Slow-release oral morphine as maintenance therapy for opioid dependence

  • Review
  • Intervention

Authors


Abstract

Background

Opioid substitution treatments are effective in retaining people in treatment and suppressing heroin use. An open question remains whether slow-release oral morphine (SROM) could represent a possible alternative for opioid-dependent people who respond poorly to other available maintenance treatments.

Objectives

To evaluate the efficacy of SROM as an alternative maintenance pharmacotherapy for the treatment of opioid dependence.

Search methods

We searched Cochrane Drugs and Alcohol Group's Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 3, 2013), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013) and reference lists of articles.

Selection criteria

Randomised controlled trials (RCTs) and quasi-randomised trials assessing efficacy of SROM compared with other maintenance treatment or no treatment.

Data collection and analysis

Two review authors independently selected articles for inclusion, extracted data and assessed risk of bias of included studies.

Main results

Three studies with 195 participants were included in the review. Two were cross-over trials and one was a parallel group RCT. The retention in treatment appeared superior to 80% in all the three studies (without significant difference with controls). Nevertheless, it has to be underlined that the studies had different durations. One lasted six months, and the other two lasted six and seven weeks. The use of opioids during SROM provision varied from lower to non-statistically or clinically different from comparison interventions, whereas there were no differences as far as the use of other substances was concerned.

SROM seemed to be equal to comparison interventions for severity of dependence, or mental health/social functioning, but there was a trend for less severe opiate withdrawal symptoms in comparison with methadone (withdrawal score 2.2 vs. 4.8, P value = 0.06). Morphine was generally well tolerated and was preferred by a proportion of participants (seven of nine people in one study). Morphine appeared to reduce cravings, depressive symptoms (measured using the Beck Depression Inventory; P value < 0.001), physical complaints (measured using the Beschwerde-Liste (BL); P value < 0.001) and anxiety symptoms (P value = 0.008). Quality of life in people treated with SROM resulted in no significant difference or a worst outcome than in those taking methadone and buprenorphine. Other social functioning measures, such as finances, family and overall satisfaction, scored better in people maintained with the comparison substances than in those maintained with SROM. In particular, people taking methadone showed more favourable values for leisure time (5.4 vs. 3.7, P value < 0.001), housing (6.1 vs. 4.7, P value < 0.023), partnerships (5.7 vs. 4.2, P value = 0.034), friend and acquaintances (5.6 vs. 4.4, P value = 0.003), mental health (5.0 vs. 3.4, P value = 0.002) and self esteem (8.2 vs. 5.7, P value = 0.002) compared to people taking SROM; while people taking buprenorphine obtained better scores for physical health.

Medical adverse events were consistently higher in people in SROM than in the comparison groups. None of the studies included people with a documented poor response to other maintenance treatment.

Authors' conclusions

The present review did not identify sufficient evidence to assess the effectiveness of SROM for opioid maintenance because only three studies meeting our inclusion criteria have been identified. Two studies suggested a possible reduction of opioid use in people taking SROM. In another study, the use of SROM was associated with fewer depressive symptoms. Retention in treatment was not significantly different among compared interventions while the adverse effects were more frequent with the people given SROM.

Résumé scientifique

Morphine orale à libération prolongée comme traitement d'entretien dans la dépendance aux opiacés

Contexte

Les traitements de substitution aux opiacés permettent aux patients de poursuivre leur traitement et de ne plus consommer d'héroïne. Une question ouverte demeure, à savoir si la morphine orale à libération prolongée (SROM) peut constituer une éventuelle alternative pour les personnes dépendantes aux opiacés qui répondent mal aux autres traitements d'entretien disponibles.

Objectifs

Évaluer l'efficacité de la SROM en tant que pharmacothérapie d'entretien alternative pour le traitement de la dépendance aux opiacés.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais du groupe Cochrane sur les drogues et l'alcool, le registre Cochrane des essais contrôlés (CENTRAL - The Cochrane Library numéro 3, 2013), MEDLINE (de janvier 1966 à avril 2013), EMBASE (de janvier 1980 à avril 2013) et les listes bibliographiques des articles.

