Impact of Harm Reduction Treatment with or without Pharmacotherapy on Polysubstance Use among People Experiencing Homelessness and Alcohol Use Disorder.

OBJECTIVES: A prior randomized controlled trial showed behavioral harm reduction treatment for alcohol use disorder (AUD), or HaRT-A, was effective in improving alcohol outcomes and quality of life for people experiencing homelessness and AUD when provided with or without pharmacotherapy (ie, extended-release naltrexone). Because nearly 80% of the sample also reported baseline polysubstance use, this secondary study tested whether HaRT-A also positively impacted other substance use. METHODS: In the parent study, 308 adults with AUD and homelessness were randomized to receive HaRT-A plus intramuscular injections of 380-mg extended-release naltrexone (HaRT-A + extended-release naltrexone), HaRT-A plus placebo (HaRT-A + placebo), HaRT-A alone, or community-based services as usual (control). In this secondary study, we used random intercept models to detect changes in other substance use after exposure to any of the HaRT-A conditions. For less prevalent behaviors, outcomes included past-month use (cocaine, amphetamines/methamphetamines, opioids). For more prevalent behaviors (polysubstance, cannabis), outcomes were past-month use frequency. RESULTS: Compared with controls, participants who received HaRT-A showed significantly reduced 30-day frequency of cannabis use (incident rate ratio = 0.59, 95% CI = 0.40-0.86, P = 0.006) and polysubstance use (incident rate ratio = 0.65, 95% CI = 0.43-0.98, P = 0.040). No other significant changes were detected. CONCLUSIONS: Compared with services as usual, HaRT-A is associated with reduced cannabis and polysubstance use frequency. The benefits of HaRT-A may thus extend beyond its impact on alcohol and quality of life outcomes to positively reshape overall substance use patterns. A randomized controlled trial is needed to further investigate the efficacy of such combined pharmacobehavioral harm reduction treatment for polysubstance use.

Possible therapeutics for Pseudomyxoma peritonei: a rare, lethal, and the least investigated disease

Pseudomyxoma peritonei (PMP) refers to a growth disorder characterized by glycoprotein neoplasm in the peritoneum, where mucin oversecretion occurs. The tumors of the appendix region are well associated with PMP; however, ovarian, colon, stomach, pancreas, and urachus tumors have also been linked to PMP. Other mucinous tumors in the pelvis, paracolic gutters, greater omentum, retrohepatic space, and Treitz ligament can be the reason for PMP. Despite being rare and having a slow growth rate, PMP can be lethal without treatment. It is treated with neoadjuvant chemotherapy with the option of cytoreductive surgery and intraperitoneal chemotherapy. In the current study, we hypothesize that there may be novel gentle ways to inhibit or eliminate the mucin. Dr. David Morris has used mucolytics - such as bromelain and N-acetyl cysteine to solubilize mucin. In the present review, we aimed to study the regulation of mucin expression by promoter methylation, and drugs that can inhibit mucin, such as boldine, amiloride, naltrexone, dexamethasone, and retinoid acid receptors antagonist. This review also explored some possible pathways, such as inhibition of Na + , Ca2+ channels and induction of DNA methyltransferase along with inhibition of ten-eleven translocation enzymes, which can be good targets to control mucin. Mucins are strong adhesive molecules that play great roles in clinging to cells or cell to cell. Besides, they have been greatly involved in metastasis and also act as disease markers for cancers. Diagnostic markers may have exclusive roles in disease initiation and progression. Therefore, the present review explores various drugs to control and target mucin in various diseases, specifically cancers. (AU)

Characteristics associated with the availability of therapeutic acupuncture in substance use disorder treatment facilities in the United States.

BACKGROUND: We examine the characteristics associated with the availability of therapeutic acupuncture in substance use disorder (SUD) treatment facilities in the United States (US). METHODS: This study utilizes data from the 2018 National Survey of Substance Abuse Treatment Services (N-SSATS). Multivariable logistic regression was performed. RESULTS: Only 5.5% (n = 814) of all SUD treatment facilities offered acupuncture therapy. Facilities operating an opioid treatment program (OTP) were 1.60 times more likely to offer therapeutic acupuncture than non-OTP facilities. Facilities that offered oral naltrexone pharmacotherapy or buprenorphine with naloxone pharmacotherapy were 1.63 and 1.37 times more likely to offer therapeutic acupuncture, respectively, compared to facilities that did not offer these pharmacotherapies. Federal government facilities were over four times more likely to offer acupuncture than those operated by state governments and had triple the odds of having acupuncture than private nonprofit organizations. Tribal facilities were over five times more likely than state government-operated facilities to offer acupuncture. Facilities located in the Western region of the US were 1.59, 1.39, and 1.30 times more likely than Northeastern, Midwestern, and Southern US regions, respectively, to offer acupuncture therapy. CONCLUSIONS: Although complementary and holistic approaches such as acupuncture are accepted adjunct methods to treat persons with SUD, the findings suggest that their utilization in SUD treatment facilities in the US is minimal. Results, however, highlight that facilities operated by tribal and federal governments, those that are located in the Western region of the US, and non-hospital facilities have the highest odds of incorporating therapeutic acupuncture as treatment for SUD.Supplemental data for this article is available online at https://doi.org/10.1080/10550887.2022.2056401 .

Review of medication-assisted treatment for opioid use disorder.

CONTEXT: The American opioid epidemic has necessitated the search for safe and effective means of treatment for opioid use disorder (OUD). Medication-assisted treatment (MAT) encompasses select medications that are proven effective treatments for OUD. Understanding the mechanisms of action, indications, and implementation of MAT is paramount to increasing its availability to all individuals struggling with opioid addiction. OBJECTIVES: This review is based on an educational series that aims to educate healthcare providers and ancillary healthcare members on the use of MAT for the treatment of OUD. METHODS: The database PubMed was utilized to retrieve articles discussing the implementation of MAT. Boolean operators and Medical Subject Headings (MeSHs) were applied including: MAT and primary care, MAT and telehealth, methadone, buprenorphine, naltrexone, MAT and osteopathic, MAT and group therapy, and MAT and COVID-19. RESULTS: Three medications have been approved for the treatment of OUD: methadone, naltrexone, and buprenorphine. Identifying ways to better treat and manage OUD and to combat stigmatization are paramount to dismantling barriers that have made treatment less accessible. Studies suggest that primary care providers are well positioned to provide MAT to their patients, particularly in rural settings. However, no study has compared outcomes of different MAT models of care, and more research is required to guide future efforts in expanding the role of MAT in primary care settings. CONCLUSIONS: The coronavirus disease 2019 (COVID-19) pandemic has led to changes in the way MAT care is managed. Patients require a novel point-of-care approach to obtain care. This review will define the components of MAT, consider the impact of MAT in the primary care setting, and identify barriers to effective MAT. Increasing the availability of MAT treatment will allow for greater access to comprehensive treatment and will set the standard for accessibility of novel OUD treatment in the future.

Prurigo excoriée treated with low dose naltrexone.

A 53-year-old woman presented with a 25-year history of acne excoriée and prurigo excoriée. Her symptoms began in 1988 coinciding with her husband's death from a brain tumour when she was 27. The pruritus affected her quality of life and disturbed her sleep. She had scarring on her face and body resulting from persistent scratching. The pruritus proved refractory to treatment despite a multi-modal treatment approach including multiple topicals, phototherapy and systemic agents such as isotretinoin, antibiotics, anxiolytic agents and neuromodulators. She was extremely frustrated that various treatments had been ineffective at controlling the itch-scratch cycle. She was commenced on low dose naltrexone (LDN), 3 mg nocte, and she became itch free within a few weeks. She reports that the LDN has had a beneficial impact on her quality of life.

