Opioid antagonists for smoking cessation

  • Conclusions changed
  • Review
  • Intervention

Authors


Abstract

Background

The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking.

Objectives

To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone.

Search methods

We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies.

Selection criteria

We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence.

Data collection and analysis

We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel-Haenszel fixed-effect model.

Main results

Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes.

Authors' conclusions

Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources.

摘要

背景

使用類鴉片拮抗劑(Opioid antagonists)戒菸

尼古丁增強的特性可能藉由在中樞神經系統及全身釋放各種傳經傳導物質,吸菸者會出現正向增強作用,如愉悅、警醒及放鬆,也有負向減免作用,如減少負面的情緒、緊張及焦慮。類鴉片拮抗劑讓人特別感到興趣的是有潛力減少吸菸的報償反應的藥劑。

目標

目標為評估類鴉片拮抗劑增強長期戒菸的效用。這些藥物包括naloxone和長效類鴉片拮抗劑naltrexone。

搜尋策略

我們在2006年3月搜尋了Cochrane Tobacco Addiction Group specialized register關於naloxone、naltrexone 及其他類鴉片拮抗劑的試驗,且在MEDLINE使用Narcotic antagonists及smoking專有名詞搜尋相關的研究。我們也盡可能的接洽未發表研究的研究者。

選擇標準

我們選擇的是隨機對照試驗比較類鴉片拮抗劑跟安慰劑或其他的治療方式於戒菸的效果。我們納入統合分析(metaanalysis)中的研究至少是要有戒除六個月以上的資料才採用。為了敘述的目的,我們也對於以實驗室為主,評估類鴉片拮抗劑對於與尼古丁依賴相關的心理生理變項的短期試驗進行回顧。

資料收集與分析

我們擷取相關的資料包括研究人口的特質、藥物治療的本質、結果的測量、隨機的方法、和後續追蹤的完成狀況。主要的預後指標是使用cotinine或是carbon monoxide檢測證實從基準點至少已經戒菸六個月. 適合的話還會使用固定效應模式(fixedeffect model)來進行統合分析。

主要結論

四個有關Naltrexone的試驗符合納入進行有關常時期戒菸的統合分析的標準。四個試驗都無法證實naltrexone與安慰劑在戒菸率上有何不同,在彙集分析(pooled analysis)中,naltrexone對於長期戒菸也沒有出現顯著的效果,而且信賴區間很寬(odds ratio 1.26, 95% confidence interval 0.80 to 2.01) 。有關naloxone或是buprenorphine的研究,沒有一個有做長期追蹤的。

作者結論

由於從四個試驗只能得到有限的資料,並無法確定或否定naltrexone是否能協助戒菸。其信賴區間是介於臨床有顯著差異及可能無促進戒菸效果,進行更大型的naltrexone研究是需要的,才能回答是否能有效戒菸。

翻譯人

本摘要由彰化基督教醫院許文郁翻譯。

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

總結

現在並無充足的證據顯示類鴉片拮抗劑,如naltrexone,長期戒菸的效果如何。尼古丁替代療法及特定抗憂鬱劑可以協助戒菸。然而,他們的效用很小,因為尼古丁依賴涉及許多因素,包括學習行為社會環境和各種藥物的影響。Naltrexone是一種長效藥物,可以弱化麻醉藥效果如海洛因和嗎啡(類鴉片拮抗劑),並可能藉由阻斷一些吸菸報償反應,來協助處理尼古丁依賴。我們的回顧發現沒有足夠的證據(四個試驗共582位吸菸者)顯示類鴉片拮抗劑,如naltrexone能戒菸。一些類鴉片拮抗劑(如naltrexone和naloxone;十三個試驗共455位吸菸者)在戒斷症狀及吸菸的愉悅效果並不清楚。

Résumé scientifique

Les antagonistes des opiacés pour le sevrage tabagique

Contexte

Les propriétés de renforcement de la nicotine peuvent être induites par la libération de différents neurotransmetteurs à la fois au niveau central et systémique. Les personnes qui fument signalent des effets positifs, tels que le plaisir, l'excitation et la détente, ainsi qu'un soulagement de l'affect négatif, de la tension et de l'anxiété. Les antagonistes des opiacés (narcotiques) intéressent particulièrement les chercheurs en tant qu'agents potentiels pour atténuer les effets de renforcement de la cigarette.

Objectifs

Évaluer l'efficacité des antagonistes des opiacés afin de promouvoir le sevrage tabagique à long terme. Les médicaments comprennent la naloxone et la naltréxone, un antagoniste des opiacés à action plus prolongée.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre Cochrane des essais contrôlés (CENTRAL) afin de trouver des essais portant sur la naloxone, la naltréxone et d'autres antagonistes des opiacés, et avons réalisé une recherche supplémentaire dans MEDLINE en utilisant les termes « Narcotic antagonists » et smoking en juin 2009. Lorsque cela était possible, nous avons également contacté des chercheurs afin d'obtenir des informations sur les études non publiées.

Critères de sélection

Nous avons pris en compte les essais contrôlés randomisés comparant des antagonistes des opiacés à un placebo ou à un autre traitement de référence pour le sevrage tabagique. Nous n'avons inclus dans la méta-analyse que les essais qui fournissaient des données concernant l'abstinence sur une période minimale de six mois. Nous avons également examiné, à des fins descriptives, les résultats d'études de laboratoire à court terme sur les antagonistes des opiacés conçues pour évaluer les variables psychobiologiques associées au tabagisme.

Recueil et analyse des données

Nous avons extrait les données présentes en double sur le type de population d'étude, la nature du traitement médicamenteux, les mesures des critères de jugement, la méthode de randomisation et la réalisation du suivi. La principale mesure de critère de jugement était l'abstinence tabagique, vérifiée à la cotinine ou au monoxyde de carbone, après au moins six mois de suivi chez des patients fumeurs au départ. Lorsque c'était approprié, nous avons effectué une méta-analyse au moyen d'un modèle à effets fixes (rapports de cotes de Mantel-Haenszel).

Résultats principaux

Quatre essais portant sur la naltréxone ont répondu aux critères d'inclusion pour les méta-analyses du sevrage à long terme. Les quatre essais n'ont pas détecté de différence significative du taux de sevrage entre la naltréxone et un placebo. Dans une analyse combinée, aucun effet significatif de la naltréxone sur l'abstinence à long terme n'a été observé et les intervalles de confiance étaient larges (rapport de cotes 1,26, intervalle de confiance à 95 % 0,80 à 2,01). Aucun essai portant sur la naloxone ou la buprénorphine n'a indiqué de suivi à long terme.

Conclusions des auteurs

Les données limitées issues de quatre essais ne permettent pas de confirmer ou de réfuter le fait que la naltréxone aide les personnes qui fument à se sevrer. Les intervalles de confiance sont compatibles à la fois avec un bénéfice cliniquement significatif et de possibles effets négatifs de la naltréxone pour promouvoir l'abstinence. Des données d'essais de plus grande taille sur la naltréxone sont nécessaires pour régler la question de son efficacité pour le sevrage tabagique.

Plain language summary

Do opioid antagonists such as naltrexone help people to stop smoking?

Opioid antagonists are a type of drug which blunts the effects of narcotics such as heroin and morphine, and might help reduce nicotine addiction by blocking some of the rewarding effects of smoking. Our review identified eight trials of naltrexone, a long-acting opioid antagonist. The trials included over 1200 smokers. Half the trials gave everyone nicotine replacement therapy and tested whether naltrexone had any additional benefit. Compared to a placebo, naltrexone did not increase the proportion of people who had stopped smoking, at the end of treatment, or at six months or more after treatment, either on its own or added to NRT. The available evidence does not suggest that opioid antagonists such as naltrexone assist smoking cessation.

Résumé simplifié

Les antagonistes des opiacés, tels que la naltréxone, aident-ils à arrêter de fumer ?

Si la thérapie de substitution nicotinique et certains antidépresseurs aident à arrêter de fumer, leur effet global est faible, car la dépendance à la nicotine implique de nombreux facteurs, notamment le comportement acquis, le contexte social et les effets de différents médicaments. La naltréxone est un médicament à action prolongée (un antagoniste des opiacés) qui émousse les effets des narcotiques, tels que l'héroïne et la morphine et pourrait aider à réduire la dépendance à la nicotine en bloquant certains des effets de renforcement du tabagisme. Notre revue a découvert que les preuves étaient insuffisantes (avec quatre essais portant sur 582 fumeurs) pour montrer l'effet des antagonistes des opiacés, tels que la naltréxone, sur le sevrage tabagique. Les effets de certains antagonistes des opiacés (par ex. la naltréxone, la naloxone : 13 essais établis sur 455 fumeurs) portant sur les symptômes de sevrage et les effets agréables du tabagisme n'ont pas apporté de résultats significatifs.