Critères de sélection

Des essais contrôlés randomisés (ECR) et quasi randomisés comparant l'efficacité de la SROM à un autre traitement d'entretien ou à l'absence de traitement.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné des articles en vue de leur inclusion, extrait des données et évalué les risques de biais des études incluses.

Résultats principaux

Trois études totalisant 195 participants ont été incluses dans la revue. Deux étaient des essais croisés et une était un ECR en groupes parallèles. Le maintien du traitement semblait dépasser les 80 % dans l'ensemble des trois études (sans différence significative avec les groupes témoins). Néanmoins, il doit être précisé que les études étaient de durées différentes. L'une s'étendait sur six mois et les deux autres sur six et sept semaines. La consommation d'opiacés lors de l'administration de SROM était inférieure à non statistiquement ou cliniquement différente des interventions témoins, alors qu'il n'y avait aucune différence au niveau de la consommation d'autres substances.

La SROM semblait équivalente aux interventions témoins en termes de gravité de la dépendance ou du fonctionnement social/santé mentale, mais les symptômes graves de sevrage des opiacés avaient tendance à diminuer par rapport à la méthadone (score de sevrage 2,2 contre 4,8, valeur de P = 0,06). La morphine était généralement bien tolérée et préférée par une proportion de participants (sept personnes sur neuf dans une étude). Elle semblait réduire les manques, les symptômes dépressifs (mesurés à l'aide de l'inventaire de dépression de Beck ; valeur de P < 0,001), les problèmes physiques (mesurés à l'aide de la liste de l'échelle Beschwerde-Liste (BL) ; valeur de P < 0,001) et les symptômes d'anxiété (valeur de P = 0,008). La qualité de vie des personnes traitées par SROM n'était pas significativement différente ou avait empiré par rapport aux personnes sous méthadone et buprénorphine. D'autres mesures de la fonction sociale, comme les finances, la famille et la satisfaction globale, étaient meilleures chez les personnes continuant leur traitement avec des substances témoins par rapport à celles qui continuaient de prendre de la SROM. Plus particulièrement, les personnes sous méthadone montraient des valeurs plus favorables pour les loisirs (5,4 contre 3,7, valeur de P < 0,001), le logement (6,1 contre 4,7, valeur de P < 0,023), les partenariats (5,7 contre 4,2, valeur de P = 0,034), les relations amicales et les connaissances (5,6 contre 4,4, valeur de P = 0,003), la santé mentale (5,0 contre 3,4, valeur de P = 0,002) et l'estime de soi (8,2 contre 5,7, valeur de P = 0,002) par rapport aux personnes sous SROM ; alors que celles sous buprénorphine obtenaient de meilleures scores en termes de santé physique.

Les événements indésirables médicaux étaient nettement plus nombreux chez les personnes sous SROM que dans les groupes témoins. Aucune des études n'incluait des personnes présentant une faible réponse documentée à un autre traitement d'entretien.

Conclusions des auteurs

La présente revue n'a pas identifié de preuves suffisantes pour évaluer l'efficacité de la SROM dans un traitement d'entretien aux opiacés car seules trois études répondant à nos critères d'inclusion ont été identifiées. Deux études suggéraient une éventuelle diminution de la consommation d'opiacés chez les personnes sous SROM. Dans une autre étude, l'administration de SROM était liée à une baisse des symptômes dépressifs. Le maintien du traitement n'était pas significativement différent parmi les interventions comparées, alors que ses effets indésirables étaient plus fréquents chez les personnes sous SROM.

Plain language summary

Use of slow-release oral morphine for the treatment of people with opioid dependence

Opioid dependence is associated with public health and social problems. People injecting opioids are particularly at risk, not only because they become dependent faster than with other routes of administration but also because they are exposed to consequences such as an increased risk of overdose mortality, infective diseases and health issues. At least three-quarters of global opiate users consume heroin.

Opioid substitution treatment involves prescribing an opioid to replace street heroin or other opioids. This is a long-term treatment that has been shown to reduce injecting of street heroin and the risk of death and blood-borne virus transmission, and to reduce involvement in crime.

