In veterans, the prevalence of 12-month and lifetime alcohol use disorder (AUD) is 14.8% and 42.2%, respectively. Alcohol use disorder treatment is often plagued by medication discontinuation with relapse rates being as high as 39% in patients who sought treatment. One proposed benefit of long-acting injectable (LAI) medications is improved adherence. The purpose of this trial was to compare the difference in time to relapse between patients on oral and LAI naltrexone.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 16.06 million cases have been reported worldwide. Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2). SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm. This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity. Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity. Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage. Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor. Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection. Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.Communicated by Ramaswamy H. Sarma.

Mechanical allodynia has been studied in chronic naltrexone-treated people (N.T.P.) and rats (N.T.R.). After persistent naltrexone administration, patients acquired static and dynamic mechanical allodynia, as measured by von Frey filament (vFf) and brush stimulations. Pregabalin and levodopa administrations in N.T.P. significantly reduced allodynic behaviour, albeit these molecules did not completely stop it. As evidenced by the deployment of the vFf, subchronic treatment with Naltrexone delivered peripherally or intrathecally induced allodynic behaviour in rats. Increased expressions of two pain markers, pERK1/2 and PKCγ, in the spinal dorsal horn laminae were associated with naltrexone-induced allodynic behaviour. After vFf stimulation, pERK1/2 expression was substantially higher (p < 0.001) in superficial spinal dorsal horn laminae than in non-stimulated or naive non-stimulated rats. In addition, when compared to control rats, N.T.R. showed a substantial (p < 0.001) increase in PKCγ expression. PKCγ expression was found to be strong in lamina IIi and laminae III-IV. A cellular mechanism is proposed for the naltrexone effect. In both people and rats, Naltrexone induces static mechanical allodynia, according to this study.

The present study utilized a newly developed quantitative immunohistochemical assay to measure changes in mu opioid receptor abundance following chronic administration of the opioid receptor antagonist naltrexone. These data were compared with those obtained from mu receptor radioligand binding on adjacent tissue sections, in order to determine whether the characteristic antagonist-induced increase in radioligand binding is due to an increase in the total number of mu receptors and/or to an increase in the proportion of receptors that are in an active binding conformation in the absence of a change in the total number of receptors. Adult male Sprague-Dawley rats were administered naltrexone, 7-8 mg/kg per day, or saline continuously for seven days by osmotic minipumps, after which time their brains were processed for immunohistochemistry and receptor autoradiography on adjacent fresh frozen tissue sections. Semiquantitative immunohistochemistry was performed using a radiolabelled secondary antibody for autoradiographic determination and a set of radioactive standards. Results demonstrate an overall concordance between the distribution of mu opioid receptors as measured by the two different methods with a few exceptions. Following naltrexone administration, mu receptor immunoreactivity was significantly higher in the amygdala, thalamus, hippocampus, and interpeduncular nucleus as compared with the saline-treated control animals. [3H]D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin binding to mu opioid receptors was significantly higher in the globus pallidus, amygdala, thalamus, hypothalamus, hippocampus, substantia nigra, ventral tegmental area, central gray, and interpeduncular nucleus of the naltrexone-treated rats. These findings indicate that in some brain regions chronic naltrexone exposure increases the total number of mu opioid receptors, while in other regions there is an increase in the percent of active receptors without an observable change in the total number of receptors. Quantitative receptor immunodetection together with ligand autoradiography provides a new approach for investigating the regulation of mu opioid receptors on tissue sections.

Objective: Management of borderline personality disorder (BPD) is a difficult challenge due to the complex features of this disorder. This article reviews the use of naltrexone in the treatment of BPD. Method: Published articles and clinical trials were searched in Google Scholar, MedLine, ELSEVIER, and Cochrane database of systematic reviews abstracts in English language between 1990 and 2017. Results: Naltrexone (NTX), a nonspecific competitive opiate antagonist, has been noted to be helpful in controlling self-injurious behavior (SIB) and dissociative symptoms in patients with BPD. Conclusion: Further studies should be conducted on the effects of naltrexone to confirm the role of this medication in the treatment of BPD.

The aim of this study was to explore if the administration of naltrexone together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.

Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for treatment of diseases such as fibromyalgia, Crohn's disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions.

Different regimens of agonist and antagonist drugs have been used in opioid withdrawal management, with variable results. We examined whether administering extremely small quantities of opiate antagonists in the presence of opiate agonist drugs reduces withdrawal expression.

Naltrexone is an opioid antagonist used for the treatment of patients with opioid use disorder and alcohol use disorder. This population often presents problems of follow-up and therapeutic efficacy related to adherence to treatment. The purpose of our study is to provide an exhaustive summary of the current evidence regarding naltrexone adherence in people with substance use disorders and to identify possible variables that may influence adherence to naltrexone.

Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the clinical practice. Unfortunately, together with analgesia, a number of adverse effects can occur such as nausea, vomiting, constipation, gastrointestinal alterations and cognitive impairments. Naltrexone is a competitive antagonist of opioid receptors commonly used to treat opioid addiction; its oral use against agonists side effects is limited by the decrease of opioids-therapeutic efficacy and own adverse effects. The intranasal delivery of naltrexone could offer a quick and effective achievement of CNS based on extracellular mechanisms including perineural and perivascular transport. The aim of the study was to test the efficacy of intranasal low-dose naltrexone in reducing intraperitoneal morphine and oxycodone side effects in rodents. In mice, 1 μg naltrexone intranasally administered 30 min before opioids reduced cognitive impairments and motor alteration induced by 10 mg kg-1 morphine and 60 mg kg-1 oxycodone in the Passive avoidance and Rota rod tests, respectively. Moreover, naltrexone rebalanced opioid-induced reduction of the intestinal transit and latency of feces expulsion as well as food intake inhibition. Importantly, 1 μg naltrexone instillation did not block analgesia as demonstrated by the Hot plate test. In rats, intranasal naltrexone counteracted the opioid-induced pica phenomenon related to emesis and increased water and palatable food intake. The effects were comparable to that achieved by metoclopramide used as reference drug. Treatments did not influence body weight. Lastly, the safety of the intranasal delivery has been checked by hematoxylin-eosin staining that did not show histological alterations of the nasal cavity. In conclusion, intranasal low-dose naltrexone counteracted morphine and oxycodone induced gastrointestinal and CNS side effects without impairing opioid analgesia. It is a candidate to be a valid clinical strategy deserving deep analysis.

Moral philosophers have debated the extent to which persons are individually responsible for the onset of and recovery from addiction. Empirical investigators have begun to explore counselors' attitudes on these questions. Meanwhile, a separate literature has investigated counselors' negative attitudes towards naltrexone, an important element of medication-assisted treatment for alcohol addiction. The present study bridges the literature on counselor views about responsibility for addiction with the literature on attitudes towards naltrexone. It investigates the extent to which a counselor's views of individual responsibility for alcohol addiction are related to that counselor's views of naltrexone.

Naltrexone, an antagonist of μ-opioid receptors, is clinically used as adjuvant therapy of alcohol dishabituation. The aim of the present work was to test the effect of 1 mg/kg body weight of naltrexone to revert oxidative stress-related biochemical alterations, in the hippocampus and serum of chronic alcoholic adult rats. Malondialdehyde concentration was increased and glutathione peroxidase activity was decreased in hippocampus and serum of alcohol-treated rats. Naltrexone treatment restored these alterations. The in vitro antioxidant ability of Ntx could not justify these effects considering the doses used. Thus this apparent protective effect of Ntx can only be attributed to its pharmacological effects, as herein discussed.

The role of glia in the development and treatment of behavioral abnormalities is understudied. Recent reports have observed glial activation in several disorders, including depression, autism spectrum disorders and self-injurious behaviors (SIB). In the current study, we examined SIB in the physiologically and anatomically relevant nonhuman primate (NHP) model. At the Tulane National Primate Research Center (TNPRC), approximately 5% of singly housed macaques develop symptoms of SIB. We have previously demonstrated that naltrexone hydrochloride can be effective in reducing SIB. We have also demonstrated that the astrocytes of animals with SIB are distinctly atrophic and display heightened innate immune activation compared with control animals. We have added a third group of animals (five macaques identified with SIB and treated with oral naltrexone at a dose of 3.2mg/kg) to the previous cohort (six macaques with a history of SIB but not treated, and nine animals with no history of SIB) for this study. Gray and white matter astrocytes from frontal cortical tissue were examined following necropsy. Innate immune activation of astrocytes, which was increased in SIB animals, was markedly decreased in animals receiving naltrexone, as was atrophy of both grey and white matter astrocytes. This was concomitant with improved behavioral correlates. Preventing astrocyte activation in select areas of the brain to reduce injurious behavior is an innovative concept with implications for mental health studies. Differences in multiple areas of primate brain would help determine how self-injurious behavior develops. These studies suggest a stronger role for astrocytes in the cellular events associated with self-injurious behaviors.

Socially warm experiences, when one feels connected to others, have been linked with physical warmth. Opioids, hypothesized to support social bonding with close others and, separately, physical warmth, may underlie both experiences. In order to test this hypothesis, 80 participants were randomly assigned to the opioid antagonist, naltrexone or placebo before neural and emotional responses to social and physical warmth were collected. Social and physical warmth led to similar increases in ventral striatum (VS) and middle-insula (MI) activity. Further, feelings of social connection were positively related to neural activity to social warmth. However, naltrexone (vs placebo) disrupted these effects by (i) reducing VS and MI activity to social and physical warmth, (ii) erasing the subjective experience-brain association to social warmth and (iii) disrupting the neural overlap between social and physical warmth. Results provide additional support for the theory that social and physical warmth share neurobiological, opioid receptor-dependent mechanisms and suggest multiple routes by which social connections may be maintained.