Notes de traduction

Traduit par: French Cochrane Centre 29th August, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Laički sažetak

Pomažu li antagonisti opioida poput naltreksona ljudima u prestanku pušenja?

Antagonisti opioida su vrsta lijekova koji umanjuju učinke narkotika poput heroina i morfina, a mogli bi pomoći u smanjenju ovisnosti o nikotinu blokiranjem nekih od učinaka pušenja na sustav nagrađivanja u mozgu. Cochrane sustavni pregled pronašao je osam istraživanja s naltreksonom, dugodjelujućim antagonistom opioida. Istraživanja su uključivala više od 1200 pušača. U pola ovih istraživanja svima je davana zamjenska terapija nikotinom i ispitivala su je li naltrekson pokazao bilo kakvu dodatnu korist. U usporedbi s placebom, naltrekson nije povećao udio ljudi koji su prestali pušiti na kraju liječenja, ili nakon šest ili više mjeseci nakon tretmana, bilo samostalno ili pridodan zamjenskoj terapiji nikotinom. Dostupni dokazi ne ukazuju da antagonisti opioida kao što je naltrekson pomažu u prestanku pušenja.

Bilješke prijevoda

Cochrane Hrvatska
Prevela: Katarina Vučić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Streszczenie prostym językiem

Czy antagonisty opioidów, takie jak naltrekson, pomagają w rzucaniu palenia?

Antagonisty opioidów to grupa leków hamujących działanie narkotyków takich jak heroina i morfina. Być może przez blokowanie przyjemnych efektów palenia mogłyby one być pomocne w zmniejszaniu uzależnienia od nikotyny. Do tego przeglądu znaleźliśmy 8 badań z użyciem naltreksonu, antagonisty opioidów o przedłużonym działaniu. Badania obejmowały ponad 1200 palaczy. W połowie badań oceniano korzyści z dodania naltreksonu do nikotynowej terapii zastępczej stosowanej przez wszystkich uczestników badania. W porównaniu z placebo, naltrekson nie zwiększył liczby osób, które nie paliły zaraz po zakończeniu leczenia lub po upływie co najmniej 6 miesięcy - zarówno stosowany sam, jak i jako dodatek do nikotynowej terapii zastępczej. Dostępne dane nie wskazują zatem, aby antagonisty opioidów, takie jak naltrekson, wspomagały rzucanie palenia.

Uwagi do tłumaczenia

Tłum. Bartłomiej Matulewicz, red. Łukasz Strzeszyński

Ringkasan bahasa mudah

Adakah antagonis opioid seperti naltrexone membantu orang ramai untuk berhenti merokok?

Antagonis opioid adalah sejenis ubat yang melemahkan kesan narkotik seperti heroin dan morfin, dan mungkin membantu mengurangkan ketagihan nikotin dengan menyekat sebahagian daripada kesan ganjaran merokok Ulasan kami mengenal pasti lapan kajian naltrexone, sejenis antagonis opioid yang bertindak panjang. Kajian-kajian tersebut melibatkan lebih 1200 perokok. Separuh daripada kajian-kajian tersebut memberikan semua orang terapi penggantian nikotin dan menguji sama ada naltrexone mempunyai sebarang manfaat tambahan. Berbanding plasebo, naltrexone tidak meningkatkan kadar orang yang sudah berhenti merokok, di akhir rawatan, atau enam bulan atau lebih selepas rawatan, sama ada secara sendiri atau ditambah kepada NRT. Bukti sedia ada tidak mencadangkan bahawa antagonis opioid seperti naltrexone membantu berhenti merokok.

Catatan terjemahan

Diterjemahkan oleh Wong Chun Hoong (International Medical University). Disunting oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi Wong.ChunHoong@student.imu.edu.my

Background

Tobacco use is the leading cause of preventable death (USDHHS 2010). United States clinical practice guidelines recommend the use of approved cessation pharmacotherapy for quitting smoking (Fiore 2008). Evidence-backed medications delivering abstinence at six months or longer include nicotine replacement in the form of gum, patch, lozenge, inhaler, and nasal spray (risk ratio (RR) for any NRT 1.60, 95% confidence interval (CI) 1.53 to 1.68, Stead 2012); bupropion (RR 1.69; 95% CI 1.53 to 1.85, Hughes 2007); and varenicline (RR 2.27, 95% CI 2.02 to 2.55; Cahill 2012; Mills 2012; ). Effective second-line treatments include nortriptyline (RR 2.03; 95% CI 1.48 to 2.78, Hughes 2007) and clonidine (OR 1.89, 95% CI 1.30 to 2.74, Gourlay 2008;). However long-term quit rates are relatively modest, in the range of 19.0% to 36.5% (Fiore 2008). With relapse as the norm, there is continued interest in other pharmacological agents for assisting cessation.

Nicotine dependence involves a complex interplay of learned or conditioned behaviours, personality, social settings, and pharmacological factors. The reinforcing properties of nicotine are theorised to be mediated in part through release of various neurotransmitters throughout the brain. Acute exposure to nicotine activates nicotinic cholinergic receptors resulting in the release of neurotransmitters including dopamine, norepinephrine, acetylcholine, vasopressin, serotonin, glutamate, gamma-aminobutyric acid (GABA) and beta endorphin. It has been suggested that release of beta endorphin may be associated with reduction of anxiety and tension (Benowitz 1999). Nicotine also activates nicotinic cholinergic receptors in the adrenal medulla leading to the release of epinephrine (adrenaline) and beta endorphin, which may contribute to the systemic effects of nicotine. In one study, smoking a cigarette increased beta-endorphin levels 30 to 300%, which was significantly correlated with plasma nicotine levels (Pomerleau 1983). In addition to evidence suggesting a possible reinforcing role for the endogenous opioid system in smoking, findings from other studies suggest that this system might be involved with mediating nicotine withdrawal. Studies by Malin and colleagues indicate that the opioid antagonist naloxone precipitates nicotine withdrawal in nicotine-maintained rats, and nicotine-induced reversal of this withdrawal syndrome is antagonised by naloxone (Malin 1993; Malin 1996), and these and other studies have demonstrated that naloxone may actually precipitate physical and affective symptoms of nicotine withdrawal (Biala 2005; Isola 2002; Malin 1993; Malin 1996).

Opioid antagonists are typically used in the treatment of opioid dependence and alcohol dependence. The focus of this review and meta-analysis is on evaluations of opioid antagonists for the treatment of tobacco dependence. A secondary focus is the effect of opioid antagonists on psycho-biological mediating variables associated with nicotine dependence and smoking cessation.

Naloxone (Narcan; half-life 30-100 min; Goodrich 1990), a short-acting opioid antagonist, is routinely administered to reverse the acute effects of narcotic overdose. Evidence that naloxone and related drugs may block the reinforcing properties of nicotine and affect nicotine withdrawal has led to clinical trials of naloxone to determine its effects on smoking behaviour and withdrawal symptoms.

Naltrexone (Narpan™, Revia™, Vivitrol™, half-life 240 mins Meyer 1984), a long-acting opioid antagonist, is a marketed drug which blunts certain effects of narcotics such as heroin, meperidine, morphine and oxycodone. It has been shown to help in the treatment of alcohol dependence (O'Malley 1995; Volpicelli 1992). Naltrexone occupies the μ-opioid receptors, which putatively diminishes the activation of mesolimbic dopamine and therefore may reduce craving for nicotine. Thus it is believed that NRT and naltrexone could produce additive effects by reducing craving through different mechanisms of action. Naltrexone has also been studied for its utility to reduce post-smoking cessation weight gain; a recent Cochrane review showed a modest benefit of naltrexone on reduced post-cessation weight gain at end of treatment, but this did not persist for six months or longer (Farley 2012).

Buprenorphine (Buprenex™, Subutex™, Suboxone™, Butrans™, half-life 24 - 60 hrs; SAMHSA 2013), a mixed agonist-antagonist, has also been evaluated in two published studies of smoking (°Mello 1985; °Mutschler 2002).

Since opioid antagonists are known to precipitate nicotine withdrawal in nicotine-dependent animals, using them as an adjunct to NRT may have the additional benefit of attenuating the increased withdrawal, dysphoria and sedation caused by naloxone and naltrexone.

