are discussed in focus. EXPERT OPINION: Early evidence indicates that Aticaprant may possess desirable pharmacodynamic and pharmacokinetic properties. A lack of convincing efficacy data at the time of writing precludes any definitive statement on its potential as an antidepressant.

Buprenorphine-Naloxone Maintenance and Lactation.

BACKGROUND: Breastfeeding among lactating people with opioid use disorder taking buprenorphine monotherapy is generally accepted, as low concentrations of buprenorphine and metabolites in human milk have been well-established. The use of buprenorphine-naloxone for pregnant and lactating people with opioid use disorder is expanding and there is no information available regarding the concentrations of naloxone and their metabolites in human milk to recommend the use of this combination medication during lactation. RESEARCH AIMS: To determine the concentrations of buprenorphine and naloxone and their primary metabolites in human milk, maternal plasma, and infant plasma, among lactating buprenorphine-naloxone maintained people and their infants. METHODS: Four lactating buprenorphine-naloxone maintained people provided plasma and human milk samples on Days 2, 3, 4, 14, and 30 postpartum. Infant plasma was obtained on Day 14. RESULTS: Concentrations of buprenorphine, norbuprenorphine and their glucuronide metabolites were present in maternal plasma and human milk at low concentrations, consistent with previous research in lactating buprenorphine monotherapy participants. Naloxone was not detected, or was detected at concentrations below the limit of quantification, in maternal plasma and in all except one human milk sample at Day 30. Naloxone was not detected or detected at concentrations below the limit of quantification in all infant plasma samples. CONCLUSION: Results support the use of buprenorphine-naloxone by lactating people who meet appropriate criteria for breastfeeding.

American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time.

BACKGROUND: Nalmefene is a potent opioid antagonist that has recently been reintroduced in the United States to treat known or suspected opioid overdose. NALMEFENE CLINICAL TRIAL DATA: The injection formulation, which had been withdrawn in 2008, was reintroduced in 2022, and in 2023 the United States Food and Drug Administration approved a new intranasal formulation of nalmefene. Because nalmefene had been previously approved for use in 1995 via injection, the new intranasal formulation did not require new clinical data as it was approved under an Abbreviated New Drug Application. Inherent to this abbreviated approval process, intranasal nalmefene was not studied in patients currently suffering opioid overdose. NALOXONE AND NALMEFENE: Nalmefene also has unique characteristics compared with naloxone, the current standard opioid antidote. Nalmefene has a higher affinity for opioid receptors and a longer duration of action than naloxone. Comparative effectiveness data regarding naloxone and nalmefene are sparse, and it is unclear if the inherent properties of nalmefene are beneficial in opioid overdose. We have decades of experience using naloxone safely and effectively as the primary opioid antidote, even in cases of fentanyl and fentanyl analog overdoses. There is, however, evidence to suggest nalmefene may result in more prolonged and severe opioid withdrawal than naloxone, which could be harmful to patients. POSITION: As nalmefene is untested in the current clinical environment of synthetic opioid overdoses and has the potential to cause harm via prolonged withdrawal, it is the opinion of the American College of Medical Toxicology and the American Academy of Clinical Toxicology that nalmefene should not replace naloxone as the primary opioid antidote at this time. RECOMMENDATIONS: We recommend additional clinical studies of nalmefene, administered via all approved routes, be conducted in a comparative fashion with naloxone, and that safety and effectiveness outcomes be evaluated before nalmefene is recommended as a primary opioid antidote.

Identification and Pharmacological Characterization of a Low-Liability Antinociceptive Bifunctional MOR/DOR Cyclic Peptide.

Peptide-based opioid ligands are important candidates for the development of novel, safer, and more effective analgesics to treat pain. To develop peptide-based safer analgesics, we synthesized a mixture-based cyclic pentapeptide library containing a total of 24,624 pentapeptides and screened the mixture-based library samples using a 55 °C warm water tail-withdrawal assay. Using this phenotypic screening approach, we deconvoluted the mixture-based samples to identify a novel cyclic peptide Tyr-[D-Lys-Dap(Ant)-Thr-Gly] (CycloAnt), which produced dose- and time-dependent antinociception with an ED50 (and 95% confidence interval) of 0.70 (0.52-0.97) mg/kg i.p. mediated by the mu-opioid receptor (MOR). Additionally, higher doses (≥3 mg/kg, i.p.) of CycloAnt antagonized delta-opioid receptors (DOR) for at least 3 h. Pharmacological characterization of CycloAnt showed the cyclic peptide did not reduce breathing rate in mice at doses up to 15 times the analgesic ED50 value, and produced dramatically less hyperlocomotion than the MOR agonist, morphine. While chronic administration of CycloAnt resulted in antinociceptive tolerance, it was without opioid-induced hyperalgesia and with significantly reduced signs of naloxone-precipitated withdrawal, which suggested reduced physical dependence compared to morphine. Collectively, the results suggest this dual MOR/DOR multifunctional ligand is an excellent lead for the development of peptide-based safer analgesics.

