Opioid Antagonist Research Articles

Improving Diagnosis and Management of Opioid-Induced Constipation (OIC) in Clinical Practice: An Italian Expert Opinion

Opioid-induced constipation (OIC) is a very common and troublesome gastrointestinal side effect following the use of opioids. Despite existing international guidelines, OIC is largely underdiagnosed and undertreated. ECHO OIC is a European project designed to improve the diagnosis and management of OIC at the primary care level. The next phase of the ECHO OIC project is to review and adapt the proposed European pathway at national level, considering the local patient journey and clinical practice. A multidisciplinary group of 12 Italian experts reviewed and discussed the European path and formulated a seven-step guide for the practical management of OIC that is also easily applicable in primary care: 1. When prescribing long-term opioids, the physician should inform the patient of the possibility of the onset of OIC; 2. At opioid prescription, doctors should also prescribe a treatment for constipation, preferably macrogol or stimulant laxatives; 3. The patient should be evaluated for OIC within the second week of initiating opioid treatment, by clinical history and Rome IV criteria; 4. In the presence of constipation despite laxatives, prescription of a PAMORA (Peripherally Acting Mu Opioid Receptor Antagonist) should be considered; 5. When prescribing a PAMORA, prescribing information should be carefully reviewed, and patients should be accurately instructed for appropriate use; 6. Efficacy and tolerability of the PAMORA should be monitored regularly by Bowel Function Index, considering a cut-off of 30 for the possible step-up of OIC treatment; 7. After 4 weeks of treatment, if the efficacy of PAMORA is deemed inadequate, discontinuation of the PAMORA, addition of an anti-constipation drugs, change of opioid type, or referral to a specialist should be considered. Spreading knowledge about the OIC problem as much as possible to the health community is crucial to obtain not only an early treatment of the condition but also to promote its prevention.

Opioid antagonist Utilization Patterns in United States Emergency Department Visit: A Retrospective Study

Opioid antagonist Utilization Patterns in United States Emergency Department Visit: A Retrospective Study

B-268 Detection of xylazine in fentanyl-positive urine drug screen specimens using a quantitative LCMS/MS method

Abstract Background Fentanyl, a synthetic opioid used clinically for severe pain management, sedation, and as a perioperative analgesic, has been at the forefront of fatal drug-involved overdoses for almost a decade. Xylazine, an α-2 adrenergic receptor agonist, is an increasingly common adulterant in illicitly manufactured fentanyl products and analogs. Given its class, xylazine is non-responsive to naloxone, an opioid receptor antagonist used to reverse opioid overdose. Importantly, the U.S. Drug Enforcement Administration reported xylazine in 23% of seized fentanyl powders and 7% of fentanyl pills; additionally, a recent study by Kariisa et. al. identified an increase of xylazine presence in fatal fentanyl-involved overdoses (2.9% in January 2019 to 10.9% in June 2022) across twenty states.1 Collectively, these trends indicate a need for increased surveillance of xylazine in overdose-presenting patients to inform appropriate clinical responses. In this study, we developed a sensitive LC-MS/MS method for xylazine quantitation and used it to determine xylazine presence in our fentanyl positive patients. Methods An LC-MS/MS method for quantitation of xylazine from urine samples was developed using a Waters Xevo TQ-XS and reversed-phase CORTECS C8 2.7 µm column. MRMs and optimal MS tuning parameters were generated for xylazine and xylazine-d6 via IntelliStart, with transition ions of 221.18→90.04 (Quan) and 221.18→136.31 (Qual) selected for xylazine quantitation against a 227.23→89.98 xylazine-d6 transition as an internal standard. An LC method was developed using water (2 mM Ammonium Acetate; 0.1% Formic Acid v/v) and methanol (2 mM Ammonium Acetate; 0.1% Formic Acid v/v) gradient for a 4-minute runtime. Calibrators were prepared by addition of the pure drug to water, while QCs were prepared using healthy volunteer urine that was confirmed negative in a routine urine drug screen (UDS). Calibrators were value-assigned using a reference laboratory. A simple processing method consisting of the addition of 200 µL methanol containing 25 ng/mL xylazine-d6 to 50 µL of standards, QCs, or urine was used for sample preparation. Remnant fentanyl-positive patient samples (determined by ARK Fentanyl II Immunoassay - Abbott Architect C16000 analyzer) submitted for routine UDS evaluation were collected for xylazine analysis. Results Using custom xylazine standards, the method yielded a linear range from 2 ng/mL to 500 ng/mL with an average R2 of 0.9995 across runs (n = 12). The LLoQ for this assay was 2 ng/mL with a CV of 18.1%. The intra-assay CVs were < 5.0% and inter-assay CVs were < 15.0%. Of preliminary patient samples tested (n = 25), xylazine was detected in 32% of fentanyl-positive samples, ranging in concentration from 2.8 ng/mL to 192.8 ng/mL with an average of 64.8 ng/mL. Conclusions Here we report a simple LC-MS/MS method for quantitation of xylazine in remnant fentanyl-positive UDS specimens by LC-MS/MS. Preliminary testing revealed a xylazine positivity rate of 32% in fentanyl-positive patients. Uncomplicated sample work-up makes this method applicable to xylazine surveillance in all UDS-positive patient samples in high-throughput clinical laboratories. Reference: 1. Kariisa M, et. al. “Illicitly Manufactured Fentanyl-Involved Overdose Deaths with Detected Xylazine.” MMWR Morb Mortal Wkly Rep 2023;72:721-727.

