Sustained-release naltrexone: novel treatment for opioid dependence

The devastating costs of opioid abuse and dependence underscore the need for effective treatments for these disorders. At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is the only one that possesses no opioid agonist effects. Instead, naltrexone occupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence.     

Sustained-release naltrexone: novel treatment for opioid dependence

The devastating costs of opioid abuse and dependence underscore theneed for effective treatments for these disorders. At present, several different maintenance medications exist for treating opioid dependence, including methadone, buprenorphine and naltrexone. Of these, naltrexone is theonly one that possesses no opioid agonist effects. Instead, naltrexoneoccupies opioid receptors and prevents or reverses the effects produced by opioid agonists. Despite its clear pharmacologic effectiveness, its clinical effectiveness in treating opioid dependence has been disappointing, primarily due to non-compliance with taking the medication. However, the recent availability of sustained-release formulations of naltrexone has renewed interest in this medication. The present paper describes the development of sustained-release naltrexone formulations and discusses the clinical issues associated with their use in treating opioid dependence.     

Initiating acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence

ObjectivesThis trial compared the efficacy of acamprosate, started at the beginning of detoxification, to acamprosate started at the completion of detoxification, in the treatment of alcohol dependence.MethodsThis biphasic clinical trial consisted of a randomized, double-blind, placebo-controlled Detoxification Phase (DP), followed by a 10-week open-label Rehabilitation Phase (RP). Forty alcohol dependent patients were randomly assigned to receive either 1998 mg of acamprosate daily, or matching placebo, during the DP (5–14 days). After completing detoxification, all patients received open label acamprosate (1998 mg daily) in the RP. Outcome measures during the DP included: treatment retention, alcohol withdrawal, alcohol consumption, and oxazepam used. Outcome measures during the RP included: treatment retention and alcohol consumption.ResultsThere were no significant outcome differences between acamprosate and placebo-treated patients during the DP. Patients given acamprosate, compared to placebo, during the DP drank more alcohol in the RP.ConclusionsStarting acamprosate at the beginning of detoxification did not improve DP outcomes. Starting acamprosate after detoxification was completed was associated with better drinking outcomes during subsequent alcohol rehabilitation treatment.     

A randomised, controlled trial of low dose naltrexone for the treatment of opioid dependence

AIM: To investigate the efficacy of low doses of naltrexone in relapse prevention for heroin dependence. DESIGN: Double blind, randomised comparison of three groups-Group 1 taking 50mg per day, Group 2: 0.5mg per day, and Group 3: 0.05 mg per day. PARTICIPANTS: Sixty-six dependent heroin users. INTERVENTIONS: After detoxification followed by 1 week on 50mg per day naltrexone, participants were randomised to trial medication. All were offered counselling and monitored with weekly clinical reviews. Research interviews were conducted at three and 6 months. OUTCOME MEASURES: Retention in treatment and heroin use at 3 and 6 months. Secondary outcome measures were side effects and craving. FINDINGS: Mean days retained in randomised treatment were-Group 1: 58.9 days; Group 2: 46.6 days; and Group 3: 47.8 days. Differences in retention were not significant using survival analysis. However, nine of the first 60 participants, transferred to the 50 mg dose, and one transferred to a lower dose (chi-square = 0.142; P = 0.018). At follow-up, there was no relationship between abstinence from heroin and naltrexone dose, nor between level of heroin use and dose. There were no differences between groups in craving or depression. CONCLUSION: Low doses of naltrexone had no discernible advantage, and participants preferred 50mg per day. Despite preference for blocking doses of naltrexone, outcomes appeared to be independent of naltrexone dose.     

A systematic review of the effectiveness of naltrexone in the maintenance treatment of opioid and alcohol dependence.

This systematic review summarises evidence of the effectiveness of naltrexone (NTX) and the added value of psychosocial treatment in the maintenance treatment of opioid and alcohol dependence. Studies were selected through a literature search conducted in March 2004. Seven opioid and seventeen alcohol studies were identified. When possible, meta-(regression) analyses were performed. There is lack of evidence about the effectiveness of NTX in the maintenance treatment of opioid dependence. There is evidence for the effectiveness and applicability of NTX in the management of alcohol dependence. The opioid studies combined NTX with a variety of psychosocial interventions, which plagued the evaluation of their value. Concomitant psychosocial interventions used in the alcohol studies were mainly cognitive behavioural, which seems to be more effective than NTX combined with supportive therapy. Available data do not allow firm conclusions regarding the added effect of psychosocial interventions. However, the data suggest that a combination of naltrexone with cognitive behavioural relapse prevention therapy is beneficial in alcohol dependent patients.     

