Safety of naltrexone in patients with cirrhosis.

Background & Aims: Treatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are underutilized in this population, partially due to concerns regarding drug-induced liver injury (DILI). Our aim was to evaluate the safety of naltrexone in patients with cirrhosis. Methods: This was a retrospective study of patients with cirrhosis who were prescribed naltrexone using the VOCAL (Veterans Outcomes and Costs Associated with Liver Disease) database. Patients with new initiation of naltrexone after diagnosis of cirrhosis who had liver enzymes checked within a 3-month time frame were included. A chart review was performed on patients who developed alanine aminotransferase or alkaline phosphatase elevations to more than 2× or 5× the upper limit of normal, respectively. The RUCAM (Roussel Uclaf causality assessment method) was used to determine if DILI occurred. Results: A total of 3,285 patients with cirrhosis were initiated on naltrexone, of whom 2,940 had laboratory testing during the high-risk DILI period. Only 2% of patients had liver enzyme elevations, and among those, 30 (48%) were classified as "DILI excluded" and 32 (52%) were classified as "DILI unlikely". No patients were classified as possible, probable, or highly probable DILI. No deaths or new decompensations were attributed to naltrexone. Conclusions: Naltrexone in patients with cirrhosis was not associated with development of DILI using RUCAM scoring. Naltrexone appears to be safe in patients with compensated and decompensated cirrhosis. Impact and Implications: Naltrexone is an effective medication for treating alcohol use disorder but is underutilized in patients with underlying liver disease due to historical concerns regarding hepatotoxicity. This retrospective study shows no drug-induced liver injury in a large cohort of patients with cirrhosis with new initiation of naltrexone. This study may encourage providers to prescribe naltrexone to patients with existing liver disease with ongoing alcohol use disorder.

Self-help groups and opioid use disorder treatment: An investigation using a machine learning-assisted robust causal inference framework.

OBJECTIVES: This study investigates the impact of participation in self-help groups on treatment completion among individuals undergoing medication for opioid use disorder (MOUD) treatment. Given the suboptimal adherence and retention rates for MOUD, this research seeks to examine the association between treatment completion and patient-level factors. Specifically, we evaluated the causal relationship between self-help group participation and treatment completion for patients undergoing MOUD. METHODS: We used the Substance Abuse and Mental Health Services Administration's (SAMHSA) Treatment Episode Data Set: Discharges (TEDS-D) from 2015 to 2019. The data are filtered by the patient's opioid use history, demographics, treatment modality, and other relevant information. In this observational study, machine learning models (Lasso Regression, Decision Trees, Random Forest, and XGBoost) were developed to predict treatment completion. Outcome Adaptive Elastic Net (OAENet) was used to select confounders and outcome predictors, and the robust McNemars test was used to evaluate the causal relationship between self-help group participation and MOUD treatment completion. RESULTS: The machine-learning models showed a strong association between participation in self-help groups and treatment completion. Our causal analysis demonstrated an average treatment effect on treated (ATT) of 0.260 and a p-value < 0.0001 for the robust McNemars test. CONCLUSIONS: Our study demonstrates the importance of participation in self-help groups for MOUD treatment recipients. We found that participation in MOUD along with self-help groups caused higher chances of treatment completion than MOUD alone. This suggests that policymakers should consider further integrating self-help groups into the treatment for OUD to improve the adherence and completion rate.

Characterizing reward and relief/habit drinking profiles in a study of naltrexone, varenicline, and placebo.

INTRODUCTION: This study aims to clarify differences in mood, craving, and treatment response between reward and relief/habit individuals in a study of naltrexone, varenicline, and placebo. We hypothesized that relief/habit individuals would have a poorer mood during early abstinence and higher levels of alcohol craving than reward individuals. We hypothesized that reward individuals would demonstrate better drinking outcomes on naltrexone versus placebo. METHODS: Data were culled from a randomized, double-blind, placebo-controlled human trial of 53 individuals (18F/16M) with alcohol use disorder randomized to varenicline (n = 19), naltrexone (n = 15), or matched placebo (n = 19). In this 6-day practice quit trial, participants attempted to abstain from drinking and completed daily diaries. Participants were classified into reward or relief/habit subgroups based on self-reported motivation for drinking. Multilinear models tested differences in mood and alcohol craving between reward and relief/habit individuals. General linear models tested differences between reward and relief/habit individuals' drinking outcomes on each medication versus placebo. RESULTS: Relief/habit individuals showed decreases in positive mood and increases in negative mood over the quit attempt across medications, compared to reward individuals (P's < .05). Reward individuals' tension decreased on naltrexone, while relief/habit individuals' tension remained stable (F = 3.64, P = .03). Reward individuals in the placebo group had higher percent days abstinent than relief individuals in the placebo group (P < .001). DISCUSSION: This study suggests relief/habit individuals' mood worsens during early abstinence. Our finding that reward individuals' tension decreased on naltrexone and increased on placebo may suggest a clinical response to the medication.