Chronic olanzapine treatment leads to increased opioid receptor expression and changes in feeding regulating neurons in the female rat hypothalamus

Opioid receptor antagonists have shown increasing promise as an adjunct therapy to psychotropic medication. The goal is to reduce the weight gain and metabolic adverse effects that are associated with certain second-generation antipsychotics, such as olanzapine and clozapine. In this study, female rats were treated for 4 weeks with a long-acting injectable formulation of olanzapine to assess effects on hypothalamic feeding regulation. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the mu, kappa and delta opioid receptors were defined in the five hypothalamic areas: paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamus (LH). In addition, hypothalamic neuron number and size were estimated using the unbiased optical fractionator and spatial rotator methods. Hyperphagia was observed after only 24hours of olanzapine treatment, with continued weight gain throughout the duration of the study. In contrast, the observed food intake reversed to control levels after 2 weeks of olanzapine treatment. Chronic olanzapine treatment increased expression of kappa opioid receptor mRNA and receptor availability in the PVN, as well as increased mu opioid receptor availability in the PVN, ARC and VMN. These changes were accompanied by fewer anorexigenic proopiomelanocortin-expressing neurons of the ARC and corticotropin-releasing hormone expressing neurons of the PVN. This study links olanzapine-driven metabolic effects to increased opioid receptor expression in the hypothalamus, thus providing a rationale for the positive effects of using opioid receptor antagonists to relieve olanzapine adverse effects.

Take-home naloxone in multicentre emergency settings: the TIME feasibility cluster RCT.