Serious adverse events are uncommon when these drugs are used in the treatment of alcohol dependence (CSAT 2009). The most common side effects have included nausea, vomiting, headache, dizziness, fatigue, nervousness, anxiety, and somnolence. Less common side effects include gastrointestinal distress, chest and joint/muscle pain, rash, difficulty sleeping, excessive thirst, loss of appetite, sweating, increased tears, mild depression, and delayed ejaculation. Side effects of buprenorphine are similar to those of other opioids and include nausea, vomiting, and constipation.

Objectives

The primary objective of the review was to evaluate the efficacy of opioid antagonists (including naltrexone, naloxone, buprenorphine), alone or in combination with nicotine replacement, in promoting smoking cessation.
The secondary objectives of the review were to evaluate the efficacy of opioid antagonists in treating withdrawal symptoms, attenuating the reinforcing value of smoking, and reducing ad libitum smoking. In the analysis, specific opioid antagonists were considered separately rather than grouping these medications as a class. For example, studies evaluating naltrexone were compared only to other studies evaluating naltrexone and not grouped with naloxone.

The main hypotheses were:
1. Opioid antagonists are more effective than placebo in promoting sustained abstinence from smoking.
2. Opioid antagonists used in combination with nicotine replacement therapy are more effective than either opioid antagonists or nicotine replacement therapy alone in promoting sustained abstinence from smoking.

Methods

Criteria for considering studies for this review

Types of studies

This review includes two tiers of evidence. We used randomised controlled trials (RCTs) of opioid antagonists that report smoking status at least six months after intervention to assess the efficacy for long-term cessation. We also considered RCTs of opioid antagonists with short-term follow-up that report the outcomes of withdrawal, reinforcing properties of smoking, or ad libitum smoking.

Types of participants

Adults who smoke.

Types of interventions

Naltrexone, naloxone, buprenorphine or other opioid antagonists, with or without concurrent nicotine replacement therapy.

Types of outcome measures

Abstinence at six months or longer was the primary outcome measure. Abstinence at end of treatment was a secondary outcome. We used a sustained cessation rate in preference to point prevalence, and biochemical verification of self-reported quitting where reported. We regarded people lost to follow-up as continuing smoking. We noted any adverse effects.
Other secondary outcome measures included withdrawal, reinforcing or hedonic effects of smoking, mood states, and ad libitum smoking.

Search methods for identification of studies

We searched the Cochrane Tobacco Addiction Group Specialised Register in April 2013 using the terms 'naloxone' or 'naltrexone' or ' opioid antagonist*' or 'opiate antagonist*' or 'narcotic antagonist*' in the title or abstract, or as key words (see Appendix 1 for details). At the time of the search the Register included the results of searches of the Cochrane Central Register of Controlled trials (CENTRAL), issue 3, 2013; MEDLINE (via OVID) to update 20130329; EMBASE (via OVID) to week 201313; PsycINFO (via OVID) to update 20130401. See the Tobacco Addiction Group Module in the Cochrane Library for full search strategies and list of other resources searched (CTAG Module). An additional search of MEDLINE (via OVID, to update 20130417) used the terms (explode "Narcotic-Antagonists"/ all subheadings) AND ("Smoking-Cessation"/ all subheadings OR "Tobacco-Use-Disorder"/ all subheadings OR "Smoking"/ all subheadings).

Data collection and analysis

Two authors checked the studies generated by the search strategy for relevance, according to the inclusion criteria. One author extracted data and a second author checked them. Discrepancies were resolved by mutual consent. If significant disagreement had arisen at either stage this would have been resolved with the participation of a third author, as required. We noted reasons for the non-inclusion of studies.

Data extraction and management

The following information about each trial is reported in the table 'Characteristics of Included Studies':

  • Country

  • Criteria for recruitment (whether current smokers only, or recent quitters) and whether selected according to willingness to make a quit attempt

  • Other relevant inclusion/exclusion criteria for trial

  • Method of randomisation, blinding, allocation concealment

  • Smoking behaviour and characteristics of participants

  • Adverse events

  • Support measures

  • Primary outcome measures - definition of long-term abstinence used in review, use of biochemical validation

  • Secondary outcomes - withdrawal symptoms, ad libitum smoking, hedonic effects

Assessment of risk of bias in included studies

We evaluated studies on the basis of the following items, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  • Random sequence generation (selection bias)

  • Allocation concealment (selection bias)

  • Blinding (performance bias and detection bias)

  • Incomplete outcome data (attrition bias)

Measures of treatment effect

For the abstinence outcomes we extracted the numbers reported quit at longest follow-up and at end of treatment using the strictest definition used in the study, i.e. preferring sustained over point prevalence rates, with biochemical validation where possible. We calculated risk ratios using as the denominators the numbers of patients randomised to each arm excluding any deaths and treating those who dropped out or were lost to follow-up as continuing to smoke. We noted any deaths and adverse events in the results tables. If necessary, we contacted authors for clarification of specific points.

Data synthesis

We combined the results of studies evaluating long-term cessation using the Mantel-Haenszel fixed-effect model for pooling risk ratios. Interventions including nicotine replacement therapy were grouped separately from those without. In previous versions of this review we used odds ratios to summarise effects, but the Cochrane Tobacco Addiction Group now recommends the use of risk ratios, as being less likely to be misinterpreted (Deeks 2011). Data on other outcomes were tabulated and described narratively. In a sensitivity analysis we estimated the effect at end of treatment of adding in the results from studies excluded due to lack of long-term follow up.

Results

Description of studies

Further details are presented in the Characteristics of included studies table.

Studies evaluating long-term abstinence

Naltrexone:

We identified eight trials evaluating naltrexone and reporting long-term abstinence data (six months or more).

Covey 1999 randomised 80 volunteers to either naltrexone or placebo daily for four weeks. All smokers began taking 25 mg naltrexone or placebo at least three days before the target quit date (TQD) and the dose was increased to 50 mg on the TQD. Medication was continued for four weeks and all subjects received individual counselling. The investigators reported continuous abstinence verified by saliva cotinine at three and six months.

Wong 1999 randomised 100 volunteers to receive 12 weeks of either placebo only, naltrexone only, placebo with nicotine patches, or naltrexone with nicotine patches. The naltrexone dose was 50 mg taken once daily, and the nicotine patch dose was 21 mg/24-hour for the first eight weeks and 14 mg/24-hour for the remaining four weeks. Treatment with naltrexone and/or the nicotine patches started on the TQD. The trial therefore contributed separate data to both the naltrexone versus placebo and the naltrexone plus NRT versus placebo plus NRT subgroups. All participants received brief (15 to 20 minutes) counselling sessions throughout the treatment phase. Brief behavioural intervention was provided at each visit. The outcomes used in the meta-analysis were continuous abstinence at end of treatment and six months This study was part of a multicentre, partially-blinded, 2 x 2 factorial design study of naltrexone (50 mg, active versus placebo) and nicotine patch (active versus no treatment). Three hundred and fifty subjects were enrolled at five centres in the United States. However, the authors could report only the data from the Mayo Clinic site which enrolled 100 people. We made several attempts to obtain unpublished data in order to include them for the other 250 participants, but the funder, Dupont, has not disclosed further results (Croop 2000).

King 2006 randomised 110 smokers to either naltrexone 50 mg/day or placebo for six weeks. Both groups received weekly smoking cessation counselling sessions. All participants received nicotine patch. Prolonged abstinence was assessed at eight and 24 weeks, verified by carbon monoxide (CO). Change in body weight, withdrawal symptoms, smoking urges and affect were also assessed.

O'Malley 2006 randomised 385 volunteers to four treatment conditions: placebo, 25 mg, 50 mg or 100 mg of naltrexone for six weeks. All participants also received 21 mg active nicotine patch throughout the study period, and brief weekly counselling sessions and self-help support. Abstinence, weight gain and adverse events were the main outcomes of interest. The published report gives outcomes at six weeks. CO-verified quit rates at six and 12 months were provided to us by the authors. The longer term outcome is used in the meta-analysis, combining 50 mg and 100 mg dose arms.

Baltieri 2009 randomised 155 alcohol-dependent individuals, of which 105 were smokers, to three treatment conditions: placebo, naltrexone 50 mg/day or topiramate up to 300 mg/day for 12 weeks after a one-week alcohol detoxification period. The authors provided unpublished six-month follow-up abstinence data without biochemical verification. The authors also reported changes in cigarettes/day, mood and alcoholic relapse.

Meszaros 2010 randomised 79 patients with schizophrenia or schizoaffective disorder and comorbid alcohol and nicotine dependence to naltrexone thrice weekly (100 mg twice, + 150 mg) or placebo for 12 weeks. The authors provided unpublished six-month follow-up abstinence data without biochemical verification. No effects on withdrawal or cigarette consumption were reported.

Toll 2010a randomised 172 treatment-seeking smokers and concerned about their weight to either naltrexone 25 mg a day or placebo for 27 weeks. Self-reported abstinence with CO verification was reported at six months after the quit date. In addition, changes in body weight, cigarettes smoked per day, withdrawal and craving were assessed.

King 2012 randomised 315 treatment-seeking smokers to either naltrexone 50 mg a day plus nicotine patch or placebo plus nicotine patch for 12 weeks. Both groups received weekly smoking cessation counselling sessions. Self-reported CO-validated abstinence was measured at 12 weeks, 6 months and 12 months. We have used the longer term outcome in the meta-analysis. In addition, change in body weight and self-reported ratings of smoking urges and depression symptoms were assessed.

Studies evaluating effects on other outcomes

The remaining included studies do not report long-term abstinence and are not included in the meta-analysis. However, they fall into our second eligible category of studies that cover withdrawal or craving, reinforcing or hedonic effects of smoking, mood states, and ad libitum smoking. Studies in this category have ° preceding the study identifier (e.g. °Boureau 1978). There was methodological heterogeneity in assessments of effects of opioid antagonists on these secondary outcomes. There were cue reactivity studies (elicited craving or withdrawal) and static (no smoking cue, unelicited craving or withdrawal) assessments of withdrawal or craving or smoking urges, and some trials combined treatment with nicotine replacement while others did not. For measures and methods with more than one trial to evaluate them, results were mixed and inconclusive.

Naltrexone:

Naltrexone was also evaluated for its effects on withdrawal syndrome, ad libitum smoking, and/or the reinforcing properties of smoking in 14 randomised, double-blind, placebo-controlled cross-over or within-subject designed studies in laboratory settings (°Brauer 1999; °Caskey 2001; °Epstein 2004; °Houtsmuller 1997; °Hutchison 1999; °King 2000; °Knott 2007; °Lee 2005; °Ray 2006; °Ray 2007; °Rohsenow 2007; °Rukstalis 2005; °Sutherland 1995; °Wewers 1998) and in eight non-laboratory-based randomised controlled trials (Covey 1999; King 2006; King 2012; °O'Malley 1998; O'Malley 2006; °Rohsenow 2003; Toll 2010a; Wong 1999).

Naloxone:

The studies of naloxone and buprenorphine were designed to evaluate effects on withdrawal syndrome, ad libitum smoking, and/or the reinforcing properties of smoking. Five studies of naloxone were small sample, placebo-controlled, cross-over or within-subject designed studies carried out in controlled laboratory environments (°Boureau 1978; °Gorelick 1988; °Karras 1980; °Krishnan-Sarin 1999; °Nemeth-Coslett 1986).

Buprenorphine:

The effect of buprenorphine on amount smoked was assessed in two studies. °Mello 1985 administered buprenorphine to seven heroin addicts, and °Mutschler 2002 randomised 23 opioid- and cocaine-dependent detoxification inpatients to 4 or 8 mg of buprenorphine for 12 days.

Risk of bias in included studies

Studies included in the meta-analysis were evaluated on their attempts to control bias in randomisation, allocation, assessment and analysis. None of the eight studies was judged to be at high risk for selection bias due to inadequate randomisation or allocation concealment procedures, but three (Baltieri 2009; Covey 1999; Meszaros 2010) did not report methods in sufficient detail for the possibility of allocation bias to be discounted. Two of these studies (Baltieri 2009; Meszaros 2010) have only been reported as abstracts with limited methodological detail. All studies were described as being double-blind. Six of the eight long-term cessation studies confirmed abstinence with biochemical verification, the exceptions being Baltieri 2009 and Meszaros 2010. King 2006, King 2012, O'Malley 2006, Toll 2010a and Wong 1999 reported exhaled carbon monoxide (CO) verification and did not report plasma or urine cotinine (although O'Malley 2006 tested serum cotinine at baseline). Covey 1999 reported plasma cotinine concentration. Covey 1999 was assessed as being at risk of bias from attrition because drop-out was high in both groups and occurred earlier in the naltrexone group. Ten people in the naltrexone and two in the placebo group dropped out prior to the target quit day, for reasons including drug-related side effects. We have included these people as treatment failures.

Effects of interventions

Studies evaluating long term abstinence

Eight published studies of opioid antagonists (Baltieri 2009; Covey 1999; King 2006; King 2012; Meszaros 2010; O'Malley 2006; Toll 2010a; Wong 1999) reported long-term abstinence data and are included in the primary outcome meta-analysis. All of these trials evaluated the efficacy of naltrexone for smoking cessation. We summarise the results of studies of opioid antagonists evaluating other outcomes (withdrawal symptoms, ad libitum smoking, hedonic effects) below as a review of extant data with potential utility for clinical practice pending further and more generalisable studies.

Naltrexone versus placebo without NRT

Five studies with a total of 450 participants in the relevant arms contributed to this subgroup of the meta-analysis. The pooled estimate did not detect a significant benefit for naltrexone over placebo (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.66 to 1.51 Analysis 1.1). All studies reported outcomes at six months. Two studies were included based on unpublished data without biochemical validation of abstinence (Baltieri 2009; Meszaros 2010). The pooled estimate was not sensitive to the exclusion of these studies.

Naltrexone versus placebo as an adjunct to NRT

Four studies with a total of 768 participants in the relevant arms contributed to this subgroup. We used the 100 mg and 50 mg arms from the O'Malley 2006 study.The pooled results from the relevant arms in these four studies did not give any indication of a treatment effect for naltrexone as an adjunct to the nicotine patch (RR 0.95; 95% CI 0.70 to 1.30). Including the 25 mg arm of the O'Malley 2006 study in the meta-analysis left the RR virtually unchanged.

There was no evidence of heterogeneity in subgroups with or without NRT. We also pooled both subgroups to estimate the effect of naltrexone irrespective of the use of NRT. The pooled estimate gave no evidence of a treatment effect (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants Figure 1; Analysis 1.1).

Figure 1.

Naltrexone versus placebo (single pharmacotherapy or adjunct to NRT), Abstinence at longest follow up.

Short-term outcomes of long-term studies

In the absence of any evidence of long-term effect, we did a secondary analysis using end-of-treatment outcomes (week 6 for Toll 2010a which provided 27 weeks of treatment). This supported the longer-term analysis, showing no evidence that there was any early treatment effect either, and with a slightly narrower confidence interval (RR 1.03; 95% CI 0.88 to 1.22, Analysis 1.2). Since three studies (Byars 2005; Krishnan-Sarin 2003; Toll 2010b) that reported only short-term outcomes had been excluded, we also did a sensitivity analysis including them in the short-term analysis. The additional 116 participants from these trials did not greatly alter the estimates (RR 1.09 95% CI 0.93 to 1.27, data not shown).

Studies evaluating effects on withdrawal symptoms

Naltrexone:

Ten studies indicated no effect of naltrexone on withdrawal symptom scores (°Brauer 1999; Covey 1999; °Houtsmuller 1997; °King 2000; King 2006; °Knott 2007; °Lee 2005; °Sutherland 1995; Toll 2010a; Wong 1999), while five studies reported reductions in withdrawal or smoking urge symptoms (°Caskey 2001; King 2006; King 2012; °Lee 2005; O'Malley 2006). Three trials indicated diminished withdrawal symptoms following provocative smoking cues during sustained abstinence (°Epstein 2004; °Hutchison 1999; °Rohsenow 2007) and one trial (O'Malley 2006) reported reduced withdrawal but only at the 100 mg dose compared to placebo and not at lower dose. °Ray 2007 reported that naltrexone reduced the enhancing effect of ethanol on smoking urge symptoms but had no main effect on smoking urges.

Naloxone:

°Wewers 1998 found no significant difference in withdrawal symptoms or mood states between the naloxone and control groups. °Gorelick 1988 did not find any impact of naloxone on withdrawal. °Krishnan-Sarin 1999 found that naloxone apparently increased urge to smoke (craving) and tiredness at lower dosages.

Studies evaluating ad libitum smoking

Naltrexone:

The results regarding ad libitum smoking were mixed. There were no significant effects of naltrexone on ad libitum smoking in three of the laboratory-based trials (°Brauer 1999; °Houtsmuller 1997; °Sutherland 1995). However, six trials (°Caskey 2001; °Epstein 2004; °King 2000, °Lee 2005; °Olmstead 2002; °Rohsenow 2003) demonstrated statistically significant reductions in the number of cigarettes smoked ad libitum. Four trials designed to evaluate abstinence and other outcomes during smoking cessation (King 2012; O'Malley 2006; Toll 2010a; Wong 1999) reported effects of naltrexone on daily or weekly smoking during and/or after treatment with naltrexone. Wong 1999 did not find any association between naltrexone and the number of cigarettes smoked among continuing smokers. O'Malley 2006 reported that cigarettes per week increased more in the placebo group compared to the naltrexone group at only the 100 mg dose of naltrexone, whilst King 2012 and Toll 2010a reported significantly lower weekly cigarettes smoked in the naltrexone (versus placebo) arms of the respective trials. Baltieri 2009 and Meszaros 2010 reported no difference in cigarettes per day between naltrexone and placebo groups.

Naloxone:

The results for naloxone are mixed. °Gorelick 1988 and °Karras 1980 found significant reductions in number of cigarettes smoked in the naloxone group compared with placebo. However, °Nemeth-Coslett 1986 did not find an effect of naloxone over a wide range of dosages for any measure of cigarette smoking, including number of cigarettes, number of puffs, or expired air carbon monoxide.

Buprenorphine:

°Mello 1985 found that cigarette consumption by seven heroin addicts increased compared to the pre-buprenorphine baseline. °Mutschler 2002 detected a significant increase among detoxified opioid- and cocaine-dependent inpatients in the rate of ad libitum smoking with buprenorphine administration.

Studies evaluating reinforcing effects of smoking

Naltrexone:

Studies have reported mixed results for the effect of naltrexone on hedonic effects. °Sutherland 1995 did not find any significant effect of naltrexone on self-reported satisfaction from smoking. °Wewers 1998 found a significant reduction in self-reported satisfaction with smoking for subjects treated with naltrexone compared to placebo. °Brauer 1999 found that naltrexone increased negative mood following smoking. °King 2000 found that naltrexone significantly reduced post-cigarette craving and increased lightheadedness, dizziness, and head rush following a cigarette. °Ray 2006 did not observe any effect of naltrexone on smoking reinforcement. However, °Rohsenow 2007 found that naltrexone did not affect reinforcing or aversive measures of smoking.

Naloxone:

Neither °Gorelick 1988 nor °Karras 1980 found an effect of naloxone on the reinforcing properties of smoking cigarettes.

Discussion

Eight trials of naltrexone with a total of 1213 smokers randomised to naltrexone at doses of 25 - 100 mg/day or placebo tablets have now reported long-term abstinence data. The point estimate for the risk ratio (RR) pooling all studies, 0.97 (95% confidence interval (CI) 0.76 to 1.24), suggests that naltrexone has no effect on abstinence whether used alone or in combination with NRT. The addition of four studies in this update has narrowed the confidence interval sufficiently to conclude that the likelihood of any clinically important effect is very small. The consistency of the effects seen so far suggest that further research is only likely to reduce the CI around no effect. We also know that one study remains unpublished, the likelihood being that it too did not detect evidence of benefit (Croop 2000). Further studies would probably strengthen the evidence of lack of benefit, but may not be the best use of resources. In a secondary analysis added for this update we pooled short-term outcomes, which also showed no evidence of any early treatment effect. Three randomised clinical trials with a total of 116 participants were excluded because of lack of assessing or reporting long-term abstinence rates, and including their results in the short-term analysis did not affect the conclusions. By comparison, the RR of long-term abstinence rates for NRT from 117 trials with over 50,000 participants was 1.60 (95% CI 1.53 to 1.68) (Stead 2012).

At least three study reports (Covey 1999; King 2006; King 2012) raised the possibility that there could be a difference in effect by gender, with women showing more evidence of a benefit than men. The other five abstinence studies (Baltieri 2009; Meszaros 2010; O'Malley 2006; Toll 2010a; Wong 1999) did not report quit rates for men and women separately, so we could not conduct a meta-analysis without risk of reporting bias.

Although not an end point of this systematic review, it should be noted that the King 2006 and King 2012 studies showed significant benefits of naltrexone for reducing post-cessation weight gain, but Toll 2010a did not find a significant effect of naltrexone for this outcome. The effects on weight gain are evaluated in a separate Cochrane review (Farley 2012). There are mixed results with regard to whether or not naltrexone reduces withdrawal symptoms, diminishes the reinforcing effects of nicotine and tobacco or reduces post-cessation weight gain. However, because of heterogeneity of methods and data reporting we are unable to examine withdrawal symptoms and reinforcing effects using meta-analytic techniques. Also, we do not have enough data to examine whether or not the use of combination naltrexone and nicotine replacement has a significant effect on withdrawal symptoms compared to nicotine replacement plus placebo.

There were no clear trends suggesting positive or negative effects of naloxone on withdrawal, ad libitum smoking or hedonic effects. In any case, the very short half-life, and route of administration of naloxone (intravenous, intramuscular or subcutaneous) precludes its use as an agent for smoking cessation in clinical settings.

Given the purported role of opioid pathways in nicotine dependence, it would seem biologically plausible that opioid antagonists would blunt the rewarding effects of smoking. Moreover, we would expect, if opioid antagonists diminished the reinforcing properties of smoking, that this would translate to decreased tobacco consumption or ad libitum smoking. However, we found no such trends. This lack of observed effects of opioid antagonists on smoking rates and aversive or reinforcing properties of nicotine is consistent with a study in rats that showed no effect on nicotine self administration (Corrigall 1991).

A large body of converging evidence suggests that nicotine stimulates the release of dopamine in the mesocorticolimbic system and plays an important role in the reinforcing properties of smoking. Blum 1995 and others have suggested that individuals may be at higher risk for dependence on nicotine and other substances because of deficiencies in dopamine transmission in the mesocorticolimbic system. However, the neurobiology of nicotine addiction is complex and involves interactions between multiple neurotransmitter systems (Benowitz 2010). The dopamine re-uptake inhibitor bupropion appears to diminish the rewarding effects of smoking and also appears to decrease withdrawal (Shiffman 2000) and the nicotine receptor partial agonist varenicline has shown similar effects (Brandon 2012). While we cannot draw any firm conclusions on the effect of opioid antagonists on the reinforcing properties of smoking or withdrawal, the literature to date suggests that dopamine and other interacting pathways play a more important role in nicotine dependence.

Authors' conclusions

Implications for practice

The current evidence suggests that the clinical use of naltrexone or other opioid antagonists is of no benefit for smoking cessation.

Implications for research

Further research is unlikely to change the conclusion of lack of benefit.

Longer-term smoking cessation outcomes data (six months or more), if collected by investigators in past, present, or future studies, should be made available in the public domain, to improve the reliability and generalisability of meta-analyses for smoking cessation medications such as opioid antagonists and other classes of pharmacological agents.

Acknowledgements

Our thanks to Drs Baltieri, Batki, Hutchison, Niaura, O'Malley and Szombathyne-Meszaros for assistance with additional information or data on studies.

Data and analyses

Download statistical data

Comparison 1. Naltrexone versus placebo (single pharmacotherapy or adjunct to NRT)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Abstinence at longest follow-up81213Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.76, 1.24]
1.1 Naltrexone versus placebo (no NRT)5445Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.66, 1.51]
1.2 Naltrexone + NRT versus Placebo + NRT4768Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.70, 1.30]
2 Abstinence at end of treatment81213Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.88, 1.22]
2.1 Naltrexone versus placebo (no NRT)5445Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.67, 1.21]
2.2 Naltrexone + NRT versus Placebo + NRT4768Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.90, 1.35]
Analysis 1.1.

Comparison 1 Naltrexone versus placebo (single pharmacotherapy or adjunct to NRT), Outcome 1 Abstinence at longest follow-up.

Analysis 1.2.

Comparison 1 Naltrexone versus placebo (single pharmacotherapy or adjunct to NRT), Outcome 2 Abstinence at end of treatment.

Appendices

Appendix 1. Register search strategy

1(naloxone):AB,TI,MH,EMT,KY,XKY8
2(naltrexone):AB,TI,MH,EMT,KY,XKY82
3(opioid antagonist*):AB,TI,MH,EMT,KY,XKY15
4(opiate antagonist*):AB,TI,MH,EMT,KY,XKY10
5(narcotic antagonist*):AB,TI,MH,EMT,KY,XKY31
6opioid*:XKY36
7#1 OR #2 OR #3 OR #4 OR #5 OR #6102
8(#1 OR #2 OR #3 OR #4 OR #5 OR #6) AND (INREGISTER)85
92009 or 2010 or 2011 or 2012 or 2013:YR5231
10#8 AND #1123

What's new

DateEventDescription
18 April 2013New search has been performedSearches updated. Four new studies with long term outcomes.
18 April 2013New citation required and conclusions have changedEvidence supports absence of a treatment effect. Meta-analysis of short term outcomes added. Judith Prochaska became a co-author.

History

DateEventDescription
12 June 2009New search has been performedUpdated for issue 4, 2009. No new long term cessation studies, four laboratory/ short term studies
29 October 2008AmendedConverted to new review format.
9 August 2006New citation required but conclusions have not changedUpdated for issue 4, 2006. Two new studies with long term cessation data. Dr Eden Evins became a co-author.
24 October 2002New citation required and minor changesUpdated for issue 1, 2003. One new study of effect of buprenorphine on ad libitum smoking, not relevant to clinical intervention

Contributions of authors

SD initiated the review, drafted the protocol, checked relevant studies, extracted data and drafted the review. LS and SD extracted data. LS and JP assisted in finalising the review. SD, LS, TL, EE and JP reviewed and approved the update for the 2013 version of the review.

Declarations of interest

Nil.

Sources of support

Internal sources

  • Brown University/Memorial Hospital of Rhode Island, USA.

  • Department of Primary Care Health Sciences, University of Oxford, UK.

  • National School for Health Research School for Primary Care Research, UK.

External sources

  • National Institute for Health Research (NIHR), UK.

  • National Institute of Mental Health (NIMH), USA.

    R01 MH083684 (Dr Prochaska)

  • National Institute on Drug Abuse, USA.

    P50 DA009253 (Dr Prochaska)

  • Tobacco-Related Disease Research Program (TRDRP), USA.

    17RT-0077

Differences between protocol and review

The following changes to methods were made in the 2013 update:

  • Short-term (end of treatment) abstinence was added as a secondary outcome for meta-analysis. Studies that only report short-term abstinence outcomes are still excluded, but short-term outcomes were extracted for a sensitivity analysis of the effect of including them in this analysis.

  • Studies were not required to have biochemical validation of abstinence for inclusion (no studies had previously been excluded for this reason).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Baltieri 2009

Methods

NALTREXONE

Country: Brazil

Recruitment: Unclear

Design: Double-blind, placebo-controlled trial

Participants155 male alcohol-dependent outpatients (52 nonsmokers and 103 smokers), 18 – 60 years of age, with ICD-10 diagnosis of alcohol dependence
Interventions

1) Naltrexone 50 mg/day for 12 wks

2) Placebo

3) Topiramate up to 300 mg/day (not used in this review)

After a 1-wk alcohol detoxification period

OutcomesSelf-reported smoking abstinence at 12 wks (EOT) and 6 months from baseline, time to first relapse, adherence to treatment, cigarettes smoked/day, mood
NotesOnly smokers included in meta-analysis. No biochemical verification of abstinence. Unpublished 6-month data provided by authors
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomised", method not stated
Allocation concealment (selection bias)Low riskMedication was dispensed under double-blind conditions. Only two pharmacists from the pharmacy sector ... knew which medication corresponded to the specific
code. The packages containing the capsules were distributed to patients by two blinded research assistants, who also assessed patient outcomes throughout the study.
Blinding (performance bias and detection bias)
All outcomes
Low risk"patients received standardized brief cognitive behavioural interventions from their doctors who were blind to medication conditions"; "Medications codes were revealed to researchers only after all patients had completed the study." (Baltieri 2008)
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-out rates 40.8% naltrexone, 57.4% placebo,

Covey 1999

MethodsNALTREXONE
Country: USA
Recruitment: By notices at University and newspaper adverts
Design: Randomised double-blind, placebo-controlled trial
Participants80 smokers, ≥ 20 cpd, age 18 - 65, smoked before leaving house in morning, had made at least 1 quit attempt, and experienced withdrawal symptoms during quit attempt
Interventions1. Naltrexone 25 mg/day at least 3 days before TQD, increased to 50 - 75 mg/day on quit date and continued for 4 wks
2. Placebo
Both groups received weekly individual behavioural counselling
OutcomesSelf-reported continuous abstinence at 4 wks and 6 months, verified at all visits by plasma cotinine ≤15 ng/mL
Mood
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly assigned"; method not stated
Allocation concealment (selection bias)Unclear riskno details given
Blinding (performance bias and detection bias)
All outcomes
Low risk"double-blind"
Incomplete outcome data (attrition bias)
All outcomes
High riskSubject drop-out high and differential. 32.5% (n = 13) dropped out in naltrexone group; 32.5% (n = 13) also dropped out in placebo group. However 10/13 drop-outs in naltrexone group occurred before quit date for wide range of side effects or excuses. All drop-outs included as smokers in meta-analysis

King 2006

Methods

NALTREXONE AS AN ADJUNCT TO NICOTINE PATCH
Country: USA
Recruitment: Newspaper adverts, flyers, word of mouth

Design: Double-blind, placebo-controlled trial

Participants110 smokers (15 - 40 cpd), 51% F, av age 44
Interventions1. Naltrexone 25 mg for 3 days then 50 mg for 2 months, nicotine patch for 1month
2. Placebo + nicotine patch
All participants received 6 individual 45 - 60 mins behavioural therapy sessions
OutcomesContinuous abstinence at 8 wks (EOT) and 24 wks, validated by CO ≤10 ppm
Smoking urges, withdrawal, side effects, body weight changes
NotesPreliminary results presented in King 2002, King 2003. Gender difference noted in outcomes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomly assigned via a computer-generated random number list"
Allocation concealment (selection bias)Low risk"Both subjects and trial staff were blinded to study medication assignment"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Both subjects and trial staff were blinded to study medication assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low risk8/52 naltrexone, 13/58 placebo lost to follow-up, all included as smokers in meta-analysis.

King 2012

Methods

NALTREXONE AS AN ADJUNCT TO NICOTINE PATCH

Country: USA

Recruitment: Internet, print and radio

Randomisation: Stratified by gender

Participants

315 treatment-seeking smokers

Subjects were eligible if they were 18 to 65 years old, smoked 10 - 40 cpd for at least 2 years, had a body mass index (kg/m²) of 19 to 38, had a breath CO ≥10 ppm, and a urinary Nicalert reading > 500 ng/mL cotinine, confirming regular smoking

Interventions

1. Naltrexone (50 mg/day) x 12 wks plus nicotine patch (21 mg/day x 2 wks, 14 mg/day x 1 wk, 7 mg/day x 1 wk)

2. Placebo x 12 wks, + nicotine patch (same schedule)

OutcomesSelf-reported abstinence at 12 wks (EOT), 6 and 12 months verified with expired air CO, cpd
Self-reported ratings of smoking urges and depression symptoms
Notes12w & 12m outcomes used in meta-analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomly assigned by computer"
Allocation concealment (selection bias)Low risk"Participants and study staff were blinded to treatment assignment"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Participants and study staff were blinded to treatment assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low risk7 Naltrexone, 11 Placebo did not start treatment, not included in MA. All other drop-outs included as smokers in meta-analysis

Meszaros 2010

Methods

NALTREXONE

Country: USA

Recruitment: Unclear

Design: Randomised, double-blind, placebo-controlled trial

Participants

79 patients with schizophrenia or schizoaffective disorder and comorbid alcohol and tobacco dependence

Subjects in alcohol treatment trial were eligible if ages 18 to 69, DSM-IV schizophrenia or schizoaffective disorder, major depressive disorder w/psychotic features, bipolar type I or II or psychosis and alcohol dependence, but not opioid dependence

Interventions

1. Naltrexone 3 times/wk (100 mg Mon and Tue; 150 mg Fri) x 3 months

2. Placebo (same schedule)

OutcomesSelf-reported abstinence at 12 wks (EOT), 6 months, cpd
NotesNot yet published in full. Conference abstract and data from author
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, method not stated
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind" no further details
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll randomised participants included in denominators

O'Malley 2006

MethodsNALTREXONE AS AN ADJUNCT TO NICOTINE PATCH
Country: USA
Recruitment: Patients at a Connecticut mental health centre and a VA healthcare centre, recruited through press, advertisements and mailings to physicians
Design: Double-blind randomised controlled trial, to test effects of naltrexone, with and without NRT, on smoking cessation and on weight gain. Block randomisation stratified by gender after 150 enrolments. Allocation by random sequence provided to pharmacist
Participants385 smokers (from 400 eligible), age ≥ 18, ≥ 20 cpd, CO > 10 ppm
46% F, av cpd 28, av age 46
Interventions1. Naltrexone 100 mg
2. Naltrexone 50 mg
3. Naltrexone 25 mg
4. Placebo
All participants also received 21 mg NRT patch x 6 wks, initial 45 min counselling session, weekly 15 min counselling sessions for 6 wks, plus self-help materials including dietary and exercise tips
OutcomesPPA at 12 months (also 6 months, and 6 wk continuous abstinence) validated by expired CO < 10ppm
Adverse events
NotesAnalyses were ITT and per protocol (completers); weight change was a secondary outcome. 50 mg and 100 mg dose groups combined in main analysis. Sensitivity analysis using individual groups, and 6 month outcomes did not alter conclusions.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomized in blocks to treatment arms, with stratified (for sex) randomization implemented after the first 150 participants to ensure that the important predictor, sex,would be distributed similarly among treatment groups."
Allocation concealment (selection bias)Low risk"Random sequence was provided to the pharmacist, who assigned
participants; others were blinded to treatment assignment."
Blinding (performance bias and detection bias)
All outcomes
Low risk" ... others were blinded to treatment assignment."
Incomplete outcome data (attrition bias)
All outcomes
Low risk15/400 who did not start treatment excluded from analyses. All other losses included as smokers in meta-analysis

Toll 2010a

Methods

NALTREXONE

Country: USA

Recruitment: Adverts, mailings, fliers, healthcare provider referrals, press releases and websites

Design: Randomised, double-blind, placebo-controlled trial

Participants

172 treatment-seeking smokers

Subjects were eligible if "weight-concerned", 18 yrs or older, at least 1 prior quit attempt, had a breath CO ≥ 10 ppm, smoked > 10 cpd x ≥1 yr

Interventions

1. Naltrexone (25 mg/day) x 27 wks

2. Placebo x 27 wks

OutcomesSelf-reported abstinence to 6 wks and 6 months verified with expired air CO, cigarettes smoked/wk, withdrawal and craving
NotesStudy stopped early after interim analysis. Abstinence at 6 wks used for short-term/EOT analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"... blocked stratified (for gender) randomization ..."
Allocation concealment (selection bias)Low risk"Random sequence was provided by one of the authors (RW) to the pharmacist who assigned participants; all others were blind to treatment assignment."
Blinding (performance bias and detection bias)
All outcomes
Low riskSee above
Incomplete outcome data (attrition bias)
All outcomes
Low risk28/87 naltrexone and 30/85 placebo completed treatment. All randomized participants included in analyses, losses classified as smoking.

Wong 1999

Methods

NALTREXONE AS AN ADJUNCT TO NICOTINE PATCH
Country: USA
Recruitment: Adverts and press releases
Randomisation: By subject after stratification by gender

Design: Randomised, partially-blinded, 2 x 2 factorial trial using naltrexone

Participants100 smokers, ≥ 10 cpd at least 1 yr, age 18 - 65, baseline CO ≥ 15 ppm without history of depression or alcohol/drug dependence
Interventions1. Naltrexone 50 mg/day for 12 wks
2. Nicotine patch (21 mg 8 wks/14 mg 4 wks) + placebo pill
3. Naltrexone (50 mg/day) + nicotine patch (21/14) for 12 wks
4. Placebo pill for 12 wks.
All groups received weekly counselling. No placebo patches used
OutcomesSelf-reported abstinence to 12 wks (EOT) and 6 months verified with expired air CO, cpd
Self-reported ratings of urges and craving
NotesData reported from only 1 of 5 centres involved in study. Additional data sought from the DuPont Merck Pharmaceutical Company but was not provided (Croop 2000).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer generated randomization schedules prepared by
the clinical operations group of the study sponsor."
Allocation concealment (selection bias)Low risk"Identification numbers were randomized to the medication kits ... Randomization schedules were retained by the study sponsor in sealed envelopes."
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPartially blinded, NRT condition open
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDifferential loss to follow-up; 31% placebo, 61% naltrexone, 12% placebo + NRT, 27% naltrexone + NRT.

°Boureau 1978

MethodsNALOXONE
Country: France
Recruitment: Not clear, abstract only
Design: Laboratory-based, double-blind, placebo-controlled, cross-over study
Participants20 smokers, 35% F
Interventions

1. Naloxone 0.4 mg

2. Placebo

OutcomesNumber of cigarettes smoked per day
NotesNot long-term abstinence

°Brauer 1999

MethodsNALTREXONE
Country: USA
Recruitment: Newspaper adverts
Design: Laboratory, double-blind, double-dummy, within-subject trial
Participants19 smokers aged 18 - 55, smoked ≥ 20 cpd for at least 2 yrs, in good health
Interventions1. Naltrexone 50 mg plus placebo patch
2. Placebo tablet plus nicotine patch
3. Naltrexone plus nicotine patch
4. Placebo tablet plus placebo patch
1 week on each condition, day 7 smoked normal and denicotinized cigarettes in laboratory
Abstinence not attempted
OutcomesCigarette satisfaction, depression, withdrawal symptoms, mood, smoking behaviour, cardiovascular measures, and cognitive and psychomotor performance
NotesNo attempt at ascertaining abstinence

°Caskey 2001

Methods

NALTREXONE
Country: USA
Recruitment: Not clear, abstract only

Design: Randomised, placebo-controlled trial

Participants16 smokers
Interventions1. Naltrexone 100 mg
2. Naltrexone 50 mg
3. Placebo
OutcomesSmoking topography, urge to smoke, serum nicotine and cotinine
NotesNo abstinence data reported

°Epstein 2004

Methods

NALTREXONE
Country: USA
Recruitment: Flyers and newspaper adverts

Design: Within-subject, placebo-controlled laboratory study

Participants44 regular smokers, 48% F
InterventionsNaltrexone 50 mg/day and placebo in random sequence
OutcomesAd lib smoking, smoking urges, positive and negative affect, withdrawal symptoms, exhaled CO
NotesNo abstinence data reported

°Gorelick 1988

MethodsNALOXONE
Country: USA
Recruitment: Hospital employees and outpatients
Design: Laboratory, double-blind, placebo-controlled, cross-over trial
Participants10 male chronic smokers with severe nicotine dependence (mean FTQ score of 7.4 and past failure to quit smoking)
InterventionsEach subject evaluated in 2 laboratory sessions receiving either naloxone 10 mg sc or placebo (drug vehicle)
OutcomesNumber of cigarettes smoked, CO content of expired air, subjective aspects of smoking and withdrawal, physiologic data
NotesNo abstinence data reported

°Houtsmuller 1997

MethodsNALTREXONE
Country: USA
Recruitment: No data given in abstract on recruitment
Design: Laboratory, double-blind, placebo-controlled, within-subject trial
Participants14 smokers. No data given in abstract on gender, age, inclusion or exclusion criteria
InterventionsNaltrexone 50 mg/day and placebo for 4 days each, with 10-day washout period between
OutcomesWithdrawal symptoms, ad lib smoking using smoking topography measures
NotesDid not report hedonic effects or ad lib smoking

°Hutchison 1999

MethodsNALTREXONE
Country: USA
Recruitment: Newspaper adverts and flyers
Design: Laboratory, randomised, double-blind, placebo-controlled trial
Participants20 smokers, ≥ 20 cpd
InterventionsNaltrexone 50 + nicotine patch vs placebo pill + nicotine patch. Cue reactivity evaluate after 9-hr abstinence
OutcomesNicotine dependence severity, (FTQ), positive and negative affect, withdrawal symptoms
NotesNo abstinence data reported

°Karras 1980

MethodsNALOXONE
Country: USA
Recruitment: Unclear from manuscript
Design: Laboratory-based double-blind, drug-placebo, cross-over trial
Participants7 smokers, employees at medical centre, ≥ 20 cpd
InterventionsNaloxone 10 mg/ml or 1ml or placebo sc
OutcomesNumber of puffs smoked, weight of smoked portion, desire for cigarette, satisfaction, mood, side effects
NotesNo abstinence data reported

°King 2000

MethodsNALTREXONE
Country: USA
Recruitment: Adverts
Design: Laboratory-based, randomised, double-blind, placebo controlled within-subject trial
Participants22 regular cigarette smokers aged 19 - 50. Excluded if history of major psychiatric illnesses or positive blood or urine toxicology for cocaine, opiates, benzodiazepines, amphetamine, barbiturates, and phencyclidine
InterventionsEach subject participated in 2 identical testing sessions in double-blind study. Sessions spaced 8 days apart. Each subject received pre-administration of either 50 mg naltrexone or identical placebo in random order, after overnight abstinence. Offered up to 4 cigs over 2 hrs
OutcomesWithdrawal symptoms and ad lib smoking
NotesNo long-term abstinence data

°Knott 2007

Methods

NALTREXONE
Country: Canada
Recruitment: Not described

Design: Laboratory-based, randomised, double-blind, placebo-controlled trial

Participants18 smokers, ≥ 10 cpd, 40% F, av age 23
Interventions

Four sessions:

1. 2-sessions active naltrexone 50 mg;

2. 2-sessions placebo tablets;

3. 2-session nicotine gum 4 mg;

4. 2-session placebo gum

OutcomesChange in withdrawal symptoms or hedonic effects of nicotine
Notes 

°Krishnan-Sarin 1999

MethodsNALOXONE
Country: USA
Recruitment: Newspaper adverts in community
Design: Laboratory-based, single group, within-subject design
Participants9 smokers (smoked 1 - 1½ packs per day) and 11 non-smoking volunteers
InterventionsNaloxone in dosages of 0, 0.8, and 1.6 mg iv
OutcomesNarcotic withdrawal scale, smoking urges, blood cortisol levels
NotesDid not report ad lib smoking or hedonic effects

°Lee 2005

Methods

NALTREXONE
Country: South Korea
Recruitment: Not clear, apparently recruited from clinical setting

Design: Randomised, placebo-controlled trial

Participants25 male smokers
InterventionsNaltrexone 25 mg/day x 7 days, then 50 mg/day x 7 days vs placebo
OutcomesDaily cigarette consumption, exhaled CO, nicotine dependence severity, ACTH, cortisol, prolactin, beta-endorphin, dynorphin
NotesNo abstinence data reported

°Mello 1985

MethodsBUPRENORPHONE
Country: USA
Recruitment: From drug rehabilitation clinic
Design: Laboratory-based, single group, within-subject design
Participants7 heroin addicts
InterventionsBuprenorphine ascending dosages (0.5 - 8mg/day)
OutcomesNumber of cigarettes smoked
NotesDid not report hedonic effects or withdrawal symptoms

°Mutschler 2002

MethodsBUPRENORPHONE
Country: USA
Recruitment: Pts admitted to a clinical research ward for concurrent opioid and cocaine dependence
Design: Randomised trial with randomisation to 4 mg or 8 mg of buprenorphine
Participants23 adult men with DSM III-R diagnosis of concurrent opioid and cocaine dependence
InterventionsBuprenorphine with randomisation to 4 or 8 mg/day with ascending dosages following 6 days of detoxification on methadone
OutcomesSmoking topography, urge to smoke, serum nicotine and cotinine
NotesDid not report hedonic effects or withdrawal symptoms

°Nemeth-Coslett 1986

Methods

NALOXONE
Country: USA
Recruitment: From clinical setting

Design: Laboratory-based, within-subject

Participants7 smokers
InterventionsInjection of naloxone HCl (0.0625, 0.25, 1.0, or 4.0 mg/kg) or placebo. Each subject received each treatment 3 times in a mixed order across days
OutcomesNumber of cigarettes smoked, number of puffs, exhaled CO
NotesDid not report abstinence outcomes

°O'Malley 1998

MethodsNALTREXONE
Country: USA
Recruitment: No information given in abstract regarding recruitment
Design: Randomised, double-blind, placebo-controlled, factorial design
Participants60 smokers who were not alcohol-dependent. No other data provided in abstract
Interventions

Naltrexone 50 mg/day orally or similar dose placebo pill and assignment to 1 of 3 nicotine patch conditions:

1. 21 mg for 4 wks;

2. 21 mg for 2 wks followed by 14 mg and 7 mg for 1 wk each;

3. No patch

OutcomesWithdrawal symptoms, ad lib smoking, self-reported abstinence at 4 wks.
NotesNo specific data on number randomised to each group or number abstinent at 4 wks given

°Olmstead 2002

Methods

NALTREXONE
Country: USA
Recruitment: Not described

Design: Laboratory-based, within-subject design

Participants29 smokers: > 15 cpd (N = 19) or < 6 cpd (N = 10).
InterventionsRepeated measures, 12-hr sessions x 3 randomised by sequence to naltrexone 100 mg/day, 50 mg/day, and placebo
OutcomesSmoking topography, smoking urges, serum cotinine and nicotine, exhaled CO
NotesNo abstinence data reported.

°Ray 2006

Methods

NALTREXONE
Country: USA
Recruitment: Not described

Design: Laboratory-based, within-subject design

Participants30 smokers, ≥ 10 cpd, 37% F, av age 43, av cpd 22
InterventionsLab-based, counterbalanced design randomised within-subjects comparison of nicotinised (0.6 mg) vs denicotinised (0.05 mg) cigarettes
OutcomesWithdrawal symptoms, craving
Notes 

°Ray 2007

Methods

NALTREXONE
Country: USA
Recruitment: Not described

Design: Laboratory-based, within-subject design

Participants10 smokers (heavy drinkers), 20% F, av age 22, av cpd 5
InterventionsLaboratory-based, quasi-experimental, repeated-measures study with 2 counterbalanced sessions of 1. naltrexone 50 mg; 2. placebo tablet; + iv etoh (alcohol) challenge
OutcomesAlcohol and cigarette craving
Notes 

°Rohsenow 2003

Methods

NALTREXONE
Country: USA
Recruitment: From subjects enrolled in a trial of naltrexone for alcohol use outcomes

Design: Randomised, placebo-controlled trial

Participants73 alcoholic smokers, abstinent from alcohol and/or drugs
InterventionsNaltrexone 50 mg/day or placebo pill for 12 wks + counselling
OutcomesCigarettes per day, stage of change
NotesAbstinence data not reported

°Rohsenow 2007

Methods

NALTREXONE
Country: USA
Recruitment: Not described

Design: Laboratory-based, within-subject design

Participants134 smokers, 54% F, ≥ 15 cpd, av age 49
Interventions3 x 3 randomised, between-subject, parallel-groups, crossed-medication (naltrexone 50 mg vs placebo) + nicotine patch (42 mg vs 21 mg); cigarette cue exposure + smoking challenge
OutcomesCue reactivity: smoking urges + withdrawal, hedonic + aversive effects of smoking
Notes 

°Rukstalis 2005

Methods

NALTREXONE
Country: USA
Recruitment: Local adverts

Design: Laboratory-based, double-blinded, within-subject design

ParticipantsSmokers, ≥ 10 cpd, ≥ 18, 42% F
Interventions

Lab-based, double-blind, within-subject, counterbalanced, 3-session study:

1. naltrexone 50 mg;

2. bupropion 300 mg;

3. placebo; with cigarette choice (nicotinised 0.6 mg vs denicotinised 0.05 mg cigarettes) smoking challenge

OutcomesSmoking urges, smoking satisfaction
Notes 

°Sutherland 1995

MethodsNALTREXONE
Country: UK
Recruitment: Newspaper adverts
Design: Laboratory-based, double-blind, placebo-controlled, cross-over trial
Participants12 heavy smokers (4 men, 8 women), ≥ 20 cpd, CO ≥ 30
InterventionsSubjects seen on 6 occasions. Sessions grouped in 2 blocks of 3 sessions. First block evaluated at baseline, during acute nicotine administration and then given naltrexone 50 mg orally or a placebo pill with trace amounts of nicotine and asked to abstain from smoking until next session 24 hours later. Then followed for 48-hour ad lib smoking period
OutcomesWithdrawal symptoms, mood, satisfaction and other subjective measures, ad lib smoking
NotesNo long-term abstinence data reported

°Wewers 1998

  1. a

    CO: Carbon monoxide; cpd: cigarettes per day; FTQ: Fagerstrom Tolerance Questionnaire; iv: Intravenous; ITT: Intention-to-treat (includes all randomised); PPA: Point prevalence abstinence; ppm: parts per million; Sc: subcutaneous;
    wks: weeks

MethodsNALTREXONE
Country: USA
Recruitment: Adverts
Design: Laboratory-based, randomised, double-blind, repeated measures experimental design
Participants43 smokers, > 10/day, age > 19, admitted to Clinical Research Centre for 6 days
InterventionsNaltrexone 50 mg or placebo pill. 22 received naltrexone and 21 received placebo for 3 days
Abstinence not attempted
OutcomesPlasma nicotine, expired air CO, number of cigarettes smoked, self-reported satisfaction with smoking, mood and withdrawal
Notes 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ahmadi 2003No placebo control group, and high drop-out rates (63 - 95%).
Byars 2005No follow-up beyond 12 wks.
Croop 2000Unpublished data not released.
Krishnan-Sarin 2003No follow-up beyond 4 wks.
O'Malley 1995Designed to evaluate effect on alcohol consumption and did not provide any data on tobacco consumption.
Roozen 2006Follow-up only 3 months, no placebo group, so did not contribute data on withdrawal or other outcomes.
Toll 2008Not randomised. Follow-up only six wks.
Toll 2010bFollow-up only 6 wks.
Wilcox 2010No placebo control group.

Ancillary