Naloxegol versus Methylnaltrexone for Opioid-Induced Constipation in Critically Ill Patients.

BACKGROUND: Constipation impacts 58% to 83% of critically ill patients and is associated with increased time on mechanical ventilation, delirium, and increased length of stay (LOS) in the intensive care unit (ICU). OBJECTIVE: The purpose of this study was to evaluate the efficacy of enteral naloxegol (NGL) versus subcutaneous methylnaltrexone (MNTX) for the management of opioid-induced constipation (OIC) in critically ill patients. METHODS: A retrospective analysis was conducted on adult patients admitted to the ICU who received a parenteral opioid infusion for at least 4 hours and experienced no bowel movement (BM) within the 48-hour period preceding the administration of NGL or MNTX. The primary outcome was time to first BM from the start of NGL or MNTX therapy. Secondary outcomes included number of BMs 72 hours following NGL or MNTX administration, ICU LOS, and cost-effectiveness. RESULTS: After exclusion criteria were applied, 110 and 51 patients were included in the NGL and MNTX groups, respectively. With a 10% noninferiority margin, NGL was noninferior to MNTX (Wald statistic = 1.67; P = 0.047). Median time to first BM was 23.7 hours for NGL and 18.3 hours for MNTX patients. Median LOS was 14 days (NGL) and 12 days (MNTX), and the average number of BMs in 72 hours was 3.9 for NGL and 3.8 for MNTX. Using wholesale acquisition cost (WAC), the cost per BM for NGL and MNTX was $21.74 and $170.00, respectively. CONCLUSION AND RELEVANCE: This study determined that NGL and MNTX had similar time to BM. NGL appears to be a safe and effective alternative with cost-saving potential in treating OIC in critically ill patients.

Pharmacotherapy and gambling disorder: a narrative review.

BACKGROUND: Gambling disorder (GD) is a psychiatric disorder classified in the DSM-5 as a non-substance-related and addictive disorder with extensive health and socioeconomic impacts. Its chronic and high-relapsing nature makes it essential to find treatment strategies that improve functioning and reduce impairment associated with it. The purpose of this narrative review is to evaluate and summarize the available evidence on the effectiveness and safety of pharmacotherapy in GD. METHODS: An electronic literature search of Medline, Embase, and Cochrane Central was conducted to identify systematic reviews, meta-analyses, and reviews on pharmacological interventions in patients with gambling disorder. A similar search of these databases and of Prospero, Clinicaltrials.gov, and Epistemonikos was conducted to identify clinical trials that were published since 2019. RESULTS: The initial search identified 1925 articles. After screening and duplicate removal, 18 articles were included in the review (11 studies were systematic reviews and meta-analyses, 6 were reviews, and 1 was an open-label trial). Eight pharmacological agents (naltrexone, nalmefene, paroxetine, fluvoxamine, citalopram, escitalopram, lithium, and topiramate) that were studied in randomized controlled trials and open-label trials showed small to moderate effect sizes in reducing GD symptoms in some studies during post-hoc analyses. CONCLUSION: The overall sum of evidence in the literature on the use of pharmacotherapy in GD is conflicting and inconclusive. Some studies have shown that pharmacotherapy's role in GD is promising, especially when the choice of the agent is guided by comorbid psychiatric disorders. However, significant limitations exist in the study designs, which need to be addressed in future research on the topic. Conducting future and more rigorous trials that address the limitations in the existing literature is necessary to establish more accurate efficacy data on the use of pharmacotherapy in this population.

Optimization of Mass Spectrometry Imaging for Drug Metabolism and Distribution Studies in the Zebrafish Larvae Model: A Case Study with the Opioid Antagonist Naloxone.