Opioids kill more people than any other drug. Naloxone is an opioid antagonist which can be distributed in take-home 'kits' for peer administration (take-home naloxone). To determine the feasibility of carrying out a definitive randomised controlled trial of take-home naloxone in emergency settings. We used Welsh routine data (2015-21) to test the feasibility of developing a discriminant function to identify people at high risk of fatal opioid overdose. We carried out a cluster randomised controlled trial and qualitative study to examine experiences of service users and providers. We assessed feasibility of intervention and trial methods against predetermined progression criteria related to: site sign-up, staff trained, identification of eligible patients, proportion given kits, identification of people who died of opioid poisoning, data linkage and retrieval of outcomes. This study was carried out in the emergency environment; sites comprised an emergency department and associated ambulance service catchment area. At intervention sites, we invited emergency department clinicians and paramedics to participate. We recruited adult patients who arrived at the emergency department or were attended to by ambulance paramedics for a problem related to opioid use with capacity to consent to receiving the take-home naloxone and related training. Usual care comprised basic life support plus naloxone by paramedics or emergency department staff. The take-home naloxone intervention was offered in addition to usual care, with guidance for recipients on basic life support, the importance of calling the emergency services, duration of effect, safety and legality of naloxone administration. With low numbers of opioid-related deaths (1105/3,227,396) and a high proportion having no contact with health services in the year before death, the predictive link between death and opioid-related healthcare events was weak. Logistic regression models indicated we would need to monitor one-third of the population to capture 75% of the decedents from opioid overdose in 1-year follow-up. Four sites participated in the trial and 299 of 687 (44%) eligible clinical staff were trained. Sixty take-home naloxone kits were supplied to patients during 1-year recruitment. Eligible patients were not offered take-home naloxone kits 164 times: 'forgot' (n = 136); 'too busy' (n = 15); suspected intentional overdose (n = 3). Service users had high levels of knowledge about take-home naloxone. They were supportive of the intervention but noted concerns about opioid withdrawal and resistance to attending hospital for an overdose. Service providers were positive about the intervention but reported barriers including difficulty with consenting and training high-risk opioid users. We were able to calculate costs to train staff at three sites (£40 per AS and £17 in Site 1 ED). No adverse events were reported. Progression criteria were not met - fewer than 50% of eligible staff were trained, fewer than 50% of eligible patients received the intervention and outcomes were not retrieved within reasonable timescales. The take-home naloxone intervention needs to be developed and evaluated in emergency care settings, with appropriate methods. The Take-home naloxone Intervention Multicentre Emergency setting study was interrupted by coronavirus disease. This study did not meet progression criteria for intervention or trial methods feasibility, so outcomes were not followed up and a fully powered trial is not planned. This trial is registered as ISRCTN13232859. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/91/04) and is published in full in Health Technology Assessment; Vol. 28, No. 74. See the NIHR Funding and Awards website for further award information.

Study on peripheral antinociception induced by hydrogen peroxide (H2O2): characterization and mechanisms.

The present study aimed to evaluate the possible peripheral H2O2-induced antinociception and determine the involvement of opioidergic, cannabinoidergic and nitrergic systems, besides potassium channels in its antinociceptive effect. Prostaglandin E2 was used to induce hyperalgesia in male Swiss mice using the mechanical paw pressure test. H2O2 (0.1, 0.2, 0.3 µg/paw) promoted a dose-dependent antinociceptive effect that was not observed in contralateral paw. Female mice also showed antinociception in the model. The partial H2O2-induced antinociception was potentiated by the inhibitor of catalase enzyme, aminotriazole (40, 60, 80 µg/paw). The antinociception was not reversed by opioid and cannabinoid receptor antagonists naloxone, AM 251 and AM 630. The involvement of nitric oxide (NO) was observed by the reversal of H2O2-induced antinociception using the non-selective inhibitor of nitric oxide synthases L-NOarg and by inhibition of iNOS (L-NIL), eNOS (L-NIO) and nNOS (L-NPA). ODQ, a cGMP-forming enzyme selective inhibitor, also reversed the antinociception. The blockers of potassium channels voltage-gated (TEA), ATP-sensitive (glibenclamide), large (paxillin) and small (dequalinium) conductance calcium-activated were able to revert H2O2 antinociception. Our data suggest that H2O2 induced a peripheral antinociception in mice and the NO pathway and potassium channels (voltage-gated, ATP-sensitive, calcium-activated) are involved in this mechanism. However, the role of the opioid and cannabinoid systems was not evidenced.

Central δ/κ opioid receptor signaling pathways mediate chronic and/or acute suckling-induced LH suppression in rats during late lactation.