Maintenance treatments that are effective in retaining people in treatment and suppressing heroin use include methadone, buprenorphine, and dyacethilmorphine, alone or combined with psychosocial treatments. In order to diversify the treatment possibilities, it is important to clarify the benefits that each specific intervention can bring to patients. Slow release oral morphine (SROM) is given once daily and has been proposed for people who cannot tolerate methadone or who respond poorly to other available maintenance treatments.

This review did not identify sufficient evidence to assess the effectiveness of SROM for opioid maintenance. Only three randomised controlled trials involving 195 participants met our inclusion criteria. The findings of two studies suggested a possible reduction of opioid use in people taking SROM. In another study, the use of SROM was associated with fewer depressive symptoms. Retention in treatment was not clearly different among the compared interventions. Adverse effects were more frequent with SROM than buprenorphine or methadone, including stomach cramps, headache, toothache, constipation, vomiting and insomnia.

These studies had small numbers of participants, very short follow -up and were designed to answer different questions. Overall, the quality of the evidence can be judged as low.

Résumé simplifié

Administration de morphine orale à libération prolongée pour le traitement de personnes dépendantes aux opiacés

La dépendance aux opiacés est liée à des problèmes sociaux et de santé publique. Les personnes s'injectant des opiacés sont particulièrement à risque, non seulement parce qu'elles deviennent dépendantes plus rapidement par rapport à d'autres voies d'administration, mais aussi parce qu'elles sont exposées à des conséquences comme des risques accrus de mortalité par overdose, des maladies infectieuses et des problèmes de santé. Au moins les trois quarts des consommateurs d'opiacés dans le monde consomment de l'héroïne.

Un traitement de substitution aux opiacés consiste à prescrire un opiacé pour remplacer l'héroïne illicite ou d'autres opiacés. Il s'agit d'un traitement à long terme qui réduit l'injection d'héroïne illicite, les risques de décès, la transmission de virus par le sang et la criminalité.

Les traitements d'entretien qui incitent les patients à continuer leur traitement et à cesser toute consommation d'héroïne contiennent de la méthadone, de la buprénorphine et de la diacéthilmorphine, seules ou associées à des traitements psychosociaux. Afin de diversifier les possibilités de traitement, il est important de clarifier les effets bénéfiques que chaque intervention spécifique peut apporter aux patients. La morphine orale à libération prolongée (SROM pour « Slow Release Oral Morphine ») est administrée une fois par jour et proposée aux patients qui ne tolèrent pas la méthadone ou qui réagissent mal aux autres traitements d'entretien disponibles.

La présente revue n'a identifié aucune preuve suffisamment probante pour évaluer l'efficacité de la SROM dans un traitement d'entretien aux opiacés. Seuls trois essais contrôlés randomisés impliquant 195 participants répondaient à nos critères d'inclusion. Les résultats de deux études suggéraient une éventuelle diminution de la consommation d'opiacés chez les personnes sous SROM. Dans une autre étude, l'administration de SROM était liée à une baisse des symptômes dépressifs. Le maintien du traitement n'était pas clairement différent parmi les interventions comparées. Des effets indésirables étaient plus fréquents avec la SROM par rapport à la buprénorphine ou à la méthadone, notamment des crampes d'estomac, des céphalées, des douleurs dentaires, des constipations, des vomissements et des insomnies.

Ces études se composaient d'un nombre réduit de participants, d'un suivi très court et étaient conçues de sorte à répondre à différentes questions. Dans l'ensemble, la qualité des preuves peut être considérée comme étant médiocre.

Notes de traduction

Traduit par: French Cochrane Centre 16th July, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Laički sažetak

Korištenje sporo otpuštajućeg morfina uzetog na usta za liječenje ovisnosti o opioidima

Ovisnost o opioidima povezana je s društvenim problemima i javnim zdravljem. Posebni rizik nosi ubrizgavanje opioida, ne samo zbog bržeg razvitka ovisnosti tim putem primjene nego i zbog povećanog rizika od zaraznih bolesti, zdravstvenih problema i smrti od predoziranja. Barem tri četvrtine svjetskih ovisnika o opioidima koriste heroin.

Zamjenska (supstitucijska) terapija opioidima uključuje propisivanje opioida kako bi zamijenili ulični heroin ili druge opioide. To je dugoročna terapija koja je pokazala smanjenje injiciranja uličnog heroina i smrtnosti te prijenos krvno prenosivih virusa i smanjuje sudjelovanje ovisnika u kriminalnim aktivnostima.

