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The New England Journal of Medicine Jan 2021The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.
METHODS
We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.
RESULTS
A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.
CONCLUSIONS
Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).
Topics: Administration, Oral; Adolescent; Adult; Aged; Amphetamine-Related Disorders; Bupropion; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Injections; Male; Medication Adherence; Methamphetamine; Middle Aged; Naltrexone; Narcotic Antagonists; Young Adult
PubMed: 33497547
DOI: 10.1056/NEJMoa2020214 -
British Journal of Clinical Pharmacology Apr 2020To compare the benefits and harms of naltrexone-bupropion using evidence from clinical study reports. (Meta-Analysis)
Meta-Analysis Review
AIMS
To compare the benefits and harms of naltrexone-bupropion using evidence from clinical study reports.
METHODS
We searched Food and Drug Administration and European Medicines Agency websites, PubMed, and Clinicaltrials.gov (May 2016) to identify pivotal trials; we then sent a freedom of information request to the European Medicines Agency (July 2016). We included pivotal, phase III placebo-controlled trials. We assessed the risks of bias using the Cochrane criteria, and the quality of the evidence using GRADE. We used a random-effects model for meta-analyses.
RESULTS
Over a 27-month period (July 2016 to August 2018), we received 31 batches of clinical study report documents containing over 65 000 pages of data from 4 pivotal trials (n = 4536). Significantly more participants who took naltrexone-bupropion achieved ≥5% reduction in body weight: risk ratio (RR) = 2.1 (95% confidence interval 1.35-3.28), P = .001, GRADE = low, number needed to treat (NNT) to benefit = 5 (3-17); this represents a 2.53 kg (1.85-3.21) reduction in baseline body weight compared with placebo. Naltrexone-bupropion had significantly beneficial effects on other cardiovascular risk factors; however, the true effect sizes for these are uncertain because of incomplete outcome data. Naltrexone-bupropion significantly increased the risk of adverse events: RR = 1.11 (1.05-1.18, P = .0004, GRADE = low, NNT to harm = 12 7-27); serious adverse events: RR = 1.70 (1.38-2.1, P < .00001, GRADE = moderate, NNT to harm = 21 13-38); and discontinuation because of adverse events: RR = 1.92 (1.65-2.24, P < .00001, GRADE = moderate, NNT to discontinue treatment = 9 8-13).
CONCLUSIONS
Naltrexone-bupropion significantly reduces body weight by a small amount but significantly increases the risk of adverse events. A rigorous process of postmarketing surveillance is required.
Topics: Bupropion; Drug Combinations; Humans; Naltrexone; Obesity
PubMed: 31918448
DOI: 10.1111/bcp.14210 -
Clinical Rheumatology Apr 2014Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional... (Review)
Review
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn's disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone's better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.
Topics: Anti-Inflammatory Agents; Chronic Pain; Fibromyalgia; Humans; Naltrexone; Neuroglia
PubMed: 24526250
DOI: 10.1007/s10067-014-2517-2 -
Addiction (Abingdon, England) Feb 2018Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders (AUDs) is an emerging concept. Our objective was to explore the... (Meta-Analysis)
Meta-Analysis
Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders: a systematic review with direct and network meta-analyses on nalmefene, naltrexone, acamprosate, baclofen and topiramate.
BACKGROUND AND AIMS
Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders (AUDs) is an emerging concept. Our objective was to explore the comparative effectiveness of drugs used in this indication.
DESIGN
Systematic review with direct and network meta-analysis of double-blind randomized controlled trials (RCTs) assessing the efficacy of nalmefene, naltrexone, acamprosate, baclofen or topiramate in non-abstinent adults diagnosed with alcohol dependence or AUDs. Two independent reviewers selected published and unpublished studies on Medline, the Cochrane Library, Embase, ClinicalTrials.gov, contacted pharmaceutical companies, the European Medicines Agency and the Food and Drug Administration, and extracted data.
SETTING
Thirty-two RCTs.
PARTICIPANTS
A total of 6036 patients.
MEASUREMENTS
The primary outcome was total alcohol consumption (TAC). Other consumption outcomes and health outcomes were considered as secondary outcomes.
FINDINGS
No study provided direct comparisons between drugs. A risk of incomplete outcome data was identified in 26 studies (81%) and risk of selective outcome reporting in 17 (53%). Nalmefene [standardized mean difference (SMD) = -0.19, 95% confidence interval (CI) = -0.29, -0.10; I = 0%], baclofen (SMD = -1.00, 95% CI = -1.80, -0.19; one study) and topiramate (SMD = -0.77, 95% CI = -1.12, -0.42; I = 0%) showed superiority over placebo on TAC. No efficacy was observed for naltrexone or acamprosate. Similar results were observed for other consumption outcomes, except for baclofen (the favourable outcome on TAC was not reproduced). The number of withdrawals for safety reasons increased under nalmefene and naltrexone. No treatment demonstrated any harm reduction (no study was powered to explore health outcomes). Indirect comparisons suggested that topiramate was superior to nalmefene, naltrexone and acamprosate on consumption outcomes, but its safety profile is known to be poor.
CONCLUSIONS
There is currently no high-grade evidence for pharmacological treatment to control drinking using nalmefene, naltrexone, acamprosate, baclofen or topiramate in patients with alcohol dependence or alcohol use disorder. Some treatments show low to medium efficacy in reducing drinking across a range of studies with a high risk of bias. None demonstrates any benefit on health outcomes.