In mammals, secretion of tonic (pulsatile) gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) is often suppressed during lactation. Suppression of GnRH/LH pulses in lactating dams is assumed to be caused by suckling stimuli and a chronic negative energy balance due to milk production. The present study aimed to investigate whether the central enkephalin-δ opioid receptor (DOR) signaling mediated the suppression of LH secretion by acute suckling stimuli and/or chronic negative energy balance due to milk production in rats during late lactation when dams were under a heavy energy demand. On postpartum day 16, the number of Penk (enkephalin mRNA)-expressing cells in the arcuate nucleus was significantly higher in lactating rats than in non-lactating control rats. Pulsatile LH secretion was suppressed in rats with chronic suckling or acute 1-h suckling stimuli 6 h after pup removal on day 16 of lactation. Central DOR antagonism significantly increased the mean LH concentrations and the baseline of LH pulses in rats with chronic suckling but not with acute suckling stimuli on day 16 of lactation. Besides, central κ opioid receptor (KOR) antagonism increased the amplitude of LH pulses in rats with the acute suckling stimuli on day 16 of lactation. These results suggest that central DOR signaling mediates the suppression of LH secretion caused by a negative energy balance in rats receiving chronic suckling during late lactation. On the other hand, central KOR signaling likely mediates acute suckling stimuli-induced suppression of LH secretion in rats during late lactation.

Stimulation of kappa opioid receptors in the nucleus accumbens promotes feeding behavior in mice: Acute restoration of feeding during anorexia induced by 5-fluorouracil

Though μ and δ opioid receptors are reported to regulate energy homeostasis, any role for κ opioid receptors in these processes remains unclear. The present study investigated the role of κ opioid receptors in regulation of feeding behavior and plasma glucose levels using nalfurafine, a κ opioid receptor agonist used clinically. Systemic injection of nalfurafine increased food intake under non-fasted conditions, but not after food deprivation, and this effect was inhibited by the κ opioid receptor antagonist norbinaltorphimine. In contrast, nalfurafine did not affect plasma glucose levels. I.c.v. injection of nalfurafine increased food intake, whereas systemic injection of nalfurafine methiodide, which does not penetrate the blood brain barrier, was without effect. In addition, nalfurafine tended to increase preproorexin mRNA in the hypothalamus. However, neither the orexin OX1 receptor antagonist YNT-1310 nor the non-selective orexin receptor antagonist suvorexant inhibited the increase in food intake induced by nalfurafine. While nalfurafine injected into the lateral hypothalamus did not affect food intake, nalfurafine injected into the nucleus accumbens increased food intake, which was inhibited by norbinaltorphimine. Finally, we examined the effect of nalfurafine on anorexia induced by the anti-cancer agent 5-fluorouracil. Reduced food intake at 2 days following 5-fluorouracil administration was alleviated across the first 3 h following daily injection of nalfurafine, though daily food intake was not influenced. These results indicate that nalfurafine promotes feeding behavior through stimulation of κ opioid receptors in the nucleus accumbens and may be a candidate for reducing anorexia due to anti-cancer agents.

Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

The ultrasonic vocalization (USV) syllable profile during neonatal opioid withdrawal and a kappa opioid receptor component to increased USV emissions in female mice.

Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments. We sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal. We employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal. On P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice. We identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.

Itching for Answers: A Comprehensive Review of Cholestatic Pruritus Treatments

Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future.

Impacts of endogenous opioid blockade and sex on working memory among ad-libitum and abstinent smokers and non-smokers

BackgroundResearch examining the effects of opioid receptor antagonists on working memory is limited by small sample sizes that are often comprised of only male participants. Moreover, they have yielded mixed findings, and no studies have examined such effects in the context of chronic nicotine use and temporary nicotine withdrawal. MethodsMale and female participants completed two lab visits at which they were administered either 50 mg naltrexone or an identical placebo (one at each lab using double-blind, counterbalanced administration). After a medication absorption period, performance on a mental arithmetic (working memory) task was assessed by number of correct responses, errors, and number of attempts. Participants were either non-smokers or regular smokers who were randomly assigned to use nicotine ad-libitum or to abstain from nicotine for 24 h prior to both lab visits. ResultsThe results indicate a significant main effect of opioid blockade on number of correct answers and accuracy rate during the mental arithmetic task, with poorer performance after opioid blockade compared to placebo. In addition, compared to male participants, female participants made fewer answer attempts, had fewer correct answers, and a lower accuracy rate. We did not find evidence of any differences based on smoking group (non-smoker, smoking abstinence, or ad-libitum smoking), nor were there any significant interaction effects. ConclusionsThe findings suggest a modulating role of the endogenous opioid system in working memory function. Further investigation is needed to help identify the underlying mechanisms explaining the effects of the endogenous opioid system on working memory.