Depot naltrexone decreases rewarding properties of sugar in patients with opioid dependence

Background  

Opioid neurotransmission mediates hedonic value of sweet tastants; their intake may be exaggerated by the consumption of exogenous opioids (e.g., opioid dependence). Sweet Taste Test (STT) is a validated quantitative instrument assessing taste perception and hedonic features of sugar (sucrose) using a randomized and double-blind administration at five different sucrose concentrations ranging from 0.05 to 0.83 M.     

Contingency management to enhance naltrexone treatment of opioid dependence: a randomized clinical trial of reinforcement magnitude

Fifty-five detoxified opioid-dependent individuals were randomly assigned to 1 of 3 treatments delivered over 12 weeks: standard naltrexone maintenance, standard naltrexone plus low-value contingency management (CM), or standard naltrexone plus high-value CM. Results suggest that (a) assignment to either CM condition was associated with significant reductions in opioid use over time compared with standard naltrexone treatment; (b) contrasts of high- versus low-value reinforcement magnitude were not significant, suggesting no relative benefit of higher over lower value incentives in this population; (c) participants assigned to either CM group reported significant reductions in readiness to change compared with participants assigned to standard naltrexone treatment. These findings suggest that targeted behavioral therapies can play a substantial role in broadening the utility of available pharmacotherapies.     

Buprenorphine in the treatment of opioid dependence.

Buprenorphine has become of increasing interest to be an alternative to methadone in the treatment of heroin addicts. The aim of the paper is to review, from a clinical perspective, the current status of what is known about the pharmacology of buprenorphine, with a particular emphasis on the issues of maintenance therapy in heroin addiction. A systematic review of published follow-up data, from observational and experimental studies was done. Electronic databases Medline and PSYNDEXplus were searched from their earliest entries. Buprenorphine appears to be a well-tolerated drug, with a benign overall side effect. Buprenorphine is an additional treatment option for heroin dependent patients, especially for those who do not wish to start or continue with methadone or for those who do not seem to benefit from adequate dosages of methadone.     

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.     

低剂量纳曲酮治疗实验性自身反应性脑脊髓炎的初步研究

目的通过诱导小鼠实验性自身反应性脑脊髓炎(EAE)模型,观察应用低剂量纳曲酮(LDN)干预对EAE发病及炎症反应的影响,从而探究LDN是否对EAE小鼠具有保护作用。方法选取30只C57小鼠,随机分为3组,即EAE+LDN组、EAE+PBS组及健康对照组,其中,EAE+LDN组在诱导EAE模型后给予0.2 m L的LDN(0.1 mg/kg)腹腔注射,EAE+PBS组在诱导EAE模型后给予等量的PBS腹腔注射,健康对照组为未诱导EAE组。观察各组动物发病情况,每日监测小鼠体重变化,对小鼠进行行为学评分,苏木精-伊红(HE)染色法观察各组小鼠脑组织炎性细胞浸润情况,酶联免疫(ELISA)法监测血清中促炎性细胞因子水平变化。结果 LDN能有效延迟EAE小鼠的发病时间,并显著缓解发病过程中的体重下降及神经功能障碍;HE染色可见LDN干预能有效减轻EAE小鼠脑组织中的炎症反应,并能降低血清中促炎性细胞因子IFN-γ、IL-12、IL-17水平。结论 LDN能显著缓解EAE模型的发病,并减轻EAE发病过程中的炎性反应。     