Long COVID management: a mini review of current recommendations and underutilized modalities.

Long COVID is a condition that develops in a subset of patients after COVID-19 infection comprising of symptoms of varying severity encompassing multiple organ systems. Currently, long COVID is without consensus on a formal definition, identifiable biomarkers, and validated treatment. Long COVID is expected to be a long-term chronic condition for a subset of patients and is associated with suffering and incapacity. There is an urgent need for clear management guidelines for the primary care provider, who is essential in bridging the gap with more specialized care to improve quality of life and functionality in their patients living with long COVID. The purpose of this mini review is to provide primary care providers with the latest highlights from existing literature regarding the most common long COVID symptoms and current management recommendations. This review also highlights the underutilized interventions of stellate ganglion blocks and low-dose naltrexone, both with well-established safety profiles demonstrated to improve quality of life and functionality for patients suffering with some symptoms of long COVID, and encourages prompt referral to interventional pain management.

Potential pathophysiological role of the ion channel TRPM3 in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the therapeutic effect of low-dose naltrexone.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with a broad overlap of symptomatology with Post-COVID Syndrome (PCS). Despite the severity of symptoms and various neurological, cardiovascular, microvascular, and skeletal muscular findings, no biomarkers have been identified. The Transient receptor potential melastatin 3 (TRPM3) channel, involved in pain transduction, thermosensation, transmitter and neuropeptide release, mechanoregulation, vasorelaxation, and immune defense, shows altered function in ME/CFS. Dysfunction of TRPM3 in natural killer (NK) cells, characterized by reduced calcium flux, has been observed in ME/CFS and PCS patients, suggesting a role in ineffective pathogen clearance and potential virus persistence and autoimmunity development. TRPM3 dysfunction in NK cells can be improved by naltrexone in vitro and ex vivo, which may explain the moderate clinical efficacy of low-dose naltrexone (LDN) treatment. We propose that TRPM3 dysfunction may have a broader involvement in ME/CFS pathophysiology, affecting other organs. This paper discusses TRPM3's expression in various organs and its potential impact on ME/CFS symptoms, with a focus on small nerve fibers and the brain, where TRPM3 is involved in presynaptic GABA release.

Impact of hospital-administered extended-release naltrexone on readmission rates for patients with alcohol use disorder.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) is a persistent public health concern, contributing significantly to mortality and morbidity. This study aims to evaluate the impact of in-hospital extended-release naltrexone (XR-NTX) administration on alcohol-related outcomes. METHODS: This retrospective cohort study, conducted at an academic medical centre, included 141 adult patients with AUD who received XR-NTX between December 2020 and June 2021. Primary and secondary outcomes were assessed 90 days before and after XR-NTX administration to identify number of alcohol-related hospitalisations, emergency department (ED) visits and average length of hospital stay. Subgroup analyses assessed outcomes in high hospital utilisers and marginally housed or unhoused populations. RESULTS: There was a significant decrease in ED visits and length of hospital stay post XR-NTX and no significant difference in the number of rehospitalisations. Subgroup analysis showed significant reduction in hospital readmissions and ED visits among high hospital utilisers. Our sample was a predominantly middle-aged, male and white patient population. CONCLUSIONS: In-hospital initiation of XR-NTX for AUD was associated with a significant decrease in ED visits and length of hospital stay. While no significant impact on the number of hospitalisations was observed overall, there was a substantial reduction in hospital readmissions and ED visits among high utilisers. Our findings suggest the potential benefits of in-hospital XR-NTX, emphasising the need for further research to establish causal relationships, assess cost-effectiveness and explore effectiveness across diverse patient populations. Effective in-hospital interventions, such as XR-NTX, hold promise for improving patient outcomes and reducing the healthcare burden associated with AUD.

Effects of Naltrexone on Sleep Quality and Periodic Breathing at High Altitude.