Major clinical evidence on the use of low-dose naltrexone in the treatment of cancer: a systematic review

Introduction: Opioid receptors are groups of receptors (γ-, κ-, δ-, and ζ-opioid receptors) that are widely distributed in nerve cells in the brain, spinal cord, and digestive tract. Naltrexone is a type of general opioid receptor antagonist. It has been used to treat chronic pain syndrome, autoimmune diseases, and cancer at a dose of 5 mg/day, which is generally called low-dose naltrexone (LDN). Objective: It was to analyze the pharmacological functions of low-dose naltrexone, especially in anti-inflammation and immunoregulation, and its therapeutic potential against cancer. Methods: The research and development of the work were carried out from June to July 2024 in the Scopus, PubMed, Science Direct, and Scielo databases, using scientific articles from the last 15 years, following the PRISMA rules. The quality of the studies was based on the GRADE and AMSTAR2 instruments, and the risk of bias was assessed using the Cochrane instrument (Funnel Plot). Results and Conclusion: Fifteen studies were included in the systematic review out of 30. Most studies showed homogeneity in their results, with X2=94.5%>50%. Low-dose naltrexone has immunomodulatory and therapeutic effects. Low-dose naltrexone regulates the production of inflammatory cytokines, influencing the level of endogenous opioid peptides in the body. Furthermore, low-dose naltrexone has an antitumor effect and can modulate the neuroblastoma tumor response, delaying the onset and reducing the incidence rate of tumors, significantly decreasing tumor volume and weight, and DNA synthesis in cancer.

Examination of the antiallodynic effect of rosmarinic acid in neuropathic pain and possible mechanisms of action

This study aimed to explore the potential antiallodynic effects of rosmarinic acid, a natural antioxidant with a demonstrated safety profile across a broad dose range. Using a chronic constriction injury-induced neuropathic pain model, the impact of rosmarinic acid on allodynia was investigated. Furthermore, the involvement of adrenergic and opioidergic mechanisms in its activity was assessed. To evaluate rosmarinic acid’s efficacy, doses of 10, 20, and 40 mg/kg were administered and the electronic von Frey test was utilized along with an activity cage apparatus. % MPE values were calculated to gauge the extent of pain relief. Mechanistic insights were obtained by pretreating animals with the β-adrenergic receptor antagonist propranolol, the α1-adrenergic receptor antagonist prazosin, α2-adrenergic receptor antagonist yohimbine, and the opioid receptor antagonist naloxone. Rosmarinic acid demonstrated a statistically significant antiallodynic effect that was independent of locomotor activity. This effect was noteworthy as it resembled both the level and duration of relief provided by pregabalin. Additionally, the %MPE value of the group treated with 40 mg/kg rosmarinic acid showed a significant difference compared to the value of the pregabalin-treated group (P<0.001). Pre-administration of the antagonists revealed that the antiallodynic activity was shown to be mediated by the stimulation of opioid and adrenergic receptors, with a primary contribution from α2-adrenergic receptor stimulation. Our findings suggest that rosmarinic acid may hold promise as a potential therapeutic agent for neuropathic pain. By elucidating the involvement of adrenergic and opioidergic mechanisms, we have provided valuable preclinical data that could inform novel treatment approaches.

Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive effects.

In this study, we compare the central versus peripheral components underlying fentanyl-induced cardiorespiratory depression to prevent overdose deaths. Our data indicates that these effects are, at least partially, due to the activation of mu opioid receptors present in peripheral sites. These findings provide insight into peripheral contributions to fentanyl-induced overdoses and could potentially lead to the development of treatments selectively targeting the peripheral system, sparing individuals from the CNS-driven acute opioid withdrawal generally observed with the use of naloxone.

