Sustained-release Naltrexone Research Articles

In adults with opioid use disorder, does sustained-release naltrexone prevent relapse more effectively than oral naltrexone or no treatment?

University of Minnesota Medical Center Family Medicine Residency Program, Minneapolis, MN The authors declare no conflicts of interest.

Medications Available for Weight Reduction in Elective Total Joint Arthroplasty.

Arthroplasty in patients with elevated body mass index results in increased rates of reoperation, instability, revision, and infection. Preoperative weight loss may reduce the complication rate associated with orthopaedic surgery. In addition to lifestyle modification, anti-obesity medications are available to help patients to reduce their preoperative weight. Currently, there are 6 U.S. Food and Drug Administration (FDA)-approved anti-obesity medications in the United States: phentermine, orlistat, phentermine with topiramate extended release (ER), lorcaserin, sustained release (SR) naltrexone with bupropion, and liraglutide. Anti-obesity medications potentially provide a new way to optimize patients before surgery and to ensure successful recovery postoperatively.

Impact of Pharmacological Treatments for Opioid Use Disorder on Mortality

The use of pharmacological treatments for opioid use disorders, including methadone, buprenorphine and naltrexone has been associated with a reduction in mortality compared with illicit opioid use. However, these treatments can also contribute significantly to the risk of death. The opioid agonists methadone and buprenorphine achieve clinical efficacy in patients with an opioid use disorder through suppressing craving and diminishing the effectiveness of illicit opioid doses, while the antagonist naltrexone blocks the action of opioids. Pharmacological differences between opioid pharmacotherapies then create different temporal patterns of protection and mortality risk, different risks of relapse to illicit opioid use, and variations in direct and indirect toxicity, which are revealed in clinical and epidemiological studies. Induction onto methadone and the cessation of oral naltrexone treatment are associated with an elevated risk of opioid poisoning, which is not apparent in patients treated with buprenorphine or sustained-release naltrexone. Beyond drug-related mortality, these pharmacotherapies can impact a participant's risk of death. Buprenorphine may also have some advantages over methadone in patients with depressive disorders or cardiovascular abnormalities. Naltrexone, which is also commonly prescribed to manage problem alcohol use, may reduce deaths in chronic co-alcohol users. Understanding these pharmacologically driven patterns then guides the judicious choice of drug and dosing schedule and the proactive risk management that is crucial to minimising the risk of death in treatment.

A retrospective cohort study of mortality rates in patients with an opioid use disorder treated with implant naltrexone, oral methadone or sublingual buprenorphine

ABSTRACTBackground: Sustained release naltrexone has been shown to be a safer alternative to oral naltrexone in terms of mortality in patients with an opioid use disorder; however, a direct large-scale comparison has not been made between sustained release naltrexone and the more popular opioid pharmacotherapies: methadone and buprenorphine. Objective: To examine and compare mortality rates in patients with an opioid use disorder treated with implant naltrexone, methadone, and buprenorphine. Methods: Patients treated with implant naltrexone (n = 1461, 35.6% female), methadone (n = 3515, 33.3% female), or buprenorphine (n = 3250, 34.5% female) for the first time between 2001 and 2010 in Western Australia (WA) were cross-matched against the WA Death Registry. Results: Crude mortality rates in patients treated with methadone (8.1 per 1000 patient years (ptpy) (HR:1.13, CI:0.82–1.55, p = 0.447) or buprenorphine (7.2 ptpy) (HR:1.01, CI:0.72–1.42, p = 0.948) were not significantly different to those treated with implant naltrexone (7.1 ptpy). Similarly, no differences were observed between the three treatments in terms of cause-specific or age-specific mortality. However, high rates of mortality were observed in methadone-treated patients during the first 28 days of treatment (HR:8.19, CI:1.08–62.21, p = 0.042) compared to naltrexone-treated patients. Female patients treated with methadone (HR:2.96, CI:1.34–6.51, p = 0.007) also experienced a higher overall mortality rate compared to naltrexone-treated patients. Conclusions: Crude mortality rates are comparable in patients with an opioid use disorder treated with implant naltrexone, methadone, and buprenorphine. However, implant naltrexone may be associated benefits during the first 28 days of treatment and in female patients compared to methadone.

Quality of life, binge eating and sexual function in participants treated for obesity with sustained release naltrexone/bupropion.

SummaryObjectiveThis multicenter, randomized, controlled, open‐label trial examined weight‐related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention.MethodsImpact of Weight on Quality of Life‐Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26.ResultsNB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P < 0.0001). NB + CLI participants had greater improvements in Impact of Weight on Quality of Life‐Lite total score than UC participants (P < 0.0001). In participants with moderate/severe Binge Eating Scale scores at BL, 91% of NB + CLI and 18% of UC participants experienced categorical improvements. In participants with Arizona Sexual Experiences Scale‐defined sexual dysfunction at BL, 58% of NB + CLI and 19% of UC participants no longer met dysfunction criteria at week 26. The most frequent adverse events leading to discontinuation before week 26 in NB + CLI included nausea (10.5%); anxiety (3.3%); and headache, hypertension, insomnia and palpitations (1.3% each).ConclusionCompared with UC, participants treated with NB + CLI experienced greater improvements in weight‐related quality of life, control over eating behaviour, and sexual function.

Effect of combined naltrexone and bupropion therapy on the brain\u2019s functional connectivity

BackgroundThe control of food intake in environments with easy access to highly rewarding foods is challenging to most modern societies. The combination of sustained release (SR) naltrexone and SR bupropion (NB32) has been used in weight-loss and obesity management. However, the effects of NB32 on the brain circuits implicated in the regulation of food intake are unknown. Here we used functional connectivity density (FCD) mapping to evaluate the effects of NB32 on resting brain FC.MethodsThirty-six healthy women underwent magnetic resonance imaging (MRI) before and after 4-week treatment with NB32 (n = 16) or with placebo (n = 20). In each imaging visit, a 5-min resting-state functional MRI scan was conducted after 15 h of fasting. The FC of brain regions showing significant group effects on FCD were subsequently assessed using seed-voxel correlation analyses. We characterized the associations between FCD measures and craving control scores in the Control of Eating Questionnaire.ResultsAfter NB32 treatment, the group showed lower local and global FCD than the placebo group in the right superior parietal cortex and lower local FCD in the left middle frontal gyrus. Seed-voxel correlation analysis for the right superior parietal cortex seed demonstrated higher positive FC with the dorsal anterior cingulate gyrus (ACC), bilateral insula, and left superior parietal gyrus and stronger negative FC with right inferior frontal gyrus and right superior parietal cortices for the NB32 than the placebo group. Further, the NB32 group showed a significant correlation between local FCD change after treatment in left middle frontal gyrus and craving control scores (r = 0.519, p = 0.039).ConclusionsNB32 treatment decreased local and global FCD in superior parietal cortex and increased its connectivity with ACC (involved with saliency attribution), insula (interoception), and decreased local FCD in the medial prefrontal cortex (craving), which might underlie NB32 improved control over eating behaviors. ClinicalTrails.gov: NCT00711.

The role of anti-obesity drugs in the management of obese diabetics

Obesity contributes to type 2 diabetes and worsens its control. 5-10% weight loss among obese diabetics significantly improves glucose control, lipids and blood pressure. Weight loss should be a key goal of diabetes care for all overweight and obese patients with type 2 diabetes. Adjunctive therapy with weight loss drugs is indicated among obese diabetics who can not achieve weight maintenance with lifestyle alone. Metformin use is associated with weight loss during management of diabetics. Metformin may reduce BMI by 5.3 % in comparison with placebo and it is considered as first-line agent in obese patient with type 2 diabetes. SGLT-2 inhibitors may reduce body weight for 3 to 5 kg during management of type 2 diabetes. Orlistat use resulted in a significant reduction of cumulative incidence of type 2 diabetes after 4 years of treatment of obese subjects. Phentermine and topiramate combination use in patients with diabetes and prediabetes results in greater reduction in HbA1c values and fewer prediabetes patients progression to type 2 diabetes. Therapy with combination of bupropione and naltrexone sustained-release among diabetic patients with obesity resulted in reduction of HbA1c and improvements in triglycerides and HDL cholesterol values. In BLOOM-DM study lorcaserin decreased weight by 4.5-5 % together with reductions in HbA1c . Liraglutide has a therapeutic potential for both obesity and type 2 diabetes, due to its dual benefits on body weight and glycemic control. Semaglutide is a new GLP-1 analogue that reduces HbA1c and body weight and improves obesity related complications. Combination of GLP-1/glucagon dual agonist theoretically may decrease food intake and body weight according the preclinical experience. In case where patient does not lose 5 % or more of his body weight on prescribed drug, after three months of treatment, therapy with this drug should be stopped and changed with some other.

Method-of-use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity.

ObjectiveThis study assessed the effects of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) on body weight in adults with obesity, with comprehensive lifestyle intervention (CLI), for 78 weeks.MethodsIn this phase 3b, randomized, open‐label, controlled study, subjects received NB + CLI or usual care (standard diet/exercise advice) for 26 weeks. NB subjects not achieving 5% weight loss at week 16 were discontinued, as indicated by product labeling. After week 26, usual care subjects began NB + CLI. Assessments continued through week 78. The primary end point was percent change in weight from baseline to week 26 in the per protocol population. Other end points included percentage of subjects achieving ≥5%, ≥10%, and ≥15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation.ResultsNB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea.ConclusionsTreatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB‐facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated.

Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

Evolution of pharmacological obesity treatments: focus on adverse side-effect profiles.

Pharmacotherapy directed toward reducing body weight may provide benefits for both curbing obesity and lowering the risk of obesity-associated comorbidities; however, many weight loss medications have been withdrawn from the market because of serious adverse effects. Examples include pulmonary hypertension (aminorex), cardiovascular toxicity, e.g. flenfluramine-induced valvopathy, stroke [phenylpropanolamine (PPA)], excess non-fatal cardiovascular events (sibutramine), and neuro-psychiatric issues (rimonabant; approved in Europe, but not in the USA). This negative experience has helped mould the current drug development and approval process for new anti-obesity drugs. Differences between the US Food and Drug Administration (FDA) and the European Medicines Agency, however, in perceptions of risk-benefit considerations for individual drugs have resulted in discrepancies in approval and/or withdrawal of weight-reducing medications. Thus, two drugs recently approved by the FDA, i.e. lorcaserin and phentermine + topiramate extended release, are not available in Europe. In contrast, naltrexone sustained release (SR)/bupropion SR received FDA approval, and liraglutide 3.0 mg was recently approved in both the USA and Europe. Regulatory strategies adopted by the FDA to manage the potential for uncommon but potentially serious post-marketing toxicity include: (i) risk evaluation and mitigation strategy programmes; (ii) stipulating post-marketing safety trials; (iii) considering responder rates and limiting cumulative exposure by discontinuation if weight loss is not attained within a reasonable timeframe; and (iv) requiring large cardiovascular outcome trials before or after approval. We chronicle the adverse effects of anti-obesity pharmacotherapy and consider how the history of high-profile toxicity issues has shaped the current regulatory landscape for new and future weight-reducing drugs.

HCV genotype distribution among injection drug users in Taiwan

naltrexone in opioid dependent patients, including both datadriven and addressing commonly asked topics on safety (e.g., hepatic health, anhedonia/depression, post treatment overdose risk). Methods: Per-subject urine data was solicited from all RCT authors and subjected to statistical analysis in accordance with Cochrane requirements. Subjective measures of opioid agonist use and other substances were also analyzed. For safety outcomes, a qualitative assessment was conducted of all relevant RCT and non-RCT contributions. Seven databases were searched, producing n=1104 abstracts, of which n=43 were relevant articles and n=6 were RCTs. Risk of bias was assessed for all studies in accordance with Cochrane principles. Results: Meta-analysis found a main effect of sustained release naltrexone on illicit opioid use (Z=5.2, p< .01) on both urine and subjective measures. On safety outcomes, sustained release naltrexone was generally well tolerated with some variations in site reactions due to the type of administration method used. Risk of biaswas generally consideredmoderate to high, especially for nonrandomized studies. Conclusions: Sustained releasenaltrexone increases abstinence from opioids in opioid dependent patients who volunteered for this type of medication-assisted abstinence and was generally safe in use. While no larger studies have yet compared sustained release naltrexone to maintenance treatment with methadone or buprenorphine, this review indicates that sustained release naltrexone can be considered an effective an safe treatment option for opioid dependence. Note: Results & Conclusions are subject to final approval by the Cochrane Drugs & Alcohol Group editorial review board Financial Support: The University of Oslo The Research Council of Norway.

Pharmacogenetics of treatment of opioid dependence with oral naltrexone and long-acting sustained-release naltrexone implant

Pharmacogenetics of treatment of opioid dependence with oral naltrexone and long-acting sustained-release naltrexone implant

REMOVED: Sustained-release naltrexone for opioid dependence: A cochrane review and meta-analysis

REMOVED: Sustained-release naltrexone for opioid dependence: A cochrane review and meta-analysis

OR09-3 * PROTOCOLS FOR DETOX OF HIGH DOSE METHADONE PATIENTS OFF METHADONE IN 14 DAYS IN AN OUTPATIENTS PROGRAM

It has been reported that the average overdose mortality rate for patients detoxing from methadone in the UK, is 46pt/1000py in the first month following detox (Cornish et al, 2010). This highlights the need to provide safe and effective detox services alongside the provision and high quality sustained release naltrexone treatment for those seeking to detox from methadone programs. The development of protocols for assisting high dose methadone patients to detox from methadone in 14 days, using a combination of Buprenorphine and long acting naltrexone implants, will be discussed. At an outpatient clinic in Perth, Australia, a large number of patients on doses of methadone of 100mg/d and above, present with requests for assistance in stopping their methadone treatment. The patient is initially transferred from their high dose methadone onto buprenorphine over a 4 day period. Patients are then detoxed from their buprenorphine and treated with naltrexone implants. No major complications or deaths in the months immediately post detox have occurred. The provision of naltrexone implants has been associated with an overdose mortality of 0.67pt/1000py in the first four months after ceasing opiates. Therefore, the method developed is fast, efficient and provides protections from overdose mortality following methadone detox.

Naltrexone implant treatment for buprenorphine dependence – Mauritian case series

Although substitution therapy with opiate agonist treatments such as methadone and buprenorphine has resulted in a reduction of illicit drug use related harm, such treatment has also resulted in severe problems in some countries where opioid-dependent individuals now inject illicitly sold buprenorphine or buprenorphine-naloxone instead of heroin. There is no approved treatment for buprenorphine dependence. Naltrexone is an opioid antagonist which has been used for the treatment of both alcohol and opioid dependencies. Although both buprenorphine and heroin resemble each other concerning their effects, buprenorphine has a higher affinity to opioid receptors than heroin. Therefore, it is not known if naltrexone can block the psychoactive effects of buprenorphine as it does for heroin. This paper presents observational case series data on the use of a sustained-release naltrexone implant for the treatment of buprenorphine dependence. To the authors' knowledge this is the first use of sustained-release naltrexone for this indication.

Injectable and implantable sustained release naltrexone in the treatment of opioid addiction

Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1-7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction.

Effects of Naltrexone Sustained- Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes

OBJECTIVETo assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs.RESEARCH DESIGN AND METHODSThis was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids.RESULTSIn the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m2, and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (−5.0 vs. −1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (−0.6 vs. −0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia.CONCLUSIONSNB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.

P.6.d.004 Pharmacogenetics of treatment of opioid dependence with oral naltrexone and long acting sustained release naltrexone implant

P.6.d.004 Pharmacogenetics of treatment of opioid dependence with oral naltrexone and long acting sustained release naltrexone implant

Naltrexone/Bupropion Combination Therapy in Overweight or Obese Patients With Major Depressive Disorder

Objective: To evaluate the effect of 32-mg/d naltrexone sustained release and 360-mg/d bupropion sustained release (NB32) in overweight and obese patients with major depressive disorder (MDD).Method: Twenty-five female patients with a DSM-IV diagnosis of MDD, an Inventory of Depressive Symptomatology—Self-Report score > 26, and a body mass index ≥ 27 and ≤ 43 kg/m2 received up to 24 weeks of open-label treatment with NB32 with dietary and behavioral counseling (data collection: March 2008–July 2009). The primary endpoint was change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 12 weeks; secondary endpoints included MADRS total score at week 24, change in weight, and Clinical Global Impressions–Improvement scale responder status (CGI-I score ≤ 2) at weeks 12 and 24 (modified intent-to-treat [mITT]: patients with ≥ 1 postbaseline MADRS total score on study drug; N = 23).Results: MADRS scores showed significant reductions at weeks 12 and 24 (mITT–last observation carried forward [LOCF]: –13.1 ± 7.1 and –15.3 ± 8.1, respectively, P < .001 vs baseline for all). Mean ± SD weight loss was –4.0% ± 4.6% (mITT-LOCF) and –6.1% ± 4.7% (observed cases) at week 12 and –5.3% ± 6.5% (mITT-LOCF) and –9.2% ± 6.2% (observed cases) at week 24 (P < .001 vs baseline for all). By week 24, 95% of patients (mITT-LOCF) were responders (CGI-I score ≤ 2) and 70% were in remission (CGI-I score = 1). The safety/tolerability profile of NB32 was consistent with its individual components; the most common adverse events were nausea, constipation, headache, and insomnia, with no serious adverse events attributed to NB32.Conclusion: Twenty-four weeks of open-label NB32 therapy with dietary and behavioral counseling was associated with improvement in depressive symptoms and reduced body weight in overweight/obese women with MDD.Trial Registration: ClinicalTrials.gov Identifier: NCT00624858

A Retrospective Assessment of the Use of Naltrexone Implants for the Treatment of Problematic Amphetamine Use

At present there is no registered effective pharmacotherapy for the treatment of problematic amphetamine use. This study aims to examine self-reported abstinence from amphetamines following treatment with a sustained release naltrexone preparation in patients with self and clinically identified problems with amphetamine use and the relationship between naltrexone blood levels and abstinence from amphetamines. Forty-four patients with problematic amphetamine use, who were treated with a naltrexone implant, completed an interview evaluating self-reported reduction in amphetamine use following treatment. Additional data were collected from the patients' clinical treatment files. Of the 44 subjects, 29 (65.9%) interviewed reported that following treatment they ceased using and maintained abstinence from amphetamines for at least 1 month. Of these patients, 14 (48.3%) were reportedly still abstinent at 6 months. Rates of abstinence were found to be 2.27 times higher (95% CI 1.38-3.74) in patients when blood naltrexone levels were above 2 ng/ml, with rates as high as 100% and 90.9% for ≥5 and ≥2 ng/ml, respectively, compared with 42.9% for 1-2 ng/ml and 38.9% low less than 1 ng/ml. Although this study has several limitations, the findings provide preliminary data in support of the use of implant naltrexone for the treatment of problematic amphetamine use and suggest that naltrexone levels above 2 ng/ml should be targeted for use in patients. Data supports the use of implant naltrexone, as a treatment for problematic amphetamine use, for which there is currently no registered pharmacotherapy. However, further research is required.