Topics: Acamprosate; Alcoholism; Baclofen; Naltrexone; Narcotic Antagonists; Network Meta-Analysis; Topiramate; Treatment Outcome
PubMed: 28940866
DOI: 10.1111/add.13974 -
International Immunopharmacology Nov 2023The global prevalence of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) stands at approximately 43 % among individuals who have previously had acute COVID-19. In...
The global prevalence of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) stands at approximately 43 % among individuals who have previously had acute COVID-19. In contrast, in the United States, the National Center for Health Statistics (NCHS) estimates that around 11 % of individuals who have been infected with SARS-CoV-2 go on to experience long COVID. The underlying causes of PASC remains under investigation, and there are no currently established FDA-approved therapies. One of the leading hypotheses for the cause of PASC is the persistent activation of innate immune cells with increase systemic inflammation. Naltrexone is a medication with anti-inflammatory and immunomodulatory properties that has been used in other conditions that overlap with PASC. We performed a retrospective review of a clinical cohort of 59 patients at a single academic center who received low-dose naltrexone (LDN) off-label as a potential therapeutic intervention for PASC. The use of LDN was associated with a fewer number of symptoms, improved clinical symptoms (fatigue, post-exertional malaise, unrefreshing sleep, and abnormal sleep pattern), and a better functional status. This observation warrants testing in rigorous, randomized, placebo-controlled clinical trials.
Topics: Humans; COVID-19; Post-Acute COVID-19 Syndrome; Naltrexone; SARS-CoV-2; Disease Progression
PubMed: 37804660
DOI: 10.1016/j.intimp.2023.110966 -
Journal of Medical Toxicology :... Mar 2016Naltrexone is a semi-synthetic opioid with competitive antagonist activity at mu opioid receptors. Its efficacy has been demonstrated in the treatment of alcohol and... (Review)
Review
Naltrexone is a semi-synthetic opioid with competitive antagonist activity at mu opioid receptors. Its efficacy has been demonstrated in the treatment of alcohol and opioid dependence, but adherence to daily dosing has been recognized as a factor limiting long-term effectiveness. Recently, a long-acting injectable formulation of naltrexone has received FDA-approval for treating alcohol and opioid dependence. This article reviews the pharmacology of naltrexone, the current evidence supporting the use of extended-release naltrexone, and the clinical challenges in the induction of patients to this medication.
Topics: Alcoholism; Animals; Behavior, Addictive; Delayed-Action Preparations; Drug Compounding; Humans; Injections; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Risk Factors; Treatment Outcome
PubMed: 26546222
DOI: 10.1007/s13181-015-0512-x -
Arthritis and Rheumatism Feb 2013To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and... (Randomized Controlled Trial)
Randomized Controlled Trial
Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.
OBJECTIVE
To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue.
METHODS
Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain.
RESULTS
When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.
CONCLUSION
The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.
Topics: Adult; Aged; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fibromyalgia; Humans; Middle Aged; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Placebos; Self Report; Treatment Outcome
PubMed: 23359310
DOI: 10.1002/art.37734 -
CMAJ : Canadian Medical Association... Aug 2021
Topics: Alcohol Deterrents; Alcoholism; Appetite Depressants; Humans; Naltrexone; Social Support; Topiramate
PubMed: 34344780
DOI: 10.1503/cmaj.200895-f -
Hormones (Athens, Greece) 2015The combination of 32 mg naltrexone and 360 mg bupropion prolonged release (NB32) was recently approved by both the food and drug administration (FDA) and the European... (Review)
Review
OBJECTIVE
The combination of 32 mg naltrexone and 360 mg bupropion prolonged release (NB32) was recently approved by both the food and drug administration (FDA) and the European medicines agency (EMA) as an adjunct to a comprehensive lifestyle intervention to achieve weight loss.
DESIGN
Randomized controlled trials with naltrexone/bupropion prolonged release were selected through a search based on PubMed listings using the terms "bupropion AND naltrexone".
RESULTS
NB32 treatment resulted in 5.0-9.3% weight loss, while the placebo-subtracted weight loss was 3.2-5.2% during 56 weeks of treatment. The proportion of treated patients with ≥ 5% weight loss was 45-66%, while the placebo-subtracted proportion was 23-34%. NB32 was associated with a decrease in waist circumference, serum triglycerides and insulin resistance and an increase in high-density lipoprotein-cholesterol (HDL-C). Blood pressure mainly remained stable but there was a small increase in heart rate. The most common side effects were nausea, constipation, headache and vomiting. Serious adverse effects, which were very rare, included suicidal thoughts and seizures. In the majority of patients NB32 treatment was well tolerated.
CONCLUSIONS
Naltrexone/bupropion combination appears to be an effective adjunct to a comprehensive lifestyle intervention in order to achieve weight loss and treat obesity-related comorbidities.
Topics: Bupropion; Dopamine Uptake Inhibitors; Humans; Naltrexone; Narcotic Antagonists; Obesity; Outcome Assessment, Health Care
PubMed: 26188223
DOI: 10.14310/horm.2002.1600 -
Journal of Pain and Symptom Management Feb 2014
Review
Topics: Hospice Care; Humans; Internet; Naloxone; Naltrexone; Narcotic Antagonists; Palliative Care; Quaternary Ammonium Compounds
PubMed: 24512968
DOI: 10.1016/j.jpainsymman.2013.12.223