Lijekovi u terapiji održavanja, koja je učinkovita u zadržavanju ljudi u terapiji i potiskivanju korištenja heroina, uključuju metadon, buprenorfin i diacetilmorfin (heroin), samostalno ili u kombinaciji s psihosocijalnom terapijom. Kako bi se povećala raznovrsnost dostupnih terapijskih mogućnosti, važno je utvrditi korist od svake pojedine intervencije. Sporo otpuštajući oralni morfin (SROM) daje se jednom dnevno i predlaže se kao terapija osobama koje ne podnose metadon ili koji slabo reagiraju na druge dostupne održavajuće terapije.

Ovaj Cochrane sustasvni pregled nije pronašao dovoljno dokaza koji podržavaju učinkovitost SROM za terapiju održavanja. Samo su tri randomizirane studije koje su uključivale 195 ispitanika zadovoljile kriterije uključenja u sustavni pregled literature. Zaključci dvije studije upućuju na moguće smanjenje korištenja opioida kod osoba koje su primale SROM. U drugoj studiji, upotreba SROM je povezana s manje depresivnih simptoma. Zadržavanje u terapijskom programu nije bilo ništa drugačije između uspoređivanih terapijskih intervencija. Nuspojave su bile češće u osoba koje su uzimale SROM nego onih koji su uzimali buprenorfin ili metadon, uključujući grčeve u trbuhu, glavobolju, zubobolju, konstipaciju, povraćanje i nesanicu.

Studije su imale mali broj sudionika, kratko vrijeme praćenja i bile su osmišljene tako da odgovore na drugačija pitanja. Sveukupno, kvaliteta dokaza može se procijeniti kao niska.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
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

Background

Description of the condition

Opioid dependence remains associated with public health and social problems worldwide. In the most recent World Drug Report (UNODC 2011), it is estimated that between 12 and 21 million (16.5 middle point) people had used opiates at least once in the past year in 2009. The annual prevalence rate of the world's population aged 15 to 64 years was 0.3% to 0.5% (UNODC 2011). At least three-quarters of global opiate users consume heroin. The estimate for 2009 mentioned 12 to 14 million heroin users worldwide (UNODC 2011). According to the estimates by the United Nations, most opioid users are concentrated in the Americas (particularly in North America), followed by Asia and Europe. However, heroin and opium users are mainly in Asia, followed by Europe and Africa, while, in the Americas and Oceania (New Zealand and Australia), prescription opioids appear to be the main problem. In Europe, a decline in heroin use was observed after the 1990s and the early years of the century, nevertheless this trend slowed down in 2003 to 2004 and presently the indicators suggest a stable or mixed picture (EMCDDA 2011). Among the opioid drug users, those injecting heroin constitute a particularly at risk population, not only because they become dependent faster than users with other routes of administration (EMCDDA 2011), but also because they are exposed to a series of consequences such as an increased risk of overdose mortality (Davoli 2007; Ferri 2007), infective diseases and health-related consequences. The principal pharmacological treatment of heroin dependence proved to be effective is opioid substitution treatment (WHO 2009). Several pharmacological options for substitution therapy exist and they include methadone, buprenorphine, diacetylmorphine (i.e. heroin) and slow-release oral morphine (SROM).

Description of the intervention

SROM was introduced for pain relief for which it is used interchangeably with methadone (Mitchell 2003). It has also been proven to be acceptable for opioid dependence (Fischer 1996). Interest in morphine for the treatment of drug dependence relates to specific characteristics of SROM such as remaining stable in the blood stream with once-daily administration.

Formulations of SROM suitable for once-daily dosing are marketed for pain management, and their use has been investigated in maintenance treatment of opioid dependence (Mitchell 2003). The formulations studied for opioid substitution treatment are capsules containing morphine sulphate with a slow-release coating that can be swallowed and which allows for peak plasma concentrations two to six hours after administration, and release of the drug over a 24-hour period (Bond 2012).

