To determine whether topical naltrexone (NTX) treatment can decrease the elevated reactive oxygen species pathways and select proinflammatory cytokines in the rat cornea and lacrimal glands that are elevated in diabetic dry eye. Type 1 diabetic male and female Sprague-Dawley rats were rendered hyperglycemic for 6-8 weeks and then treated topically with NTX eyedrops twice daily for 15 days. Corneal epithelium and lacrimal glands were evaluated for expression of dihydroethidium, C/EBP homologous protein, and NADPH oxidase -2 (NOX-2) as well as the proinflammatory cytokines interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) to identify pathways targeted in the mitigation of diabetic dry eye. Type 1 diabetes resulted in dry eye and corneal surface insensitivity, accompanied by increased levels of oxidative stress and inflammation mediators in both corneal epithelium and lacrimal glands. Topical NTX treatment restored tear volume and corneal surface sensitivity, and significantly reduced expression of dihydroethidium, C/EBP homologous protein, and NOX-2, as well as proinflammatory cytokines IL-1β, IL-6, and TNF-α in male and female diabetic rats. Blockade of the opioid growth factor (OGF)-OGF receptor system with topical NTX rapidly reversed diabetic dry eye and restored corneal surface sensitivity. The mechanism involved downregulating oxidative stress and decreasing proinflammatory cytokines to levels at or below those of nondiabetic rats of the same sex. These findings support a mechanistic role for OGF receptor blockade in the reversal of diabetic dry eye.

Delivering drugs to the eye remains a significant challenge due to complex anatomical and physiological barriers. Naltrexone (NTX), an opioid receptor antagonist with anti-inflammatory and immunomodulatory properties, has emerged as a promising candidate for ocular therapy. This systematic review examines NTX-based ocular delivery systems advancements, focusing on nanoformulations such as niosomes, hydrogels, in situ gelling films, and polymeric matrices. A literature search (2006-2024) across PubMed, Google Scholar, and Web of Science identified 14 original studies and 4 patents. These formulations improved NTX's solubility, precorneal retention, corneal penetration, sustained release, and photostability. Using the GRADE framework, we found high certainty of evidence for enhanced solubility, retention, sustained release, and safety. Moderate certainty supported NTX's efficacy in diabetic keratopathy, tear production, corneal healing, and ocular bioavailability. Overall, nanoformulated NTX shows strong potential for managing ocular conditions, highlighting the role of advanced delivery systems in improving therapeutic outcomes while minimizing side effects.

Real-world longitudinal treatment trajectories following opioid use disorder diagnosis among commercially insured beneficiaries in the United States.

Oral squamous cell carcinoma (OSCC) is marked by profound differences in survival between the localized and disseminated disease, estimated to result in a 70% and less than a 40% five-year survival rate with surgical and/or radiation approaches (in localized cases) and chemotherapy (in metastatic cases), respectively. Given the suboptimal efficacy of current management options, new therapeutic approaches are needed to supplement existing chemotherapies and improve outcomes. One emerging therapeutic option is naltrexone (NTX), an opioid antagonist that has shown promising outcomes at low doses in other forms of cancer. This study sought to determine the effectiveness of intermittent dosing of naltrexone on oral cancer cell survival, either as a single agent or in combination with traditional chemotherapy. Two human OSCC lines (locally invasive SCC-25 and metastatic Detroit 562) were cultured. Cells were exposed to 1 µM and 10 µM NTX alone, using intermittent (5 h once, 5 h daily, 5 h every other day) or constant 72 h exposure. Cells were exposed to combination therapy with cisplatin or docetaxel under three NTX regimens (5 h, 24 h, and continuous). Cell viability was determined using Sulphorhodamine B (SRB) assay and Cell Counting Kit-8 (CCK-8). Differences across treatments were assessed using ANOVA (p < 0.05). The effect of low-dose NTX alone, across varying treatment regimens, did not yield significant, consistent changes in OSCC cell survival. Combination with cytotoxic drugs reduced cell viability more efficiently than chemotherapy alone at select doses, particularly through intermittent short-term pretreatment schedules, but the full dose response demonstrated antagonism between NTX and chemotherapy, independent of the dosing schedule. These results contrast with previous findings in other cancers, and, thus, further study and optimization will be needed to determine the clinical benefit and reproducibility of these findings.

Excessive consumption of alcohol (ethanol (EtOH)) can lead to alcohol use disorder (AUD). While AUD can be managed through behavioral interventions, there is a great need for pharmacological remedies for this condition. To date, only three pharmacotherapeutic treatments for AUD have been approved by both the U.S. Food and Drug Administration and the European Medicines Agency. This is partly due to an incomplete understanding of the intricate molecular mechanisms through which EtOH affects cellular functions. Here, we focus on EtOH effects on nanoscale organization and the lateral dynamics of molecules in the plasma membrane, the primary cellular component that is affected by this compound. In a cell culture model natively expressing opioid receptors, important targets for medications aimed at preventing relapses in AUD, we used methods with single-molecule sensitivity to characterize the lateral organization and dynamics of cholesterol (Chol)- and sphingomyelin (SM)-enriched domains. Our data reveal that EtOH triggered a reorganization of Chol/SM-enriched domains and increased the plasma membrane fluidity. The general opioid receptor antagonist naltrexone (NTX), approved for relapse prevention in AUD, caused reorganization of Chol/SM-enriched domains, while pretreatment with NTX warded off EtOH-induced plasma membrane reorganization. In contrast, the selective kappa-opioid receptor antagonist LY2444296, at concentrations tested, showed a modest effect on Chol/SM-enriched domain organization and did not protect against EtOH-induced changes in plasma membrane organization. While the significance of these findings for AUD treatment remains uncertain at this stage, our study reveals that the action of NTX is not only limited to blocking opioid receptor activity by preventing agonist binding to the orthosteric binding site, but also is protective against short- and long-range EtOH-induced plasma membrane reorganization. By protecting against EtOH-induced changes in the lateral organization and dynamics of lipids in the plasma membrane, NTX may affect physiological outcomes through previously unrecognized noncanonical mechanisms.

Abstract Background The detection of prescription and/or recreational drugs is important to ensure workplace safety, to enforce judicial actions, and to monitor detoxification. Drugs and drug metabolites are expressed in blood, urine, and oral fluid such that those specimens can be used to detect recent drug use. These specimen matrices offer varying degrees of privacy and invasiveness to the subject. In addition, the ease-of-use in workplace settings varies in terms of convenience, infrastructure requirements, and procedural controls. Sweat patches have been proposed to provide a record of an individual’s drug use, but these typically are worn for one week or longer. Analysis of fingerprint sweat offers a more convenient method of drug detection. This study assessed the comparative profiling of codeine in human fingerprint sweat following controlled codeine administration under naltrexone blockade in the clinic. Methods Thirty-nine healthy adults, including male and non-pregnant female subjects, completed a clinical trial under an ethics board-approved protocol. Each subject received three 60 mg codeine phosphate doses, with four hours between doses. To prevent any opioid effects, each subject received three 50 mg doses of naltrexone hydrochloride: 12 hours, one hour prior, and 12 hours after the first codeine phosphate administration. Fingerprint sweat, blood, and oral fluid specimens were collected at eighteen time points per subject for codeine analysis, beginning at 90 minutes prior to the first codeine phosphate dosage, with the final collection point at 24 hours after the initial codeine dosage. Specimens were collected in order of fingerprint sweat, oral fluid, and blood. Urine specimens were collected ad libitum. Codeine in fingerprint sweat, whole blood, oral fluid, and urine was determined using a validated LC-MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental analysis with PKanalix version 2023R1, Lixoft SAS, a Simulations Plus company. Results Codeine in fingerprint sweat and oral fluid follows the trend seen in whole blood, most notably in response to the three doses of 60 mg codeine phosphate administered at 0, 4, and 8 hours. The concentration versus time profile of codeine in whole blood and fingerprint sweat shows that codeine was first detected in blood and fingerprint within approximately 30 minutes after oral administration of codeine. The calculated Tmax (with standard error) for the first codeine dosage in whole blood, fingerprint sweat, oral fluid, and urine are 1.96 (0.74), 2.08 (0.88), 1.73 (0.85), and 2.20 (1.17) hours, respectively. PK parameters for the excretion of codeine in the terminal phase of the study also compared favorably. Furthermore, PK parameters for this study show broad agreement with published results for blood and oral fluid. Conclusion The time course of mean codeine in fingerprint sweat follows the same response profile as for mean codeine in whole blood and oral fluid. PK parameters computed for codeine in fingerprint sweat, whole blood, oral fluid and urine show broad agreement and statistical agreement for Tmax during the first four hours following oral ingestion of 60 mg codeine, and for T1/2 during the terminal phase of the study following the third dose of codeine.

Dual blockade of TLR-4 and mu-opioid receptor by very low-dose naltrexone prevents respiratory depression via modulating redox homeostasis and airway inflammation in chronic obstructive pulmonary disease.

Co-morbid substance use disorders (SUDs) are common but difficult to study due to the complex, interacting, and overlapping mechanisms through which they affect brain networks. Many datasets collected to investigate a specific SUD include participants with co-morbid SUDs. While most studies treat comorbid SUDs as covariates of no interest, these covariates also contain untapped information. This is particularly relevant as cannabis use disorder (CanUD) has become increasingly prevalent and co-morbid with other SUDs that have been more thoroughly studied. While treatments have been established for multiple SUDs, none have been approved for CanUD, although naltrexone (NTX) has been associated with reduced use. Here, we conducted a retrospective secondary analysis of functional magnetic resonance imaging (fMRI) data from individuals with primary opioid use disorder (OUD) with co-morbid CanUD, alcohol use disorder (AUD), or cocaine use disorder (CocUD), while controlling for opioid use. All participants underwent imaging prior to receiving a therapeutic dose of long-acting intramuscular NTX (Vivitrol®), an approved treatment for OUD and AUD but not for CocUD, and again two weeks post-administration. At baseline, OUD individuals with co-morbid CanUD, AUD, or CocUD exhibited distinct functional connectivity (FC) alterations compared to those with OUD-only. These differences were greater in younger participants and primarily involved the default mode network. Following NTX administration, FC differences between the co-morbid CanUD and OUD-only groups globally diminished. A similar FC response to NTX was observed in the parietal, subcortical, sensory, and cerebellar networks in the co-morbid AUD group. In contrast, little change in FC was observed in co-morbid CocUD. These findings, combined with prior evidence that NTX reduces cannabis use by dampening the experience of reward, suggest NTX may hold promise as a treatment for CanUD.

Naltrexone reduces bleomycin-induced lung fibrosis in rats by attenuating fibrosis, inflammation, oxidative stress, and extracellular matrix remodeling.

Explaining increased efficacy of naltrexone in the treatment of alcohol dependent patients with a family history of alcohol use disorder: A systematic review on the role of reward sensitivity and sweet liking.

Extended-release naltrexone versus oral naltrexone for substance use disorders: A systematic review and meta-analysis.

Estradiol replacement enhances sweet taste preference in ovariectomized Rats: Interaction with energy intake regulation.

IntroductionAlcohol dependence (AD) is highly prevalent and has severe consequences on health and quality of life. However, the efficacy of approved pharmacotherapies such as naltrexone (NTX) remains limited, highlighting the need for novel pharmacotherapeutic approaches. Cannabidiol (CBD) is a promising candidate, which has shown potential to reduce craving and alcohol use by modulating brain circuits involved in craving and addiction. Preclinical studies suggest that CBD may enhance NTX’s therapeutic effects.Methods and analysisThis is a three-armed, randomised, double-blind, placebo-controlled parallel group, multicentre phase II clinical trial. A total of 150 patients with AD will be randomised (1:1:1) to receive either 800 mg or 1200 mg CBD plus 50 mg oral NTX or placebo plus 50 mg oral NTX for 14 days. Alcohol craving will be assessed using the Obsessive Compulsive Drinking Scale (OCDS-G) where the primary endpoint is the change from baseline to the end of treatment. Secondary outcomes include craving during the entire study, quality of life, depressive symptoms, anxiety, patient-reported outcomes, neural brain activation, CBD plasma levels, time to relapse, alcohol use and treatment safety. For the comparison of each experimental group to the control group, a strata-adjusted (centre and baseline OCDS-G) van Elteren test is applied with adjustment for multiple testing by Bonferroni-Holm.Ethics and disseminationThe trial has been approved by the Ethics Committee and the competent authority (ID: B_03510). All participants will provide written informed consent. An independent Data and Safety Monitoring Board will monitor safety. This trial complies with national and international regulations.Trial registration numberNCT06845124; EU Trial Number: 2024-518164-12-00.

Galanin(1-15) and Naltrexone: A novel approach for alcohol use disorder in rats, involving the mesolimbic system.

Methamphetamine (MA) use has been linked to engaging in sexual risk behaviors (SRBs) that are associated with HIV/STIs, particularly among men who have sex with men (MSM) and men who have sex with men and women (MSMW; hereafter MSM/W). The objectives of this analysis were to determine whether reduced MA is associated with decreases in SRBs in a sample of MSM/W. Data came from the ADAPT- 2 trial, a randomized, double-blind, two-stage sequential parallel design trial evaluating extended-release injectable naltrexone (NTX) and oral bupropion (BUP) vs. placebo for MA use disorder. In the first 6weeks of the trial (stage 1), participants were randomized to receive NTX-BUP or placebo. In the second 6weeks, participants in the placebo group who did not have a treatment response were rerandomized (stage 2). For this secondary analysis, the independent variable was the number of MA-negative urine drug screens (UDS). The dependent variables included three different types of SRBs. Regression models of the independent and dependent variables were adjusted for age, race/ethnicity status, marital status, treatment assignment, and baseline SRBs. Of the 151 participants, median age was 40 years and majority were non-Hispanic white (52%) and completed more than high school education (82%). Each additional MA-negative UDS was associated with a 7% (adjusted rate ratio (aRR) = 0.93; 95% CI, 0.87, 0.99) reduction in total number of sex partners in stage 2 only. Each additional MA-negative UDS was associated with a 13% (aRR = 0.87 95%; confidence interval (CI), (0.76, 0.98)) and 9% (aRR = 0.91; 95% CI, 0.84, 0.99) reduction in number of condomless sexual encounters in stage 1 and stage 2, respectively. Lastly, each additional MA-negative UDS was associated with a 16% (aRR = 0.84; 95% (CI), 0.75, 0.94)) and 27% (aRR = 0.73; 95% CI, 0.64, 0.84) reduction in number of sexual encounters when high on MA. Our analysis showed that reductions in MA use was associated with reductions in several sexual risk behaviors associated with HIV/STI. These findings provide further support for exploring reductions in sexual risk behaviors as a clinical endpoint in future treatment interventions for MA use.

To determine pathways in the trigeminal ganglion and corneal epithelium that are targeted by topical naltrexone (NTX) treatment for dry eye. NTX drops were administered topically daily for 15days to the corneal surface of male and female adult type 1 diabetic rats. Schirmer scores and corneal sensitivity were measured at baseline, 5, 10, and 15days. Trigeminal ganglion and corneal epithelium were processed for immunohistochemistry to detect expression of opioid growth factor receptor (OGFr), Ki67, nerve growth factor, insulin-like growth factor-1, calcitonin gene-related peptide, substance P, and TNF-α. A proteomic study determined protein changes in the cornea. Corneal sensitivity and tear production in diabetic rats were restored to normal levels within 5days after topical NTX. Assessment of corneal tissue after 15days of treatment revealed that defects in OGFr expression, epithelial cell number, and Ki67+ expression were restored to normal by NTX. Inflammation markers (e.g., TNF-α) were reduced in tissue from diabetic rats treated with NTX. Proteomic data suggest diabetes causes dysregulation in inflammatory biological processes. The percentages of calcitonin gene-related peptide-positive neurons, but not substance P-positive neurons, in the trigeminal ganglion were increased after NTX treatment. Diabetic male and female rats responded to NTX in a comparable manner. Type 1 diabetes results in decreased tear production and altered corneal surface sensitivity. These complications coincide with dysregulated OGFr that maintains ocular homeostasis. Reversal of dry eye and restoration of corneal sensitivity in diabetic male and female rats after 15days of topical treatment with NTX occur following dual pathways of increased cellular proliferation and reduction of inflammation.

Stability-indicating HPTLC method for the determination of Naltrexone hydrochloride in bulk and tablet dosage form

BackgroundThe prevalence of alcohol use disorder (AUD) has been increased over the past decades in Taiwan. Naltrexone, an opiate antagonist, is currently approved for AUD treatment. However, relapse to heavy or uncontrolled drinking remains common. OPRM1 A118G (Asp40Asn, rs179997), a specific single nucleotide polymorphism (SNP) in the mu opioid receptor gene, moderates naltrexone efficacy.Individuals who carried the A118G G (Asp) allele, approximately 25% in Caucasians and 40-45% in Asians. However, existing evidence largely had focused on Caucasians, leaving the genetic effect unresolved in our Asian people.Aims and ObjectivesWe aimed to assess the clinical variables of patients with AUD, who were treated with naltrexone for 12 weeks, and followed the patients’ drinking outcomes at week 2, 4, 8, 12. In addition, we compared drinking outcomes and psychological assessments between patients with different OPRM1 A118G genotypes.MethodsPatients with UAD were provided with naltrexone hydrochloride dosing was titrated from 25 mg per day for the first 3 days to 50 mg per day for the remainder of treatment for 12 weeks. Frequency and quantity of alcohol consumption in the previous 90 days before entering the detoxification treatment was determined using the Time-Line Follow-Back method. We examined average drinks per day, number of drinking days and heavy drinking days per week, and abstinence days during the 12-week study. Alcohol craving was measured by visual analog scale (VAS) and Penn Alcohol Craving Scale (PACS). The individual’ s attitude (self-efficacy or confidence) to abstain from drinking was assessed by Alcohol Abstinence Self-Efficacy scale (AASES). We genotyped OPRM1 A118G genotype (rs179997) for all individuals.ResultsA total of 94 patients with AUD, who were treated with naltrexone, were recruited into our study. The numbers of patients with OPRM1 A118G AA, AG and GG genotypes are 41, 45, and 8. We combined patients with AG and GG into one group (G-allele carriers) for further analyses. There were no differences in demographic characteristics and drinking history, including mean age, sex distribution, education, age of alcohol tolerance, and duration of drinking history, between G-allele carriers and non- carriers. Regarding drinking outcomes during 12-week naltrexone treatment, we did not find differences in average drinks per day, number of drinking days per week, heavy drinking days per week, and abstinence days between the two groups. Changes of psychological assessments including VAS, PACS, and AASES also did not differ between G-allele carriers and non-carriers.Discussion and ConclusionWe did not find any significant genetic effect of OPRM1 A118G on drinking outcomes during 12-week naltrexone treatment.

Many psychiatric and neurological medications lack commercial liquid formulations, requiring extemporaneous compounding for patients unable to swallow solid dosage forms. While chemical stability data support extended beyond-use dating for various APIs in SyrSpend® SF PH4, antimicrobial effectiveness data essential for USP <795> compliance remain limited. To evaluate antimicrobial effectiveness and physicochemical stability of seven commonly compounded psychiatric and neurological drug suspensions in SyrSpend® SF PH4 to support evidence-based beyond-use dating decisions. Suspensions of amitriptyline hydrochloride (10.0 mg/mL), clonazepam (0.2 mg/mL), haloperidol (0.5 mg/mL), lorazepam (1.0 mg/mL), naltrexone hydrochloride (1.0 mg/mL), pregabalin (20.0 mg/mL), and sertraline hydrochloride (10.0 mg/mL) were prepared and stored at ambient and refrigerated conditions. USP <51> antimicrobial effectiveness testing was conducted alongside pH and visual appearance assessments. All formulations achieved USP <51> bacterial reduction criteria for E. coli, P. aeruginosa, and S. aureus. Complete C. albicans control was demonstrated in all formulations. A. brasiliensis showed variable responses, with persistent counts in naltrexone, pregabalin, and sertraline formulations, though remaining within USP acceptance limits. pH stability was maintained (3.3 - 5.1) with no visual changes observed. Storage temperature did not significantly affect stability. Results support beyond-use dating recommendations for all APIs at all conditions. These evidence-based recommendations provide compounding pharmacists with USP-compliant guidance for safe extended beyond-use dating while maintaining appropriate safety margins for pediatric, geriatric, and other vulnerable populations.

Despite the contribution of the µ-agonist fentanyl to the United States's opiate overdose epidemic, no human studies specifically address the ability of extended-release preparations of the opiate antagonist naltrexone (NTX) to block fentanyl's life-threatening µ-agonist-mediated respiratory depression. This paper presents three case histories of clinically necessary opiate challenges in opiate-abusing patients implanted with extended-release NTX (ER-NTX). It also reviews the sparse literature and is the first evidence that antagonist blood levels from ER-NTX preparations can completely block the lethal µ-agonist effects of at least 1,000 mcg of intravenous fentanyl.