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.

Pregnancy Rates Among Women Treated with Medication for Opioid Use Disorder.

BACKGROUND: Treatment-seeking people with opioid use disorder (OUD) who are capable of pregnancy need accurate information about the potential impact of medication to treat OUD (MOUD) on fertility to make informed choices about treatment that are consistent with their reproductive wishes. There is a dearth of research on fertility associated with MOUD receipt in birthing people with OUD. OBJECTIVE: To estimate the association between treatment with MOUD and odds of conception among birthing people using national administrative claims. DESIGN: Retrospective case-crossover study using multi-state US administrative data (2006-2016). Dates of conception were estimated from delivery dates and served as "case" days for which MOUD exposures were compared to those on all other ("control") days of insurance enrollment. PARTICIPANTS: Treatment-seeking people with OUD with a delivery during the observation period. MAIN MEASURES: Odds ratios for conception from within-person fixed effects models were modeled as a function of exposure to MOUD (buprenorphine, methadone, extended-release depot naltrexone, or oral naltrexone) using conditional logistic regression. KEY RESULTS: A total of 21,928 births among 19,133 people with OUD were identified. In the sample, 5873 people received buprenorphine, 1825 methadone, 486 extended-release naltrexone, and 714 oral naltrexone. Participants could receive more than one type of MOUD. Mean age was 28.2 years (SD = 2.2; range = 16-45), with 76.2% having Medicaid. vs. commercial insurance. Compared to no MOUD, periods of methadone (aOR = 0.55 [95% CI = 0.48-0.63]) or buprenorphine receipt (aOR = 0.84 [0.77-0.91]) were associated with fewer conceptions. Treatment periods with extended-release depot naltrexone compared to no medication were associated with higher odds of conception (aOR = 1.75 [1.22-2.50]) and there was no significant difference in conception with oral naltrexone (aOR = 1.02 [0.67-1.54]). CONCLUSIONS: The association between MOUD and odds of conception among birthing people varied by type of MOUD, with extended-release naltrexone associated with higher odds of conceiving compared to no treatment. Clinical studies are urgently needed to investigate these findings further.

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.

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.

Influence of sleep quality on lapse to alcohol use during a quit attempt.

AIMS: Sleep problems are common among individuals with alcohol use disorder (AUD) and is often associated with a heightened relapse risk. The present study examines the relationship between sleep and alcohol use among individuals with current AUD during a 6-day quit attempt as part of a medication study. METHODS: The current study is a secondary analysis of a medication trial for individuals with AUD. Individuals with AUD (N = 53, 26 females) were randomized to active medication or matched placebo. Randomized participants completed a week-long medication titration (Days 1-7). Following the titration period, participants attended an in-person visit (Day 8) to begin a 6-day quit attempt. During the quit attempt, participants completed daily diary assessments to report on previous day alcohol consumption, sleep quality, and alcohol craving. In the present study, medication condition was controlled for in all models. RESULTS: Baseline global sleep quality was not a significant predictor of drinks per drinking day (P = 0.72) or percent days abstinent (P = 0.16) during the 6-day practice quit attempt. Daily diary analyses found that greater sleep quality was associated with higher next-day drinks per drinking day (b = 0.198, P = 0.029). In contrast, participants reported worse sleep quality following nights of greater alcohol intake, albeit at a trend-level (b = -0.12, P = 0.053). CONCLUSIONS: These results suggest that better sleep quality was a risk factor for drinking during the 6-day quit period, such that better sleep may be associated with increased craving for alcohol and alcohol use the next day. These findings are limited to the early abstinence period and should be considered in studies exploring longer periods of abstinence.

Patterns of publicly funded naltrexone use among patients diagnosed with alcohol use disorder in Ontario.

AIMS: Naltrexone is recommended first-line to manage alcohol use disorder (AUD). With previous studies indicating poor retention on naltrexone, we determined duration of naltrexone use and assessed the association between prescription setting and time to discontinuation in Ontario. METHODS: We conducted a retrospective population-based cohort study among Ontario public drug beneficiaries diagnosed with AUD who initiated publicly funded naltrexone from June 2018 to September 2019. The primary outcome was time to naltrexone discontinuation, with a secondary analysis assessing receipt of at least one prescription refill. We used Cox proportional hazards models and logistic regression to test the association between prescription setting and each medication persistence outcome. RESULTS: Among 2531 new naltrexone patients with AUD, the median duration of naltrexone use was 31 days and 394 (15.6%) continued naltrexone for 6 months or longer. There was no association between setting of initiation and duration of naltrexone use; however, those initiating naltrexone following an acute inpatient hospital stay were more likely to fill a second prescription (aOR 1.43, 95% CI 0.96-2.14), while those initiating after an ED visit were less likely to be dispensed a second prescription (aOR = 0.69, 95% CI 0.52-0.90) compared to those starting in a physician's office. CONCLUSION: Persistence on naltrexone to treat an AUD is low, regardless of the setting of initiation. Further research is needed to elucidate the barriers encountered by patients with AUD that lead to poor treatment persistence in order to develop interventions that facilitate patient-centered access to evidence-based treatment for AUD in the province.

Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

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.

The impact of cannabis on non-medical opioid use among individuals receiving pharmacotherapies for opioid use disorder: a systematic review and meta-analysis of longitudinal studies.

Background: The relationship between cannabis use and the risk of returning to using opioids non-medically during treatment for opioid use disorder (OUD) remains unclear.Objective: We sought to quantify the impact of cannabis use on the risk of non-medical opioid use among people receiving pharmacotherapies for OUD.Methods: A comprehensive search was performed using multiple databases from March 1 to April 5 of 2023. Eligible studies longitudinally assessed the association between cannabis use and non-medical opioid use among people with OUD receiving treatment with buprenorphine, methadone, or naltrexone. We utilized a random-effects model employing the restricted maximum likelihood method. A sensitivity analysis was conducted to understand potential differences between each OUD treatment modality.Results: A total of 10 studies were included in the final meta-analysis. There were 8,367 participants (38% female). The average follow-up time across these studies was 9.7 months (SD = 3.77), ranging from 4 to 15 months. The pharmacotherapies involved were methadone (76.3%) buprenorphine (21.3%), and naltrexone (2.4%). The pooled odds ratio did not indicate that cannabis use significantly influenced non-medical opioid use (OR: 1.00, 95% CI: 0.97-1.04, p = .98). There is evidence of moderate heterogeneity and publication bias.Conclusion: There was no significant association between cannabis use and non-medical opioid use among patients receiving pharmacotherapies for OUD. These findings neither confirm concerns about cannabis increasing non-medical opioid use during MOUD, nor do they endorse its efficacy in decreasing non-medical opioid use with MOUD. This indicates a need for individualized approaches for cannabis use and challenges the requirement of cannabis abstinence to maintain OUD pharmacotherapies.

Unraveling the neuroprotective mechanisms of naltrexone against aluminum-induced neurotoxicity.

Aluminum (Al) is a known neurotoxic trace element linked to Alzheimer's disease (AD). Naltrexone, an opioid antagonist, has shown promising effects in reducing neuroinflammation at lower doses than those prescribed for addiction. This study aimed to determine the neuroprotective effects of naltrexone on Al-induced neurotoxicity in an in vitro AD model. The SH-SY5Y cells were first cultivated in a standard growth medium. Subsequently, the cells were induced to differentiate by decreasing the concentration of fetal bovine serum and introducing retinoic acid (RA) into the culture media. Subsequently, the inclusion of brain-derived neurotrophic factor (BDNF) was implemented in conjunction with RA. The process of differentiation was concluded on the seventh day. Study groups (n = 3) were designed as the control group, naltrexone group, Al group, Al-Nal group, Alzheimer' model (AD) group, Alzheimer model + Al-exposed group (AD-Al), Alzheimer model + Nal applied group (AD-Nal) and Alzheimer model + Al-exposed + Nal applied group (AD-Al-Nal). Hyperphosphorylated Tau protein as the specific marker of AD was measured in all groups. Glycogen synthase kinase-3 (GSK-3)ß, Protein phosphatase 2A (PP2A), Akt and Wnt signaling pathways were analyzed comparatively. In addition, oxidative stress parameters (total antioxidant capacity, lipid peroxidase, protein carbonyl and reactive oxygen species) were measured comparatively in the study groups. The results showed that naltrexone reduced hyperphosphorylated tau protein levels by regulating GSK-3ß, PP2A, Akt and Wnt signaling. Also, exposure to naltrexone decreased oxidative stress parameters. Based on these results, naltrexone shows promise as a potential therapy for AD, subject to additional clinical assessments.

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.

Analysis of Ohio Advanced Practice Registered Nurses' Rate of Prescribing Naltrexone for Patients With Alcohol Use Disorder Since Elimination of the X-Waiver.

BACKGROUND: Alcohol use disorder (AUD) is common and deadly. Naltrexone is a treatment for AUD. Previous research examined factors that predict Ohio Advanced Practice Registered Nurses' (APRNs) utilization of naltrexone to treat AUD. Inclusion criteria included APRNs' endorsing receipt of the X-waiver, a designation indicating providers' receipt of substance use disorder education. In 2023, the X-waiver was eliminated. The purpose of this study was to replicate the previous research design in respondents without an X-waiver and compare findings. AIMS: The aims of this study were three-fold: (1) assess whether race, age, practice setting, years in practice, or work experience with an addiction specialist physician predicted prescription of naltrexone for AUD, (2) assess whether the goal of abstinence or reduced alcohol use as desired treatment affected the likelihood of naltrexone prescription for AUD, and (3) compare differences between the answers in the current respondent group without X-waiver and the previous study's X-waivered respondents. METHOD: All Ohio APRNs were sent surveys. Eighty-eight responses were included in analysis. Descriptive statistics, logistic regression, and chi-square results were reported. RESULTS: Work experience with an addiction specialist physician was negatively associated with prescribing naltrexone for AUD. Respondents from the previous study of X-waivered APRNs were significantly more likely to prescribe naltrexone for reduced alcohol consumption as a treatment outcome than the respondents in this study. CONCLUSION: The recent policy change eliminating the X-waiver provides important context for research, adding to the substance use disorder literature.