Zebrafish (ZF; Danio rerio) larvae have emerged as a promising in vivo model in drug metabolism studies. Here, we set out to ready this model for integrated mass spectrometry imaging (MSI) to comprehensively study the spatial distribution of drugs and their metabolites inside ZF larvae. In our pilot study with the overall goal to improve MSI protocols for ZF larvae, we investigated the metabolism of the opioid antagonist naloxone. We confirmed that the metabolic modification of naloxone is in high accordance with metabolites detected in HepaRG cells, human biosamples, and other in vivo models. In particular, all three major human metabolites were detected at high abundance in the ZF larvae model. Next, the in vivo distribution of naloxone was investigated in three body sections of ZF larvae using LC-HRMS/MS showing that the opioid antagonist is mainly present in the head and body sections, as suspected from published human pharmacological data. Having optimized sample preparation procedures for MSI (i.e., embedding layer composition, cryosectioning, and matrix composition and spraying), we were able to record MS images of naloxone and its metabolites in ZF larvae, providing highly informative distributional images. In conclusion, we demonstrate that all major ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters, as part of in vivo pharmacokinetic studies, can be assessed in a simple and cost-effective ZF larvae model. Our established protocols for ZF larvae using naloxone are broadly applicable, particularly for MSI sample preparation, to various types of compounds, and they will help to predict and understand human metabolism and pharmacokinetics.

[Naloxone as rescue therapy for acute, severe pruritus]. / Naloxon als Rescue-Therapie bei akutem, schwerstem Pruritus.

This article presents the case of a patient with massive pruritus sine materia. Naloxone was proven as quick and effective therapy which led to a complete reduction of itching.

Naloxegol for Treatment of Opioid-Induced Constipation in the Pediatric Intensive Care Unit.

Opioid-induced constipation is a common problem in critically ill children requiring sedation. Naloxegol is an oral U.S. Food and Drug Administration (FDA)-approved peripherally acting mu-opioid receptor antagonist for chronic opioid-induced constipation use in adults, but data on its use in children are lacking. We performed a retrospective analysis of critically ill children that had received naloxegol for opioid-induced constipation at our institution. Of the 45 patients studied, mean stool frequency increased significantly from 0.63 ± 0.12 stools per day to 1.71 ± 0.13 stools per day after starting naloxegol (95% confidence interval [CI]: [0.75, 1.4], P < .001). There was no significant difference in the mean Withdrawal Assessment Tool 1 (WAT-1) score in the 24 hours before and after receiving the first dose (95% CI: [-0.25, 0.40], P = .63). This suggests naloxegol is effective in increasing stool output in critically ill children receiving opioids without an increase in opioid-withdrawal symptoms. It may be an effective adjunctive therapy for this population.

Individual strategies in the rat gambling task are related to voluntary alcohol intake, but not sexual behavior, and can be modulated by naltrexone.

Introduction: Gambling disorder (GD) is the first non-substance or behavioral addiction to be included in substance-related and addictive disorders in DSM-5. Since GD is a younger phenomenon relative to alcohol and substance use disorders, little is known about potential unique features in GD and to what extent characteristics are shared with alcohol and substance use disorders. The rat gambling task (rGT) is used to study decision-making in rats. This study aimed to identify individual differences in rGT strategies and explore the stability of these strategies over time. Moreover, motor impulsivity, sexual behavior, and voluntary alcohol intake were examined in rats with different rGT strategies. Finally, the response to naltrexone on performance in rats with different rGT strategies was investigated. Methods: Male Lister hooded rats (n = 40) underwent repeated testing in the rGT, repeated copulatory behavioral tests, and 7 weeks of voluntary alcohol intake through a modified intermittent two-bottle free-choice paradigm. Finally, rats were treated with naltrexone prior to testing in the rGT. Results: The results revealed individual choice strategies in the rGT that were stable over time, even after multiple interruptions and other behavioral testing. The rats with a risky choice strategy displayed higher motor impulsivity and voluntary alcohol intake than the other groups. No difference in sexual behavior was found between the different rGT groups. Finally, in all rats irrespectively of rGT strategy, treatment with naltrexone decreased the number of completed trials and premature responses, and increased omissions, which indicates an overall lowered motivation. Discussion: In conclusion, rats with risky rGT strategies had higher voluntary alcohol intake but not elevated sexual behavior, indicating shared underlying mechanisms between rGT strategies and alcohol intake but not natural rewards in terms of sexual behavior. Finally, naltrexone treatment resulted in an overall lowered motivation in the rGT.

Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose.

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects. The orvinol series of ligands are known for their high-affinity binding to opioid receptors and often extended duration of action; generally, compounds on this scaffold show agonist activity at the kappa and the mu-opioid receptor. Diprenorphine is an unusual member of this series being an antagonist at mu and only a partial agonist at kappa-opioid receptors. In this study, an orvinol antagonist, 14, was designed and synthesized that shows no agonist activity in vitro and is at least as good as naloxone at reversing the effects of mu-opioid receptor agonists in vivo.

A peripheral opioid antagonist for treating urinary retention induced by opioids: A case report.

BACKGROUND: Urinary retention is a poorly studied opioid-related adverse effect. There is a paucity of data regarding the treatment of such disturbance in patients with advanced cancer receiving opioids. ACTUAL CASE: A young man, without comorbidities, was receiving 30 mg/day of oxycodone for abdominal pain due to pancreatic cancer, unsuccessfully. He also complained of severe urinary retention that developed after initiation of opioid therapy. Methadone therapy was effective on pain intensity, but bladder dysfunction persisted. POSSIBLE COURSES OF ACTION: Only anedoctal experience exists for opioid-induced urinary retention. The options included alpha-receptor blockers and flavoxate, which are symptomatic drugs, not addressed to the possible mechanism. FORMULATION OF A PLAN: The use of a peripheral opioid antagonist was planned, according to the presumed mechanism of urinary retention. Thus, naldemedine 200 mcg was prescribed for relieving urinary retention. OUTCOME: The day after starting naldemedine, urinary retention completely reversed and pain was well-controlled. LESSONS: The rational of using naldemedine was based on the component of opioid-induced urinary retention due to involvement of peripheral receptors in the bladder and sphincter. VIEW: In this case report, the effect of the peripheral opioid antagonist was prompt and long-lasting. Future studies of this neglected adverse effect of opioids should be performed to confirm this observation.

Samidorphan for the treatment of weight gain associated with olanzapine in patients with schizophrenia and bipolar disorder.

INTRODUCTION: Olanzapine (OLZ) is one of the most effective antipsychotic agents, however, its clinical utility has been limited by weight gain. Samidorphan (SAM) is a µ-opioid receptor antagonist and it can reduce the weight gain associated with OLZ. A combination of OLZ and SAM (OLZ/SAM) has been developed to provide the antipsychotic efficacy of OLZ, while mitigating OLZ-associated weight gain. AREAS COVERED: A comprehensive literature search was conducted in PubMed. Key search terms included SAM and weight gain associated with OLZ. The pharmacological action, clinical efficacy, and safety of SAM were reviewed. EXPERT OPINION: OLZ can lead to weight gain. SAM is a new drug that acts as an opioid receptor antagonist that can decrease weight gain. SAM mitigates OLZ-associated weight gain while preserving the antipsychotic efficacy of OLZ. Clinical trials have confirmed that OLZ/SAM significantly improved psychotic symptoms, and resulted in significantly less weight gain than OLZ. OLZ/SAM was well tolerated. Therefore, it is a potential new treatment option for schizophrenia.

Factors associated with take-home naloxone kit usage in British Columbia: an analysis of administrative data.

BACKGROUND: The British Columbia (BC) Take-Home Naloxone (THN) program provides naloxone to people at risk of experiencing or witnessing an opioid overdose for use in reversing suspected overdose events. This study seeks to examine trends and correlates of individuals obtaining a THN kit in BC between 2017 and 2020. METHODS: Records of THN kits distributed between 2017 and 2020 were the primary source of data for this analysis. Frequency tables were used to describe characteristics of people obtaining kits from THN sites. Correlates of individuals obtaining a THN kit to replace a previous kit reported as used to reverse an overdose were assessed with multivariate logistic regression. RESULTS: Between January 1, 2017, and December 31, 2020, 240,606 THN kits were reported distributed by registered sites to members of the public, with 90,011 records indicating that a kit was obtained to replace a previous kit that had been used to reverse an overdose. There was a significant trend in increasing kits reported used by year (p < 0.01). The kit recipient's risk of overdose was a significant predictor of having reported using a THN kit, and the strength of the association was dependent on gender (Male: Adjusted odds ratio (AOR) 5.37 [95% confidence interval (CI) 5.08 - 5.67]; Female: AOR 8.35 [95% CI 7.90 - 8.82]; Trans and gender expansive: AOR 3.68 [95% CI 2.82 - 4.79]). CONCLUSIONS: Between 2017 and 2020, THN kits were used to reverse tens of thousands of overdose events in BC, with people at risk of overdose (i.e. people who use drugs [PWUD]) having greater odds of using a kit to reverse an overdose than those not at risk. Thus, PWUD are responsible for reversing the vast majority of overdoses. THN kits are being distributed to the people who use them most. However, additional strategies in conjunction with community-based naloxone distribution programs are needed to address the rising number of illicit drug toxicity deaths.