Extended-release naltrexone for treatment of alcohol dependence in primary care

The feasibility of using extended-release injectable naltrexone (XR-NTX) to treat alcohol dependence in routine primary care settings is unknown. An open-label, observational cohort study evaluated 3-month treatment retention, patient satisfaction, and alcohol use among alcohol-dependent patients in two urban public hospital medical clinics. Adults seeking treatment were offered monthly medical management (MM) and three XR-NTX injections (380 mg, intramuscular). Physician-delivered MM emphasized alcohol abstinence, medication effects, and accessing mutual help and counseling resources. Seventy-two alcohol-dependent patients were enrolled; 90% (65 of 72) of eligible subjects received the first XR-NTX injection; 75% (49 of 65) initiating treatment received the second XR-NTX injection; 62% (40 of 65), the third. Among the 56% (n = 40) receiving three injections, median drinks per day decreased from 4.1 (95% confidence interval = 2.9–6) at baseline to 0.5 (0–1.7) during Month 3. Extended-release naltrexone delivered in a primary care MM model appears a feasible and acceptable treatment for alcohol dependence.     

注射用纳曲酮微球预防阿片类药物依赖复吸的临床研究

目的：评估注射纳曲酮微球预防阿片类药物依赖复吸的疗效和安全性。方法：筛选符合海洛因依赖且无其他躯体疾病,年龄18~45岁,至少有3次复吸史,自愿接受戒毒治疗的患者24例。随机纳入研究组及对照组,研究组注射纳曲酮微球,对照组服用盐酸纳曲酮片;疗程均为20周,停药后随访4周。在第0、2、4、8、12、16、20、24周时观察疗效和安全性。结果：研究组和对照组各纳入12名海洛因依赖患者,1名患者未参加随访,2名患者中途退出,共有21名患者（研究组11人,对照组10人）顺利完成实验。自给药后4~24周,研究组尿检阴性率均高于对照组,其差异在接受治疗后8周时有统计学意义（P =0.035）。研究组5人（45.5%）及对照组中2人（20.0%）完成全部访视。研究组与对照组的平均脱落时间分别为18.55周与11.40周,差异有统计学意义（P=0.033）。自用药后4周,研究组用药1 h后渴求评分均低于对照组,在访视5（用药后4周）和访视7（用药后12周）时有显著性差异（P=0.028;P=0.042）。在整个研究过程中,没有出现严重的治疗相关不良事件。结论：与口服纳曲酮片相比,注射用纳曲酮微球能降低患者复吸风险,减轻患者戒毒期间对毒品的渴求程度,提高患者服药依从性,增加其自愿接受治疗的时间,无不良事件发生风险,可以考虑作为海洛因依赖防复吸治疗的有效手段。     

Extended-release naltrexone for alcohol and opioid dependence: A meta-analysis of healthcare utilization studies

Through improved adherence, once-monthly injectable extended-release naltrexone (XR-NTX) may provide an advantage over other oral agents approved for alcohol and opioid dependence treatment. The objective of this study was to evaluate cost and utilization outcomes between XR-NTX and other pharmacotherapies for treatment of alcohol and opioid dependence. Published studies were identified through comprehensive search of two electronic databases. Studies were included if they compared XR-NTX to other approved medicines and reported economic and healthcare utilization outcomes in patients with opioid or alcohol dependence. We identified five observational studies comparing 1,565 patients using XR-NTX to other therapies over 6 months. Alcohol dependent XR-NTX patients had longer medication refill persistence versus acamprosate and oral naltrexone. Healthcare utilization and costs was generally lower or as low for XR-NTX-treated patients relative to other alcohol dependence agents. Opioid dependent XR-NTX patients had lower inpatient substance abuse-related utilization versus other agents and $8170 lower total cost versus methadone.     