Alternative Reinforcers Enhance the Effects of Opioid Antagonists, but Not Agonists, on Oxycodone Choice Self-Administration in Nonhuman Primates.

Clinical reports suggest that the most effective strategies for managing opioid use disorder comprise a comprehensive treatment program of both pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective are not well characterized. This study examined whether the presence of an alternative reinforcer could alter the efficacy of Food and Drug Administration-approved opioid antagonist or agonist medications, as well as the nonopioid flumazenil, in decreasing oxycodone choice self-administration in nonhuman primates. Adult squirrel monkeys (n = 7; four females) responded under concurrent second-order fixed-ratio (FR)-3(FR5:S);TO45s schedules of reinforcement for intravenous oxycodone (0.1 mg/kg) or saline on one lever and 30% sweetened condensed milk or water on the other. Doses of naltrexone (0.00032-1.0 mg/kg), nalbuphine (0.32-10 mg/kg), buprenorphine (0.0032-0.032 mg/kg), methadone (0.32-1.0 mg/kg), or flumazenil (1-3.2 mg/kg) were administered intramuscularly prior to oxycodone self-administration sessions that occurred with either milk or water as the alternative. Naltrexone, a μ-opioid receptor antagonist, was >30-fold more potent when milk was available compared with water and abolished oxycodone intake (injections/session) while concomitantly increasing milk deliveries at the highest dose tested. Pretreatment with the low-efficacy μ-agonist nalbuphine was most effective in the presence of milk compared with water, decreasing oxycodone preference to <50% of control values. The higher efficacy μ-agonists, methadone and buprenorphine, and the benzodiazepine antagonist flumazenil did not appreciably alter the reinforcing potency of oxycodone under either condition. These results suggest that antagonist medications used in combination with alternative reinforcers may be an effective strategy to curtail opioid abuse-related behaviors. SIGNIFICANCE STATEMENT: Clinical treatment programs for opioid use disorder use a combination of pharmacological and nonpharmacological approaches. However, the conditions under which these combinations are most effective have not been fully characterized. This study examined whether the effectiveness of μ-opioid medications to decrease oxycodone self-administration is altered in the presence of an alternative reinforcer. The results suggest that alternative reinforcers enhance the effects of antagonist or low-efficacy partial agonists, suggesting they may be a more effective strategy to curtail opioid use.

Proof of Concept for High-Dose Cannabidiol Pretreatment to Antagonize Opioid Induced Persistent Apnea.

Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities. CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone. The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.

Effect of opioid receptor antagonist on mitigating tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-induced apoptolysis in pemphigus pathogenesis

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.

Methadone compared to buprenorphine

Both medications are controlled substances, and approved to treat opioid use disorder. OTPs provide both as well as opioid antagonist naltrexone. Those are the only medications approved to treat OUD.

Pharmacologic Therapy for Spinal Cord Injury.

Neuroprotective strategies aimed at preventing secondary neurologic injury following acute spinal cord injury remain an important area of clinical, translational, and basic science research. Despite recent advancement in the understanding of basic mechanisms of primary and secondary neurologic injury, few pharmacologic agents have shown consistent promise in improving neurologic outcomes following SCI in large randomized clinical trials. The authors review the existing literature and clinical guidelines for pharmacologic therapy investigated for managing acute SCI, including corticosteroids, GM-1 ganglioside (Sygen), Riluzole, opioid antagonists, Cethrin, minocycline, and vasopressors for mean arterial pressure augmentation. Therapies for managing secondary effects of SCI, such as bradycardia, are discussed. Current clinical trials for pharmacotherapy and cellular transplantation following acute SCI are also reviewed. Despite the paucity of current evidence for clinically beneficial post-SCI pharmacotherapy, future research efforts will hopefully elucidate promising therapeutic agents to improve neurologic function.