Mechanisms supporting the social regulation of neural threat responding with marital partners: A test of the opioid hypothesis.

Positive social contact predicts better health, but the mechanisms for this association remain debated. One way to explore this link is through the social regulation of emotion, particularly anticipatory anxiety. Previous research finds less neural threat response during partner handholding than when people are alone or stranger handholding. Various mechanistic accounts have been forwarded, including the hypothesis that this effect is mediated by endogenous opioid activity. This experiment critically tested the opioid hypothesis in 60 married participants and their partners. The study used a naltrexone opioid blockade in a double-blind placebo control with functional magnetic resonance imaging to determine whether endogenous opioids were necessary for handholding effects. Regulatory effects of supportive handholding manifested in threat network regions during opioid blockade, but not with placebo. Despite a surprising lack of effect in the placebo group, the overall study findings provide initial evidence that endogenous opioids may not be necessary for the social regulation of neural threat responding.

Effects of opioid receptor agonist and antagonist medications on electrocardiogram changes and presentation of cardiac arrhythmia: review article.

BACKGROUND/PURPOSE: Mortality associated with prescription opioids has significantly increased over the past few decades and is considered a global pandemic. Prescribed opioids can cause cardiac arrhythmias, leading to fatal outcomes and unexpected death, even in the absence of structural cardiac disease. Despite the extent of cardiac toxicity and death associated with these medications, there is limited data to suggest their influences on cardiac electrophysiology and arrhythmias, with the exception of methadone. The goal of our review is to describe the possible mechanisms and to review the different ECG changes and arrhythmias that have been reported. METHODS: A literature search was performed using Google Scholar, PubMed, Springer, Ovid, and Science Direct to identify studies that demonstrated the use of prescription opioids leading to electrocardiogram (ECG) changes and cardiac arrhythmias. RESULTS: Many of the commonly prescribed opioid medications can uniquely effect the ECG, and can lead to the development of various cardiac arrhythmias. One of the most significant side effects of these drugs is QTc interval prolongation, especially when administered to patients with a baseline risk for QTc prolongation. A prolonged QTc interval can cause lethal torsades de pointes and ventricular fibrillation. Obtaining an ECG at baseline, following a dosage increase, or after switching an opioid medication, is appropriate in patients taking certain prescribed opioids. Opioids are often used first line for the treatment of acute and chronic pain, procedural sedation, medication opioid use disorders, and maintenance therapy. CONCLUSIONS: To reduce the risk of cardiac arrhythmias and to improve patient outcomes, consideration of accurate patient selection, concomitant medications, electrolyte monitoring, and vigilant ECG monitoring should be considered.

Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses.

Brain kappa-opioid receptors (KORs) are implicated in the pathophysiology of depressive and anxiety disorders, stimulating interest in the therapeutic potential of KOR antagonists. Research on KOR function has tended to focus on KOR-expressing neurons and pathways such as the mesocorticolimbic dopamine system. However, KORs are also expressed on non-neuronal cells including microglia, the resident immune cells in the brain. The effects of KOR antagonists on microglia are not understood despite the potential contributions of these cells to overall responsiveness to this class of drugs. Previous work in vitro suggests that KOR activation suppresses proinflammatory signaling mediated by immune cells including microglia. Here, we examined how KOR antagonism affects microglia function in vivo, together with its effects on physiological and behavioral responses to an immune challenge. Pretreatment with the prototypical KOR antagonist JDTic potentiates levels of proinflammatory cytokines (IL-1ß, IL-6) in blood following administration of lipopolysaccharide (LPS), an immune-activating agent, without triggering effects on its own. Using magnetic-activated cell sorting (MACs), we found that KOR antagonism potentiates LPS-induced cytokine expression within microglia. This effect is accompanied by potentiation of LPS-induced hyperthermia, although reductions in body weight and locomotion were not affected. Histological analyses confirm that LPS produces visible changes in microglia morphology consistent with activation, but this effect is not altered by KOR antagonism. Considering that inflammation is increasingly implicated in depressive and anxiety disorders, these findings raise the possibility that KOR antagonist actions on microglia may detract from actions on neurons that contribute to their therapeutic potential.