Foster, Katharine, James D. Anholm, Gary Foster, Suman Thapamagar, and Prajan Subedi. Effects of naltrexone on sleep quality and periodic breathing at high altitude. High Alt Med Biol. 00:000-000, 2024. Objective: This study examined the effects of naltrexone on breathing and sleep at high altitude. Mu-opioid receptor (MOR) agonists have a depressive effect on respiration. Naltrexone is known to block the MOR. We hypothesized that MOR blockade with naltrexone would result in higher nocturnal oxygen saturations, fewer apneas, and improved sleep at high altitude. Methods: This double-blind, placebo-controlled, crossover study included nine healthy volunteers (four females, five males) aged 27.9 (4.6) (mean [standard deviation]) years. Two overnight trips spaced at least 2 weeks apart took participants from Loma Linda, CA (355 m) to the Barcroft Laboratory, CA (3,810 m) for each arm. Participants ingested either 50 mg naltrexone or matching placebo at bedtime. Sleep metrics were recorded using an ambulatory physiological sleep monitor (APSM). Subjective data were measured with the Groningen Sleep Quality Scale, Stanford Sleepiness Scale, and the 2018 Lake Louise Score (LLS) for acute mountain sickness (AMS). Results: Mean overnight SpO2 was lower after taking naltrexone, 81% (6) versus 83% (4) (mean difference 1.9% [2.1, 95% confidence interval or CI = 0.1-3.6, p = 0.040]). The lowest overnight SpO2 (nadir) was lower on naltrexone 70% (6) versus 74% (4) (dif. 4.6% [4.3], CI = 1.0-8.2, p = 0.020). Total sleep time and total apnea-hypopnea index were unchanged. Subjective sleep quality was significantly worse on naltrexone measured via the Groningen Sleep Quality Scale (p = 0.033) and Stanford Sleepiness Scale (p = 0.038). AMS measured via LLS was significantly worse while taking naltrexone (p = 0.025). Conclusion: Contrary to our hypothesis, this study demonstrated a significant decrease in nocturnal oxygen saturation, worse sleep quality, and AMS scores. Further characterization of the MOR's effects on sleep and AMS is needed to evaluate potential exacerbating mechanisms for AMS and poor sleep quality at altitude.

Design and Characterization of Chitosan-Based Smart Injectable Hydrogel for Improved Sustained Release of Antinarcotics.

The treatment adherence of narcotics-addicted individuals with reduced incidences of relapse can be enhanced by a sustained drug release formulation of antinarcotics. So far, different drug formulations have been reported with sustained drug release periods of 28 and 35 days. To further enhance this duration, different formulations of injectable hydrogels (IHs) have been developed by combining low molecular weight (LMW) and high molecular weight (HMW) chitosan (CS) with guar gum (GG) and crosslinking them by sodium bi phosphate dibasic. The structural, morphological, and physicochemical properties of LMW-CS IH, and HMW-CS IH were evaluated using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TGA), scanning electron microscopy (SEM), and rheological, swelling, and biodegradation analysis. The HMW-CS IH showed high crosslinking, increased thermal stability, high mechanical strength, elevated swelling, and low biodegradation. The antinarcotic drugs naltrexone (NTX) and disulfiram (DSF) were loaded separately into the HMW-CS IH and LMW-CS IH. The release of NTX and DSF was investigated in phosphate buffer saline (PBS) and ethanol (0.3%, 0.4%, and 0.5%) over a 56-day period using an UV spectrophotometer. The drug release data were tested in zero-order, first-order, and Korsemeyer-Peppas mathematical models. In PBS, all prepared formulations followed non-Fickian drug release, while in ethanol, only NTX HMW-CS IH followed non-Fickian release in all three different concentrations of ethanol.

TLR4 inhibitors through inhibiting (MYD88-TRIF) pathway, protect against experimentally-induced intestinal (I/R) injury.

Intestinal ischemia/reperfusion (I/R) injury is a serious condition that causes intestinal dysfunction and can be fatal. Previous research has shown that toll-like receptor 4 (TLR4) inhibitors have a protective effect against this injury. This study aimed to investigate the protective effects of TLR4 inhibitors, specifically cyclobenzaprine, ketotifen, amitriptyline, and naltrexone, in rats with intestinal (I/R) injury. Albino rats were divided into seven groups: vehicle control, sham-operated, I/R injury, I/R-cyclobenzaprine (10 mg/kg body weight), I/R-ketotifen (1 mg/kg body weight), I/R-amitriptyline (10 mg/kg body weight), and I/R-naltrexone (4 mg/kg body weight) groups. Anesthetized rats (urethane 1.8 g/kg) underwent 30 min of intestinal ischemia by occluding the superior mesenteric artery (SMA), followed by 2 h of reperfusion. Intestinal tissue samples were collected to measure various parameters, including malondialdehyde (MDA), nitric oxide synthase (NO), myeloperoxidase (MPO), superoxide dismutase (SOD), TLR4, intercellular adhesion molecule-1 (ICAM-1), nuclear factor kappa bp65 (NF-ĸBP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), macrophages CD68, myeloid differentiation factor 88 (MYD88), and toll interleukin receptor-domain-containing adaptor-inducing interferon ß (TRIF). The use of TLR4 inhibitors significantly reduced MDA, MPO, and NO levels, while increasing SOD activity. Furthermore, it significantly decreased TLR4, ICAM-1, TNF-α, MCP-1, MYD88, and TRIF levels. These drugs also showed partial restoration of normal cellular structure with reduced inflammation. Additionally, there was a decrease in NF-ĸBP65 and macrophages CD68 staining compared to rats in the I/R groups. This study focuses on how TLR4 inhibitors enhance intestinal function and protect against intestinal (I/R) injury by influencing macrophages CD86 through (MYD88-TRIF) pathway, as well as their effects on oxidation and inflammation.

Extended observation of reduced methamphetamine use with combined naltrexone plus bupropion in the ADAPT-2 trial.

BACKGROUND AND AIMS: A 12-week placebo-controlled, sequential parallel Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial evaluated the effects of extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN) on methamphetamine (MA) use over two stages. This study reports on the previously unpublished stage 2 MA use in participants randomized at stage 1 to receive NTX + BUPN through both stages compared with those assigned to placebo. DESIGN: This is a secondary analysis of the US National Institute on Drug Abuse (NIDA) ADAPT-2 network trial. SETTING: The parent ADAPT-2 trial was carried out across multiple NIDA Clinical Trials Network (CTN) sites in the United States. PARTICIPANTS: This analysis includes 403 people with MA use disorder who participated in the ADAPT-2 CTN trial. INTERVENTION AND COMPARATOR: NTX + BUPN was compared with placebo over the course of the trial. MEASUREMENT: MA use was measured by urine drug screens conducted twice weekly for 12 weeks, then once in week 13 and once in week 16 post-treatment follow-up. FINDINGS: Participants on NTX + BUPN in stage 1 showed an additional 9.2% increase [95% confidence interval (CI), 0.09%-17.9%, P = 0.038] during stage 2 in their probability of testing negative for MA, with a total increase of 27.1% (95% CI, 13.2%-41.1%, P < 0.001) over the full 12 weeks of treatment. In contrast, participants on placebo in both stages increased in probability of testing MA-negative by a total of 11.4% (95% CI, 4.1%-18.6%, P = 0.002) over all 12 weeks. The 12-week increase among participants on NTX + BUPN was significantly greater-by 15.8% (95% CI, 4.5%-27.0%, P = 0.006)-than the increase among those on placebo. CONCLUSION: For people with methamphetamine (MA) use disorder receiving treatment with extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN), continued treatment with NTX + BUPN after 6 weeks is associated with additional reductions in MA use up to 12 weeks.

Colchicine and/or Naltrexone for Hospitalized COVID-19 Patients Not Requiring High Levels of Ventilatory Support (COLTREXONE): A Prospective, Randomized, Open-Label Trial.

We assessed the efficacy and safety of colchicine and low-dose naltrexone (LDN), alone and in combination, in preventing progression to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this prospective, randomized, open-label trial, colchicine and LDN were compared to standard of care (SOC) in patients hospitalized with SARS-CoV-2 not requiring high levels of ventilatory support. Patients were randomly assigned to colchicine alone, LDN alone, colchicine/LDN in combination, or SOC. The primary outcome was time to disease recovery. Secondary outcomes included total time hospitalized, study enrollment, level of care, oxygen support, and adverse events.  One-hundred and thirty-seven patients were randomized (Nc = 34, Nc+ldn = 33, Nldn = 35, Nsoc = 35). Eighty-four patients (61%) achieved disease recovery by day 5. There was no significant difference in the proportion of patients who experienced the primary efficacy outcome among those who received colchicine, LDN, or between the four study arms.Patients receiving colchicine had a shorter length of enrollment but not a significant reduction in the length of stay. Diarrhea was the most common adverse reaction. In adults hospitalized with SARS-CoV-2 not requiring high-level ventilatory support, colchicine and LDN, alone and in combination, were not associated with significant reductions in progression to severe disease.

A Utilization Review of Patients That Respond to Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution.

Studies have demonstrated the benefits of LDN for various pain indications. This review describes the utilization of and response to LDN in patients with chronic pain within the William S. Middleton Memorial Veterans Hospital (Madison VA). This was a retrospective, single center, chart review of patients that were prescribed LDN for chronic pain. The primary outcome, change in subjective pain report via numeric rating scale (NRS), was analyzed through Wilcoxon Signed Rank Test and descriptive statistics. A total of 136 participants were included. Patients had an average pain score of 7.1 per NRS at baseline. At the initial follow up visit, participants had an average pain of 6.4 (p < 0.001). Additionally, 17.1% of patients had a greater than or equal to 30% pain reduction from baseline. At subsequent follow up, patients reported an average pain of 5.5 (p < 0.0001) per NRS. At the end of the study, 31.6% of patients were maintained on LDN at an average dose of 3.8 mg. This retrospective review demonstrated that LDN may be an effective modality for some chronic pain indications. Reported pain scores were significantly lower at initial follow up compared to baseline for the total population, and for patients with fibromyalgia (FM) specifically.

Neuroprotective effects of naltrexone in a mouse model of post-traumatic seizures.

Traumatic Brain Injury (TBI) induces neuroinflammatory response that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist, used to treat drug addiction. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI seizures can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and/or seizures post-TBI. TBI was induced by a modified Marmarou Weight-Drop (WD) method on 4-week-old C57BL/6J male mice. Mice were placed in two groups: non-telemetry assessing the acute effects or in telemetry monitoring for interictal events and spontaneous seizures both following TBI and naltrexone. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation, neurodegeneration and fiber track integrity at 8 days and 3 months post-TBI. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. Our results show an increase in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. Video-EEG revealed increased interictal events in TBI mice, with 71% mice developing post-traumatic seizures (PTS). Naltrexone treatment ameliorated neuroinflammation, neurodegeneration, reduced interictal events and prevented seizures in all TBI mice, which makes naltrexone a promising candidate against PTS, TBI-associated neuroinflammation and epileptogenesis in a WD model of TBI.

Investigation into the restoration of TRPM3 ion channel activity in post-COVID-19 condition: a potential pharmacotherapeutic target.

Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells. This research aimed to: i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS; and ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients. Methods: Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition (N = 9; 40.56 ± 11.26 years), ME/CFS (N = 9; 39.33 ± 9.80 years) and healthy controls (HC) (N = 9; 45.22 ± 9.67 years). NTX effects were assessed on post COVID-19 condition (N = 9; 40.56 ± 11.26 years) and HC (N = 7; 45.43 ± 10.50 years) where NK cells were incubated for 24 hours in two protocols: treated with 200 µM NTX, or non-treated; TRPM3 channel function was assessed with patch-clamp protocol. Results: This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients. Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC. Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX. Discussion: Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients. This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after in vitro treatment with NTX. The TRPM3 restoration consequently may re-establish TRPM3-dependent calcium (Ca2+) influx. This investigation proposes NTX as a potential therapeutic intervention and TRPM3 as a treatment biomarker for post COVID-19 condition.

Optimizing Process Parameters for Controlled Drug Delivery: A Quality by Design (QbD) Approach in Naltrexone Microspheres.

The formulation of microspheres involves a complex manufacturing process with multiple steps. Identifying the appropriate process parameters to achieve the desired quality attributes poses a significant challenge. This study aims to optimize the critical process parameters (CPPs) involved in the preparation of naltrexone microspheres using a Quality by Design (QbD) methodology. Additionally, the research aims to assess the drug release profiles of these microspheres under both in vivo and in vitro conditions. Critical process parameters (CPPs) and critical quality attributes (CQAs) were identified, and a Box-Behnken design was utilized to delineate the design space, ensuring alignment with the desired Quality Target Product Profile (QTPP). The investigated CPPs comprised polymer concentration, aqueous phase ratio to organic phase ratio, and quench volume. The microspheres were fabricated using the oil-in-water emulsion solvent extraction technique. Analysis revealed that increased polymer concentration was correlated with decreased particle size, reduced quench volume resulted in decreased burst release, and a heightened aqueous phase ratio to organic phase ratio improved drug entrapment. Upon analyzing the results, an optimal formulation was determined. In conclusion, the study conducted in vivo drug release testing on both the commercially available innovator product and the optimized test product utilizing an animal model. The integration of in vitro dissolution data with in vivo assessments presents a holistic understanding of drug release dynamics. The QbD approach-based optimization of CPPs furnishes informed guidance for the development of generic pharmaceutical formulations.

Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats.

Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.

New-Onset Wrist Drop After a Night of Drinking: A Case Report.

This case report highlights the clinical approach to evaluating a patient with substance use disorder presenting with a sudden onset of peripheral neuropathy in the left hand. Our patient had significant cardiovascular risk factors, which further broadened the differential diagnosis beyond common causes of mononeuropathy. The use of detailed and appropriate clinical history, physical examination, and careful selection of relevant laboratory and radiological tests was instrumental in ruling out multiple medical differential diagnoses, including common mononeuropathies and life-threatening ones, such as cerebrovascular accidents, which facilitated the involvement of necessary consults while also treating both the presenting medical complication and underlying severe alcohol use disorder with additional efforts at relapse prevention.

Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial.

OBJECTIVE: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications. METHODS: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events. RESULTS: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response. CONCLUSIONS: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

Total and H-specific growth/differentiation factor 15 levels are unaffected by liraglutide or naltrexone/bupropion administration.

AIM: To investigate growth/differentiation factor 15 (GDF-15) levels in response to antiobesity medications, namely, liraglutide (Lira) and naltrexone/bupropion (N/B), in individuals with overweight or obesity. MATERIALS AND METHODS: This was a prospective, non-randomized clinical trial with a two-arm, parallel design. A total of 42 individuals with overweight or obesity without type 1 or type 2 diabetes mellitus were enrolled. The participants received either Lira 3 mg or N/B 32/360 mg, along with diet and exercise, according to comorbidities, cost and method of administration. Participants underwent clinical and laboratory measurements at baseline, as well as at the 3- and 6-month time points. Anthropometric measurements and body composition analysis via bioelectrical impendence analysis were performed. Total blood samples for GDF-15 and H-specific GDF-15 were collected in the fasting state and every 30 min for 3 h after the consumption of a standardized mixed meal. RESULTS: Overall, participants' weight was reduced by 9.29 ± 5.34 kg at Month 3 and 11.52 ± 7.52 kg at Month 6. Total and H-specific GDF-15 levels did not show significant changes during the mixed meal compared to values before the meal when all participants were examined at baseline, and at 3 and 6 month follow-ups. No statistical significance was found when participants were examined by subgroup (Lira vs. N/B). No significant differences between treatment groups in postprandial area under the curve (AUC) or incremental AUC values were found at baseline or in the follow-up months with regard to total and H-specific GDF-15 levels. CONCLUSION: Neither total nor H-specific GDF-15 levels are affected by Lira or N/B treatment in patients with overweight or obesity.

Opioid-positive urine drug screen during treatment with oral naltrexone and the clinical implications.

Introduction: Naltrexone is an opioid antagonist that is FDA approved to treat alcohol dependence and opioid dependence. It is available as an oral tablet and an extended-release injectable suspension. Naltrexone is metabolized to the primary metabolite, 6-ß-naltrexol, and to 2 minor metabolites, 2-hydroxy-3-methoxy-6-ß-naltrexol and 2-hydroxy-3-methyl-naltrexone. One of the lesser-known metabolites of naltrexone is noroxymorphone. Methods: A 27-year-old man taking oral naltrexone seen in the outpatient setting for alcohol use disorder and cannabis use disorder was found to have multiple positive urine drug screens (UDSs) for oxycodone. Confirmatory urine drug testing was completed and noroxymorphone was detected. A naloxone challenge test was conducted with negative results and the patient tolerated the transition from oral naltrexone to the extended-release injectable suspension of naltrexone. Results: This case illustrates that it is possible for a patient stabilized on oral naltrexone to have a false-positive oxycodone UDS. Confirmatory urine drug testing was used to substantiate that the metabolite of naltrexone, noroxymorphone, was the cause of the false-positive oxycodone UDS. Conclusions: One of the lesser-known metabolites of naltrexone, noroxymorphone, can cause a positive oxycodone UDS during treatment with oral naltrexone. Confirmatory urine drug testing should be conducted to confirm the presence of noroxymorphone and rule out alternative opioids.