How the intervention might work

SROM could represent a possible alternative for opioid-dependent people who respond poorly to other available maintenance treatments as shown in a small non-comparative study testing SROM in opioid-dependent people and intolerant to methadone or with inadequate withdrawal suppression, which reported promising results (Kastelic 2008).

Why it is important to do this review

The present review considers maintenance treatment, in which the participants enter programmes of pharmacological administration to achieve stabilisation. Opioid substitution treatment involves prescribing an opioid to substitute for street heroin or other opioids. This is a long-term treatment that has been shown to reduce injecting of street heroin, the risk of death and blood-borne virus transmission, and reduce involvement in crime (WHO 2009).

Many drugs have been studied for this purpose and their efficacies have been reported in a series of trials included in different Cochrane reviews: methadone (Faggiano 2003; Mattick 2009), buprenorphine (Mattick 2008), levo-alpha-acetyl-methanol (LAAM) (Clark 2008) and heroin (Ferri 2011), alone or combined with psychosocial treatments (Amato 2011). SROM has been proposed for people who cannot tolerate methadone. In order to diversify the offer of treatment, it is important to clarify which benefit each specific intervention can bring to patients. The present review focuses on maintenance treatment through the prescription of SROM.

Key questions of the present review are about the effectiveness of SROM for unselected participants or for people who tolerate methadone poorly.

Objectives

To evaluate the efficacy of SROM as an alternative maintenance pharmacotherapy for the treatment of opioid dependence.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled studies (RCTs) and controlled clinical trials (CCTs).

Types of participants

Adults (aged ≥ 18 years) dependent on heroin according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (or International Classification of Diseases (ICD)-10) criteria seeking for maintenance treatment. Pregnant women were excluded.

Types of interventions

Treatment intervention
  • SROM for opioid dependence maintenance treatment irrespective of dosages, setting and duration of treatment.

Controls
  • No intervention.

  • Placebo.

  • Methadone maintenance.

  • Buprenorphine maintenance.

  • Waiting list for conventional treatments.

  • Psychosocial interventions.

  • Any other maintenance treatments that are compared against SROM.

Types of outcome measures

Primary outcomes
  1. Retention in treatment measured as number of participants still in treatment at the end of the study.

  2. Relapse to street heroin use measured as number of people who self reported relapse (objective measures were included if available) use of heroin during the study.

  3. Use of other substances measured as number of people who self reported use of other substances (objective measures were included if available) during the study.

  4. Death (number of people died during the study).

  5. Medical adverse events (number of people who self reported medical adverse events during the study).

Secondary outcomes
  1. Criminal offence (all information about the participants' criminal activities during the study).

  2. Incarceration/imprisonment (see Criminal offence above).

  3. Social functioning (integration at work, family relationship) (all information available about the outcomes in the study).

  4. Participant's satisfaction (participant's perception of treatment, irrespective of the evaluation instruments used).

Outcomes were not used as criteria for including studies.

Search methods for identification of studies

Electronic searches

The following electronic databases were searched for relevant trials:

  1. Cochrane Drugs and Alcohol Group's Register of Trials.

  2. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2013).

  3. PubMed (January 1966 to April 2013).

  4. EMBASE (January 1974 to April 2013).

Databases were searched using MeSH terms and free-text terms relating to opioid dependence and SROM as shown in Appendix 1. For the MEDLINE search, the Cochrane Highly Sensitive Search Strategy (sensitivity maximising version) was used to filter for RCTs (Higgins 2011). This strategy was revised appropriately for each database to take into account the differences in controlled vocabulary and syntax rules.

We also searched the following main electronic sources of ongoing trials:

Searching other resources

  • Reference lists of all relevant papers to identify further studies.

  • Conference proceedings likely to contain trials relevant to the review (e.g. the College on Problems of Drug Dependence).

  • We contacted investigators seeking information about unpublished or incomplete trials.

All searches included non-English language literature and studies with English abstracts were assessed for inclusion. When considered likely to meet inclusion criteria, studies were translated.

Data collection and analysis

Selection of studies

Two review authors (MF, SM) independently screened titles and abstracts of studies obtained by the search strategy. Each potentially relevant study located in the search was obtained in full text and assessed for inclusion independently by two review authors. In case of disagreement, a third review author (MD) was consulted.