Treatment of overdose in the synthetic opioid era.

Overdose deaths are often viewed as the leading edge of the opioid epidemic which has gripped the United States over the past two decades (Skolnick, 2018a). This emphasis is perhaps unsurprising because opioid overdose is both the number-one cause of death for individuals between 25 and 64 years old (Dezfulian et al., 2021) and a significant contributor to the decline in average lifespan (Dowell et al., 2017). Exacerbated by the COVID 19 pandemic, it was estimated there were 93,400 drug overdose deaths in the United States during the 12 months ending December 2020, with more than 69,000 (that is, >74%) of these fatalities attributed to opioid overdose (Ahmad et al., 2021). However, the focus on mortality statistics (Ahmad et al., 2021; Shover et al., 2020) tends to obscure the broader medical impact of nonfatal opioid overdose. Analyses of multiple databases indicate that for each opioid-induced fatality, there are between 6.4 and 8.4 non-fatal overdoses, exacting a significant burden on both the individual and society. Over the past 7-8 years, there has been an alarming increase in the misuse of synthetic opioids ("synthetics"), primarily fentanyl and related piperidine-based analogs. Within the past 2-3 years, a structurally unrelated class of high potency synthetics, benzimidazoles exemplified by etonitazene and isotonitazene ("iso"), have also appeared in illicit drug markets (Thompson, 2020; Ujvary et al. 2021). In 2020, it was estimated that over 80% of fatal opioid overdoses in the United States now involve synthetics (Ahmad et al., 2021). The unique physicochemical and pharmacological properties of synthetics described in this review are responsible for both the morbidity and mortality associated with their misuse as well as their widespread availability. This dramatic increase in the misuse of synthetics is often referred to as the "3rd wave" (Pardo et al., 2019; Volkow and Blanco, 2020) of the opioid epidemic. Among the consequences resulting from misuse of these potent opioids is the need for higher doses of the competitive antagonist, naloxone, to reverse an overdose. The development of more effective reversal agents such as those described in this review is an essential component of a tripartite strategy (Volkow and Collins, 2017) to reduce the biopsychosocial impact of opioid misuse in the "synthetic era".

Blockade of kappa opioid receptors reduces mechanical hyperalgesia and anxiety-like behavior in a rat model of trigeminal neuropathic pain.

It has been shown that kappa opioid receptor (KOR) antagonists, such as nor-binaltorphimine (nor-BNI), have antinociceptive effects in some pain models that affect the trigeminal system. Also, its anxiolytic-like effect has been extensively demonstrated in the literature. The present study aimed to investigate the systemic, local, and central effect of nor-BNI on trigeminal neuropathic pain using the infraorbital nerve constriction model (CCI-ION), as well as to evaluate its effect on anxiety-like behavior associated with this model. Animals received nor-BNI systemically; in the trigeminal ganglion (TG); in the subarachnoid space to target the spinal trigeminal nucleus caudalis (Sp5C) or in the central amygdala (CeA) 14 days after CCI-ION surgery. Systemic administration of nor-BNI caused a significant reduction of facial mechanical hyperalgesia and promoted an anxiolytic-like effect, which was detected in the elevated plus-maze and the light-dark transition tests. When administered in the TG or CeA, the KOR antagonist was able to reduce facial mechanical hyperalgesia induced by CCI-ION, but without changing the anxiety-like behavior. Moreover, no change was observed on nociception and anxiety-like behavior after nor-BNI injection into the Sp5C. The present study demonstrated antinociceptive and anxiolytic-like effects of nor-BNI in a model of trigeminal neuropathic pain. The antinociceptive effect seems to be dissociated from the anxiolytic-like effect, at both the sites involved and at the dose need to achieve the effect. In conclusion, the kappa opioid system may represent a promising target to be explored for the control of trigeminal pain and associated anxiety. However, further studies are necessary to better elucidate its functioning and modulatory role in chronic trigeminal pain states.