Low-Dose Naltrexone as an Adjuvant in Combined Anticancer Therapy.

Naltrexone (NTX) is a non-selective antagonist of opioid receptors, primarily used in the therapy of opioid and alcohol dependence. Low-dose naltrexone (LDN) exhibits antagonistic action against the opioid growth factor receptor (OGFr), whose signaling is associated with the survival, proliferation, and invasion of cancer cells. The mechanism of action of LDN depends on the dose and duration of the OGFr blockade, leading to a compensatory increase in the synthesis of the opioid growth factor (OGF), which has an inhibitory effect on carcinogenesis. Numerous studies on in vitro and in vivo models provide evidence of LDN's positive impact on inhibiting the OGF-OGFr axis in cancers. LDN's unique mechanism of action on cancer cells, lack of direct cytotoxic effect, and immunomodulating action form the basis for its use as an adjuvant in chemotherapy and immunotherapy of cancerous lesions.

Efficacy and Safety of Low Dose Naltrexone for Chronic Pain.

Naltrexone is a mu-opioid receptor antagonist increasingly used as an analgesic for chronic pain at low doses. This retrospective, observational cohort study was conducted at an academic medical center to evaluate low-dose naltrexone (LDN) efficacy and describe its use in routine clinical practice. Adults receiving LDN, doses <10 mg for ≥1 month, seen at an outpatient pain clinic from January 1, 2014 to April 1, 2022 were included. The primary outcome was change in the Pain, Enjoyment of Life, and General Activity (PEG) score after LDN. Thirty-one patients were included. Median age was 50 years and 71% were female. Median duration of pain at baseline was 5 years. Mean PEG scores were 7.27 ± 1.39 and 6.62 ± 2.04 at baseline and follow-up, respectively. Mean difference was 0.66 (95% CI [0.10-1.21], p = 0.022). Eighty-seven percent (27) of patients discontinued LDN, 52% (16) for lack of benefit, 23% (7) for loss of benefit, 10% (3) for side effects, and 3% (1) for other reasons. Seven (23%) reported side effects. LDN was associated with a statistically significant reduction in PEG in adult chronic pain patients, however the clinical significance is unclear as over 75% of patients discontinued LDN due to lack of benefit.

Multimodal Acute Pain Management in the Parturient with Opioid Use Disorder: A Review.

The opioid epidemic in the United States has led to an increasing number of pregnant patients with opioid use disorder (OUD) presenting to obstetric units. Caring for this complex patient population requires an interdisciplinary approach involving obstetricians, anesthesiologists, addiction medicine physicians, psychiatrists, and social workers. The management of acute pain in the parturient with OUD can be challenging due to several factors, including respiratory depression, opioid tolerance, and opioid-induced hyperalgesia. Patients with a history of OUD can present in one of three categories: 1) those with untreated OUD; 2) those who are currently abstinent from opioids; 3) those being treated with medications to prevent withdrawal. A patient-centered, multimodal approach is essential for optimal peripartum pain relief and prevention of adverse maternal and neonatal outcomes. Medications for opioid use disorder (MOUD), previously referred to as medication-assisted therapy (MAT), include opioids like methadone, buprenorphine, and naltrexone. These are prescribed for pregnant patients with OUD, but appropriate dosing and administration of these medications are critical to avoid withdrawal in the mother. Non-opioid analgesics such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) can be used in a stepwise approach, and regional techniques like neuraxial anesthesia and truncal blocks offer opioid-sparing options. Other medications like ketamine, clonidine, dexmedetomidine, nitrous oxide, and gabapentinoids show promise for pain management but require further research. Overall, a comprehensive pain management strategy is essential to ensure the well-being of both the mother and the fetus in pregnant patients with OUD.

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.

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.

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.

Low-Dose Naltrexone for Excoriation Disorder.

Excoriation (skin-picking) disorder (ED) is a condition characterized by the repeated compulsion to pick at the skin, causing physical trauma and psychiatric distress. Patients often desire to cease skin-picking behavior but are unable to do so. Multiple treatment modalities are effective for ED, including naltrexone. Previous reports of naltrexone for ED were at a high dose of 50 mg. The efficacy of low-dose naltrexone (LDN) at 4.5 mg in managing ED has not been reported. We present a case of a 51-year-old female with ED who was evaluated in the pain clinic for fibromyalgia management. Her medications included gabapentin 600 mg PO TID and a history of opioid prescription for diffuse pain. She was started on naltrexone 4.5 mg PO QD for the management of fibromyalgia. Three months later, the patient reported improvement in her skin-picking disorder, with a lessened compulsion to itch at her skin and improved healing of existing lesions. When the naltrexone was temporarily interrupted for an elective procedure, her lesions worsened. Her lesions improved after she resumed the medication. Thereby, this patient experienced a therapeutic benefit from naltrexone for her skin-picking disorder, as demonstrated by the temporal changes in her symptoms. To our knowledge, this is the first reported case of ED improving with LDN, as other cases utilized 50 mg. Though few clinical trials or systematic reviews recommend the use of naltrexone for EDs, our case supports trialing LDN in the appropriate context.