Effect of Withania somnifera (L.) Dunal aqueous root extract on reinstatement using conditioned place preference and brain GABA and dopamine levels in alcohol dependent animals.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (WS), a known'Rasayana' (rejuvenating agent) as per Ayurveda is prescribed to promote health, to increase longevity and to hasten recovery in disease convalescent stages. WS has demonstrated protective effect on alcohol dependence and withdrawal anxiety in previous experimental studies. AIM OF THE STUDY: To evaluate effect of WS on conditioned place behavioral paradigm (model of relapse) and on GABA and dopamine levels in critical brain areas in alcohol dependent animals. METHODOLOGY: Following Animal Ethics Committee permission, the mice (n = 24) were divided into the following study groups for experiment 1: 1 -distilled water (vehicle control), 2 -WS and 3 -Naltrexone. They were conditioned on conditioned place preference (CPP) using alcohol (2 gm/kg)/saline (1 ml) administered intraperitoneally for 8 days. WS and Naltrexone were administered during the period of extinction (6-8 days). Effect of WS (650 mg/kg) on reinstating behaviour of mice (time spent in alcohol paired compartment) primed with alcohol injection was noted. In experiment 2, effect of WS (450 mg/kg/) on GABA and dopamine levels in the midbrain, striatum and cortex (ng/gm) were measured in alcohol dependent rats (n = 24) following the first phase of standardisation assay (n = 36). The rats were made alcohol dependent for 15 days (intermittent access model) and WS was administered concurrently. GABA and dopamine levels were measured on Day 16. RESULTS: WS group showed decrease in time spent in alcohol paired compartment alike Naltrexone and it differed significantly compared to the distilled water control group (p < 0.05) Alcohol-dependent rats showed significant decrease in GABA and increase in dopamine levels vs distilled water in the midbrain, striatum and cortex. WS and Naltrexone administration showed rise in GABA and fall in dopamine in all the isolated brain parts in the respective groups (p < 0.05 vs alcohol treated group). CONCLUSION: Withania somnifera protected animals from relapse and showed beneficial effects on the brain neurotransmitters involved in alcohol dependence. The study provides substantial evidence for its potential application in alcohol use disorder.

What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 1: prevention and topical therapies.

This review is part of a series of annual updates that summarize the evidence base for atopic eczema (AE). The aim is to provide a succinct guide for clinicians on the key findings from 14 systematic reviews on the prevention and topical treatment of AE published or indexed in 2018. Various supplements, including long-chain polyunsaturated fatty acids, vitamin D and the probiotic Lactobacillus rhamnosus GG, given prenatally and postnatally, have not been shown to prevent AE in infants, although mixed strains of probiotics may decrease the risk of AE if given to the mother during pregnancy and to the infant for the first 6 months of life. In the postnatal period, there is no evidence that hydrolysed formula, compared with cow's milk formula (CMF), reduces the risk of AE in partially breastfed infants. However, weak evidence suggests that a specific partially hydrolysed whey formula decreases the risk of AE compared with CMF. No specific skin practices can be recommended to reduce the eczema risk in healthy term babies. There is weak evidence of a low risk of reversible hypothalamic-pituitary-adrenal axis suppression following 2-4 weeks of treatment with low-potency topical steroids, and conflicting evidence as to whether bleach bathing affects skin flora or AE severity. A single study demonstrated that the topical Janus kinase inhibitor tofacitinib at 2% significantly reduces the Eczema Area and Severity Index compared with vehicle. Topical naltrexone cream 1% improves pruritus (measured using a visual analogue scale) by 30% more than placebo. There is weak evidence that topical alternative therapies, including antioxidants, micronutrients and some herbal medicines, may improve AE.

New-generation anti-obesity drugs: naltrexone/bupropion and liraglutide. An update for endocrinologists and nutritionists.

The prevalence of obesity increases worldwide and has a significant economic impact on health care systems. A comprehensive program of lifestyle modification, including diet, exercise, and behavior therapy is considered the first option for achieving the significant weight loss. However, the intrinsic difficulties associated with maintenance of lifestyle changes contribute to the unsatisfactory long-term outcomes reported and weight regain in the obesity management. In this context, pharmacological approaches are useful to maximize non-pharmacological interventions in the long-term management of obesity. As add-on to lifestyle modification, pharmacological interventions are useful to facilitate clinically weight loss. In the past, anti-obesity drugs were limited. To date, the landscape has changed and naltrexone/bupropion and liraglutide have been recently added as new-generation anti-obesity drugs on obesity treatment and could represent important tools to manage of obesity. Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist that shares 97% homology to native GLP-1 with effects on the limbic system. The treatment with liraglutide 3.0 mg, in combination with a hypocaloric diet and increased physical activity, provides a clinically meaningful weight loss. The combination of naltrexone 32 mg and bupropion 360 mg acts on the mesolimbic reward pathway and the hypothalamic hunger system, two areas of the central nervous system. The combination of naltrexone/bupropion, an adjunct to a hypocaloric diet and increased physical activity, is approved for chronic weight management in adults with obesity or overweight and ≥1 weight-related comorbidity. In the present review, we have focused on the current evidence on two new-generation anti-obesity drugs, naltrexone/bupropion and liraglutide 3.0 mg addressing the main studies that investigated these two new drugs for obesity treatment. Furthermore, evidence on semaglutide, currently in the pipeline for potential future therapeutic use for weight loss, are reported.