纳曲酮治疗男同性恋甲基苯丙胺依赖患者的效果

目的:探讨纳曲酮治疗男同性恋甲基苯丙胺依赖患者的效果。方法:2013年8月-2018年6月北京高新医獉獉獉獉院戒毒医疗科50例男同性恋甲基苯丙胺依赖患者作为研究对象,用盐酸纳曲酮(50 mg·d-1)进行治疗。治疗第4、8、12周时检测甲基苯丙胺尿检阳性率;评价性风险行为(自我报告过去4周内情况),包括男伴数量、使用冰毒男伴数量和无套肛交次数等;采用依赖严重程度量表(Severity of Dependence Scale,SDS)和视觉模拟量表(Visual Analog Scale,VAS)评价甲基苯丙胺依赖程度;用汉密尔顿抑郁量表(24-item Hamilton Depression Rating Scale for Depression,HAMD-24)评价抑郁情绪的严重程度。结果:基线时甲基苯丙胺尿检阳性率为100%,治疗第4周为獉獉86. 96%(40/46)、第8周为72. 50%(29/40)、第12周为61. 54%(24/39)。与基线时比较,第12周时患者的尿检阳性率明显下降,差异有统计学意义(P <0. 05)。治疗后患者的男伴数量、使用冰毒的男伴数量和无套肛交次数均逐渐减少,与基线时比较,第4周时、第8周、第12周患者的上述三种性风险行为均明显下降,差异有统计学意义(P<0. 05)。治疗后患者SDS量表、VAS量表和HAMD-24量表评分均明显改善,与基线时比较,治疗第12周时SDS量表、VAS量表和HAMD-24量表评分明显降低,差异有统计学意义(P <0. 05)。结论:纳曲酮可减少男性同性恋獉獉患者对甲基苯丙胺使用,进而改善性风险行为。     

Plasma naltrexone during opioid detoxification

Orogastric naltrexone is used for opioid detoxification, but it is not known how gastric absorption affects plasma concentrations of the drug. We measured plasma naltrexone during orogastric naltrexone, given in repeated doses of 12.5 mg, 25 mg, 50 mg and 50 mg. Plasma naltrexone was measured after each naltrexone dose. The increase in plasma naltrexone was highly variable between patients during orogastric administration. Adequate detoxification was questioned in 4 of 10 patients because plasma naltrexone did not increase above 5 ng/ml. There was a negative correlation between plasma naltrexone and the presence of withdrawal symptoms on the day after the procedure (r = -0.78, P < 0.05). These results show that the increase in plasma naltrexone is variable during orogastric administration and this may impair successful detoxification.     

Naltrexone and buprenorphine combination in the treatment of opioid dependence

Naltrexone treatment has demonstrated some advantages for special populations of heroin addicted individuals, but patients' compliance seems to be very poor, with a low adherence and low retention rate. Kappa-opioid system overdrive seems to contribute to opioid protracted abstinence syndrome, with dysphoria and psychosomatic symptoms during naltrexone treatment. The objective of this observational study was to determine the effectiveness of a functional k antagonist in improving naltrexone treatment outcome. A partial mu agonist/kappa antagonist (buprenorphine) and a mu antagonist (naltrexone) were combined during a 12 weeks protocol, theoretically leaving k antagonism as the major medication effect. Sixty patients were submitted to outpatient rapid detoxification utilizing buprenorphine and opioid antagonists. Starting on the fifth day, 30 patients (group A) received naltrexone alone. Alternatively, 30 patients (group B) received naltrexone (50mg oral dose) plus buprenorphine (4 mg sublingual) for the 12 weeks of the observational study. The endpoints of the study were: retention in treatment, negative urinalyses, changes in psychological symptoms (Symptom Checklist-90 Revised: SCL-90) and craving scores (visual analysis scale (VAS)). Thirty-four subjects (56.67%) completed the 12 weeks study. Twenty-one patients (35.0%) had all urine samples negative for opiates and cocaine. nine subjects (15.0%) had urine samples negative for cocaine and opiates for the last 4 weeks of the study. five subjects (8.3%) continued to use cocaine during the 12 weeks of the study. No significant change in pupillary diameter after buprenorphine administration was evidenced during clinical observations from baseline across the weekly measurements. Retention rates in group A (naltrexone) and group B (naltrexone + buprenorphine) at week 12 were respectively 40% (12 patients) and 73.33% (22 patients), with a significant difference in favour of group B (p= 0.018). Patients treated with naltrexone in combination with buprenorphine (B patients) showed a significantly lower rate of positive urines for morphine (4.45%) and cocaine metabolites (9.09%) than those treated with naltrexone alone (A) (25%, morphine; 33.33% cocaine) (p< 0.05; p< 0.05). Irritability, depression, tiredness, psychosomatic symptoms and craving scores decreased significantly less in Group A patients than in group B patients. The dysfunction of opioid system with kappa receptors hyper-activation provoked by heroin exposure, probably underlying dysphoric and psychosomatic symptoms during naltrexone treatment, seems to be counteracted, at least in part, by buprenorphine. The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving.