Sustained-Release Naltrexone For Opioid Dependence

 

Abstract

Background

Naltrexone is an opioid antagonist which effectively blocks heroin effects. Since opioid dependence treatment with naltrexone tablets suffers from high dropout rates, several depot injections and implants are under investigation. Sustained-release formulations are claimed to be effective, but a systematic review of the literature is lacking.

Objectives

To evaluate the effectiveness of sustained-release naltrexone for opioid dependence and its adverse effects in different study populations.

Search methods

The following databases were searched from their inception to November 2007: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, LILACS, PsycINFO, ISI Web of Science, trial database at http://clinicaltrials.gov, available NIDA monographs, CPDD and AAAP conference proceedings. The reference lists of identified studies, published reviews and relevant web sides were searched manually. Study authors and drug companies were contacted to obtain any unpublished material or missing data.

Selection criteria

To evaluate effectiveness only RCTs were included. To evaluate safety, any clinical trial reporting adverse effects was assessed. Treatment condition was extended to include alcohol dependent subjects and healthy volunteers.

Data collection and analysis

Reviewers independently evaluated the reports, rated methodological quality and extracted data. Analyses were performed separately for opioid dependent, alcohol dependent and healthy participants.

Main results

Foe effectiveness, one report met inclusion criteria. Two dosages of naltrexone depot injections (192 and 384 mg) were compared to placebo. High-dose significantly increased days in treatment compared to placebo (WMD 21.00, 95% CI 10.68 to 31.32, p<0.0001). High-dose compared to low-dose significantly increased days in treatment (WMD 12.00, 95% CI 1.69 to 22.31, p=0.02). Number of patients retained in treatment did not show significant differences between groups.

For adverse effects, seventeen reports met inclusion criteria analyses, six were RCTs. Side effects were significantly more frequent in naltrexone depot groups compared to placebo. In alcohol dependent samples only, adverse effects appeared to be significantly more frequent in the low-dose naltrexone depot groups compared to placebo (RR 1.18, 95% CI 1.02 to 1.36, p=0.02). In the opioid dependent sample, group differences were not statistically significant. Reports on systematic assessment of side effects and adverse events were scarce.

Authors' conclusions

There is insufficient evidence to evaluate the effectiveness of sustained-release naltrexone for treatment of opioid dependence.
For naltrexone injections, administration site-related adverse effects appear to be frequent, but of moderate intensity and time limited. For a harm-benefit evaluation of naltrexone implants, more data on side effects and adverse events are needed.

 

Plain language summary

People with opioid dependence require substantial therapeutic effort to keep them drug free. Their use of illicit opioids can be reduced and retention in treatment improved with supervised agonist replacement therapy with

methadone, which is a highly addictive drug. Naltrexone is a long-acting, opioid-antagonist that blocks heroin effects. It is used to prevent relapse of both opioid and alcohol dependence. Highly motivated people do best with
naltrexone. Most opioid users are sceptical about treatment with naltrexone tablets and many drop out early on. Dropouts can be reduced with supervised tablet taking, offering incentives and using sustained-release naltrexone
such as subcutaneous implants or depot injections.
There is insufficient evidence from randomised controlled trials to evaluate the effectiveness of sustained-release naltrexone. In the one controlled study that met inclusion criteria, 60 outpatients were randomised to one of three groups that received two sequential depot injections of naltrexone (192 or 384 mg) or placebo injections. The mean dropout time was 48 days with high dose naltrexone compared with 27 days on placebo; an increase in
treatment of 21 days (range 11 to 31 days). The lower depot dose gave a lesser benefit. The number retained in treatment at eight weeks did not show a clear difference and ranged from a mean of 68% to 39% of participants in
the different groups. 'Wanting heroin' did not differ on naltrexone but 'needing heroin' scored significantly lower with depot naltrexone compared to placebo. The most prominent adverse effects were general symptoms of
fatigue and pain at the injection site. Seventeen reports met inclusion criteria for assessing adverse effects. Seven looked specifically at naltrexone implants for treatment of opioid dependence and wound infection, allergic reaction to the implant and number of implants removed. The majority of the trials did not have a control group and systematic assessment of adverse effects was lacking.

 

摘要

背景

持續釋出劑型naltrexone治療鴉片依賴

Naltrexone是一能有效阻斷海洛因效力之鴉片拮抗劑，由於之前以naltrexone錠劑治療鴉片依賴的中斷率頗高，幾個深部肌肉注射與植入物研究進行中，持續釋出劑型naltrexone宣稱有效，但此類文章的系統性回顧闕如。

目標

評估釋出劑型naltrexone於治療鴉片依賴之不同研究群體的療效與不良反應。

搜尋策略

我們搜尋以下資料庫自2007年11月起：考科藍臨床試驗註冊中心，MEDLINE, EMBASE, CINAHL, LILACS, PsycINFO,科學ISI網絡、試驗資料庫 http://clinicaltrials.gov, NIDA專題文章, CPDD和AAAP研討會會刊。手工搜尋納入研究的參考目錄、刊登的評論及相關的網站。接觸研究作者和藥物公司，以獲得任何未刊登的資料或未呈現的資料。

選擇標準

為了評估療效，僅納入RCT的研究。包括評估安全性，任何臨床試驗之不良反應通報都被評估。治療狀況包括酒精依賴和健康自願者。

資料收集與分析

審閱者獨立評估報告，就方法學品質分級和選取數據，針對鴉片依賴、酒精依賴與健康參與者分別完成分析。

主要結論

針對療效觀之，僅ㄧ個報告符合收錄標準，兩種劑量naltrexone深部肌肉注射(192和384 mg)與安慰劑相較，高劑量較安慰劑明顯增加治療天數(WMD 21.00, 95% CI 10.68至31.32, p<0.0001)，高劑量相較低劑量明顯增加治療天數(WMD 12.00, 95% CI 1.69至22.31, p = 0.02)，兩組間持續接受治療患者數未顯示差異。針對不良反應，17個報告符合分析標準，6個是RCTs，naltrexone深部肌肉注射組的副作用明顯較安慰劑高，僅取樣酒癮者，低劑量naltrexone深部肌肉注射組的副作用明顯較安慰劑常見(RR 1.18, 95% CI 1.02 to 1.36, p = 0.02)；取樣酒癮者，組間差異並不明顯。缺少系統性評估副作用與不良反應事件的報告。

作者結論

評估以持續釋出劑型naltrexone治療鴉片成癮治療效益的證據不足，注射naltrexone部位經常出現不良反應，且受中度強度與時間限制，naltrexone植入物的優缺點評估，需要更多的副作用與不良反應事件相關資料。

翻譯人

本摘要由高雄榮民總醫院毛志民翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

鴉片成癮者需要實際的療效以確保不受藥癮所累，減少非法使用鴉片，固定用極易上癮的美沙冬(methadone)致效劑替代療法，在監控下接受治療。Naltrexone是能能阻斷海洛因(heroin)效果之長效鴉片拮抗劑，可預防鴉片成癮者及酒癮者再次上癮，是非常積極戒癮者的最佳選擇，大多數鴉片使用者懷疑naltrexone錠的治療效果，許多人更在治療早期便退出，在監控下服用、提供獎勵和使用如皮下植入物、深部肌肉注射等naltrexone持續釋出劑型皆可減少退出的狀況，由隨機控制試驗評估naltrexone持續釋出劑型效果的證據不足，在ㄧ個符合收錄標準的控制試驗中，60位門診患者隨機分成深部注射naltrexone (192或384 mg)或安慰劑三個組，平均退出時間是48天，安慰劑是27天，增加了21天的治療時間(範圍11至31天)。低劑量投與的效果較差，固定接受治療在第週與各組並沒有明確的差異，naltrexone組與安慰劑相較，並沒有改變對「海洛因的渴望」，但對「需要海洛因」的分數則明顯較低。最顯見的不良反應是ㄧ般的疲勞症狀和注射部位疼痛。17個報告符合評估不良反應的標準，7個針對naltrexone植入物治療鴉片成癮，可見到對植入物傷口感染、過敏反應和植入物移除數目。大多數的試驗沒有控制組及缺少不良反應系統性評估。