What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 2: systemic therapies.

This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.

Cannabinoids and Opioids in the Treatment of Inflammatory Bowel Diseases.

In traditional medicine, Cannabis sativa has been prescribed for a variety of diseases. Today, the plant is largely known for its recreational purpose, but it may find a way back to what it was originally known for: a herbal remedy. Most of the plant's ingredients, such as Δ-tetrahydrocannabinol, cannabidiol, cannabigerol, and others, have demonstrated beneficial effects in preclinical models of intestinal inflammation. Endogenous cannabinoids (endocannabinoids) have shown a regulatory role in inflammation and mucosal permeability of the gastrointestinal tract where they likely interact with the gut microbiome. Anecdotal reports suggest that in humans, Cannabis exerts antinociceptive, anti-inflammatory, and antidiarrheal properties. Despite these reports, strong evidence on beneficial effects of Cannabis in human gastrointestinal diseases is lacking. Clinical trials with Cannabis in patients suffering from inflammatory bowel disease (IBD) have shown improvement in quality of life but failed to provide evidence for a reduction of inflammation markers. Within the endogenous opioid system, mu opioid receptors may be involved in anti-inflammation of the gut. Opioids are frequently used to treat abdominal pain in IBD; however, heavy opioid use in IBD is associated with opioid dependency and higher mortality. This review highlights latest advances in the potential treatment of IBD using Cannabis/cannabinoids or opioids.

Behavioral effects of the kappa opioid receptor partial agonist nalmefene in tests relevant to depression.

Compounds with high affinity at kappa and mu opioid receptors may have clinical utility in treating major depressive disorder. Nalmefene (NMF) is a partial kappa opioid receptor agonist and potent mu opioid receptor antagonist, but there has been no preclinical evaluation of NMF in rodent tests relevant to depression and anxiety. To address this, the effects of NMF on neurochemical and behavioral endpoints in C57BL/6J mice were examined and contrasted with a structurally related analog, naltrexone (NTX). NMF exhibited kappa opioid receptor agonist activity, measured as a reduction in extracellular dopamine release in the nucleus accumbens using in vivo microdialysis following acute but not chronic administration. In the mouse forced swim test, female mice were more responsive to higher doses of NMF and NTX compared to male mice. The behavioral effects of NMF in the forced swim test were blocked in Oprk1-/- and Oprm1-/- mice. Conversely, the effects of NTX were blocked only in Oprm1-/- mice. These results indicate that both kappa and mu opioid receptors mediate the behavioral effects of NMF, but the effects of NTX in this test were modified only by mu opioid receptor engagement. Unlike NTX, NMF did not produce conditioned place aversion in either sex. Finally, NMF's activity in the marble burying test and forced swim test were retained following chronic administration. The sustained effects exerted by NMF on tests that are sensitive to antidepressant and anxiolytic compounds support further investigation of NMF as a potential therapeutic for depression.

Very Low Frequency of Drug Therapy of Alcohol Dependence in Germany - Analysis of Data of A Statutory Health Insurance.

Acamprosate and naltrexone are medications of proven efficacy in the treatment of alcohol dependence. In order to investigate the prescription of these drugs in outpatient routine treatment in Germany (frequency of prescription, duration, medical specialty of prescribing physician), data of a large statutory health insurance were analyzed. Persons were included who were discharged from inpatient treatment with an alcohol-related disorder among their diagnoses during a one year observation period and with no diagnosed additional substance-related disorder (apart from nicotine- and cannabis-related disorders). Thus 12.958 patients were identified (mainly male, 77.9%; at average 51.4 years [+/-12.7] of age). 44.3% of these patients were treated in a psychiatric hospital, the remaining patients in hospitals of other specialties (e. g. 9.2% in departments of surgery). During an observation period of 6 months after discharge, acamprosate or naltrexone were prescribed at least once to 98 persons (0.76% of 12.958 patients; acamprosate n=80, 0.62%; naltrexone n=18, 0.14%). 16 (0.12%) patients were prescribed acamprosate or naltrexone for more than 3 months. Half of the prescriptions were issued by general practitioners. Possible reasons for this under-prescription are lack of knowledge about the drug treatment of alcohol dependence outside of addiction psychiatry, neglect of biological aspects (including medication) regarding etiology and treatment of substance-related disorders, and stigma of patients with substance-related disorders.

Low-dose naltrexone: a unique treatment for amyopathic dermatomyositis.

Gottron papules, a heliotrope rash, scalp and extremity erythema, pruritus, and fatigue are the characteristic signs and symptoms of amyopathic dermatomyositis (ADM). Amyopathic dermatomyositis is considered a distinct entity from dermatomyositis (DM) because the characteristic muscle weakness and muscle enzyme elevations of DM are absent in ADM. With respects to treatment, ADM treatments have traditionally included topical corticosteroids and/or systemic immunosuppressants and immunomodulators. Herein we present a patient with refractory ADM that was responsive to low-dose naltrexone therapy.

Treating Alcohol Use Disorder in U.S. Veterans: The Role of Traumatic Brain Injury.

OBJECTIVE: The authors examined the efficacy of valproate to reduce relapse to heavy drinking among veterans with alcohol use disorder (AUD) and neuropsychiatric comorbidities and whether antecedent traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) affected treatment response. METHODS: Participants were male veterans 18-60 years old with an AUD and no other substance use besides nicotine or cannabis. Sixty-two patients were randomly assigned to receive either valproate or naltrexone. Participants were evaluated at baseline and followed weekly for 24 weeks. All participants received standardized psychosocial interventions as well as treatment for coexistent psychiatric conditions. RESULTS: During the follow-up period, nine study subjects in the naltrexone group and 14 in the valproate group relapsed to heavy drinking, but the difference did not reach statistical significance. Participants with a history of moderate to severe TBI were more likely to relapse to heavy drinking compared with those with no TBI (hazard ratio=4.834, 95% CI=1.103-21.194, p=0.033). PTSD status did not significantly affect outcome. CONCLUSIONS: Intensive outpatient programs are efficacious alternatives to treat AUD in veterans, although the role of pharmacological treatment is not completely elucidated. Glutamatergic agents appear to be less effective than opiate antagonists to prevent relapse to heavy drinking and to increase cumulative abstinence. Future studies should examine novel pharmacological and nonpharmacological options.

Use of low-dose naltrexone in the treatment of severe Hailey-Hailey disease: One case report.

Hailey-Hailey disease (HHD) or chronic benign familial pemphigus is an autosomal dominant genodermatosis with complete penetrance characterized by painful vesicles, erosions, and macerated intertriginous skin. We present a 66-year-old woman with a personal 35-year history of pruritic recurrent vesicles and erosions in both axillae and inguinal folds. HHD was confirmed by cutaneous biopsy. Past treatments had failed, including topical corticosteroids, antibiotics and oral doxycycline, minocycline, dapsone, and acitretin. Phototherapy and intralesional injection of toxin botulinum A was performed in the axillae. The patient was started on naltrexone 6.25 mg nightly. Six weeks later, complete clearing was observed. At typical doses, naltrexone blocks µ and δ opiod receptors, thereby blocking the union of ß-endorphins at those sites. Paradoxically, at low doses, the partial binding to those receptors leads to a homeostatic increase of opioid receptors and an upregulation of endogenous opioids. Low-dose naltrexone (LDN) may also exert an anti-inflammatory action through its antagonist effect on toll-like receptor 4 found on macrophages. We consider that LDN is an effective and safe alternative for the HHD, representing an important progress in the management of this disease with limited therapeutic options.

Sex differences in the effect of bupropion and naltrexone combination on alcohol drinking in mice.

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.