Establishment of in vitro-in vivo correlations (IVIVCs) for parenteral polymeric microspheres has been very challenging, due to their complex multiphase release characteristics (which is affected by the nature of the drug) as well as the lack of compendial in vitro release testing methods. Previously, a Level A correlation has been established and validated for polymeric microspheres containing risperidone (a practically water insoluble small molecule drug). The objectives of the present study were: 1) to investigate whether a Level A IVIVC can be established for polymeric microspheres containing another small molecule drug with different solubility profiles compared to risperidone; and 2) to determine whether release characteristic differences (bi-phasic vs tri-phasic) between microspheres can affect the development and predictability of IVIVCs. Naltrexone was chosen as the model drug. Three compositionally equivalent formulations of naltrexone microspheres with different release characteristics were prepared using different manufacturing processes. The critical physicochemical properties (such as drug loading, particle size, porosity, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microspheres and the reference-listed drug (Vivitrol®) were determined. The pharmacokinetics of the naltrexone microspheres were investigated using a rabbit model. The obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method, and compared with the in vitro release profiles of the naltrexone microspheres obtained using USP apparatus 4. Level A IVIVCs were established and validated for predictability. The results demonstrated that the developed USP 4 method was capable of detecting manufacturing process related performance changes, and most importantly, predicting the in vivo performance of naltrexone microspheres in the investigated animal model. A critical difference between naltrexone and risperidone loaded microspheres is their respective bi-phasic and tri-phasic release profiles with varying burst release and lag phase. These variations in release profiles affect the development of IVIVCs. Nevertheless, IVIVCs have been established and validated for polymeric microspheres with different release characteristics.

Naltrexone attenuates craving, and the subjective effects of methamphetamine and extended-release naltrexone (XR-NTX) reduces functional connectivity between regions of the striatum and limbic cortex. Naltrexone modulates neural activity at dopaminergic synapses; however, it is unclear whether naltrexone has an effect on large-scale brain networks. Functional networks interact to coordinate behavior, and as substance-use disorders are associated with an imbalance between reward and cognitive control networks, treatment approaches that target interactive brain systems underlying addiction may be a useful adjunct for behavioral therapies. The objective of this study was to examine the effect of XR-NTX on large-scale brain networks and to determine whether changes in network relationships attenuate drug use, craving, and addiction severity. Thirty-nine participants in or seeking treatment for methamphetamine-use disorder were enrolled in a clinical trial of XR-NTX between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Functional magnetic resonance imaging (fMRI) and questionnaires were conducted before and after double-blinded randomization to a 4-week injection of XR-NTX or placebo. In the XR-NTX group, methamphetamine use was reduced along with a decrease in the coupling between executive control (ECN) and default mode (DMN) networks. As decoupling of ECN and DMN networks was associated with change in the severity of dependence, the results suggest that XR-NTX may modulate and enhance ECN attentional resources and suppress DMN self-referential and emotional processing. This study identifies the effect of naltrexone on changes in the intrinsic functional coupling of large-scale brain networks and provides a more systematic understanding of how large-scale networks interact to promote behavioral change in methamphetamine-use disorder.

The development of analgesic tolerance following chronic morphine administration can be a significant clinical problem. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Many studies have also demonstrated that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive tolerance and clinical studies demonstrate that it has opioid sparing effects. In this study we demonstrate that ultra-low dose naltrexone attenuates glial activation, which may contribute to its effects on attenuating tolerance.

One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone (Nal), an opioid antagonist acting on the reward system, and exendin-4 (Ex-4), a glucagon-like peptide 1 agonist acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined.

Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at μ opioid receptors, they may alter the relationship between price and opioid intake.

Introduction In recent years, low-dose naltrexone has emerged as a novel off-label therapy for many chronic conditions including postural orthostatic tachycardia syndrome (POTS), however, there is little evidence for its efficacy. Methods In this institutional review board (IRB)-approved case series, the charts of six tilt table-confirmed patients with POTS who underwent a trial of low-dose naltrexone (LDN) at our institution were reviewed. Medical history, subjective description of symptom severity, the continuation of therapy, tolerability, and scores on patient-reported outcome measures (Patient-Reported Outcomes Measurement Information System {PROMIS} Fatigue, PROMIS physical and mental health, Generalized Anxiety Disorder Assessment {GAD}-7, Patient Health Questionnaire {PHQ}-9, and Composite Autonomic Symptom Score {COMPASS}) were collected at therapy initiation and six to 12 months after the start of LDN. Results Three out of six reviewed patients reported an improvement in their POTS after the initiation of LDN. Two patients discontinued the therapy due to a lack of perceived benefit. No side effects or adverse outcomes were reported. The patient-reported outcome measures of PROMIS Fatigue, PROMIS physical and mental health, GAD-7, PHQ-9, and COMPASS showed inconsistent changes over the course of therapy, with some patients showing improvement or stability and others showing worsening. The small sample size and incomplete response rate did not allow for extensive statistical analysis. Conclusion As seen in its use in other conditions, LDN appears to have a favorable safety and side effect profile in patients with POTS but has little evidence for efficacy. Although some patients noted benefit, patient-reported outcome measures show a variable response profile. High-quality randomized controlled trials are needed to determine if the treatment is efficacious and should be used outside of a trial basis.