Data extraction and management

Data were extracted independently by two review authors (MF, SM). Any disagreements were discussed and solved by consensus.

Assessment of risk of bias in included studies

The risk of bias assessment for RCTs and CCTs in this review was performed using the criteria recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The recommended approach for assessing risk of bias is a two-part tool, addressing seven specific domains, namely sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessor (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other source of bias. The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement relating to the risk of bias for that entry, in terms of low, high or unclear risk. To make these judgements, we used the criteria indicated by the Cochrane Handbook for Systematic Reviews of Interventions adapted to the addiction field. See Table 1 for details.

Table 1. Criteria for risk of bias in randomised controlled trials (RCTs) and controlled clinical trials (CCTs)
 Item  Judgement  Description

1. Random sequence generation (selection bias)

 

 

Low risk
  • The investigators describe a random component in the sequence generation process such as: random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation

High risk
  • The investigators describe a non-random component in the sequence generation process such as: odd or even date of birth; date (or day) of admission; hospital or clinic record number; alternation; judgement of the clinician; results of a laboratory test or a series of tests; availability of the intervention

Unclear risk
  • Insufficient information about the sequence generation process to permit judgement of low or high risk

2. Allocation concealment (selection bias)

 

 

Low risk
  • Investigators enrolling participants could not foresee assignment because 1 of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based, and pharmacy-controlled, randomisation); sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes

High risk
  • Investigators enrolling participants could possibly foresee assignments because 1 of the following method was used: open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure

Unclear risk
  • Insufficient information to permit judgement of low or high risk. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement

3. Blinding of participants and providers (performance bias):

objective outcomes 

Low risk

 

 

  • No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding

  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

4. Blinding of participants and providers (performance bias):

subjective outcomes

 

 

Low risk

 

  • Blinding of participants and providers and unlikely that the blinding could have been broken

High risk
  • No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding

Unclear risk
  • Insufficient information to permit judgement of low or high risk

5. Blinding of outcome assessor (detection bias):

objective outcomes 

Low risk

 

 

  • No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding

  • Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

6. Blinding of outcome assessor (detection bias):

subjective outcomes

 

 

Low risk

 

  • No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding

  • Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken

High risk
  • No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding

  • Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding

Unclear risk
  • Insufficient information to permit judgement of low or high risk

7. Incomplete outcome data (attrition bias):

for all outcomes except retention in treatment or dropout

 

 

Low risk

 

 

 

  • No missing outcome data

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias)

  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size

  • Missing data have been imputed using appropriate methods

  • All randomised participants are reported/analysed in the group they were allocated to by randomisation irrespective of non-compliance and co-interventions (intention to treat)

High risk
  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size

  • 'As-treated' analysis done with substantial departure of the intervention received from that assigned at randomisation

Unclear risk
  • Insufficient information to permit judgement of low or high risk (e.g. number randomised not stated, no reasons for missing data provided

  • Number of dropouts not reported for each group)

8. Selective reporting (reporting bias)

 

 

Low risk
  • The study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way

  • The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon)

High risk
  • Not all of the study's pre-specified primary outcomes have been reported

  • 1 or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified

  • 1 or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect)

  • 1 or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study

Unclear risk
  • Insufficient information to permit judgement of low or high risk

The domains of sequence generation and allocation concealment (avoidance of selection bias) were addressed in the tool by a single entry for each study.

Blinding of participants, personnel and outcome assessor (avoidance of performance bias and detection bias) were considered separately for objective outcomes (e.g. dropout, use of substance of abuse measured by urine analysis, subjects relapsed at the end of follow-up, subjects engaged in further treatments) and subjective outcomes (e.g. duration and severity of signs and symptoms of withdrawal, participant self reported use of substance, side effects, social functioning as integration at school or at work, family relationship).

Incomplete outcome data (avoidance of attrition bias) were considered for all outcomes except for the dropout from the treatment, which is very often the primary outcome measure in trials on addiction.

Two review authors (MF, SM) independently applied the 'Risk of bias' tool to included studies.

Measures of treatment effect

Dichotomous outcomes were analysed calculating the risk ratio (RR) for each trial with the uncertainty in each result being expressed by their 95% confidence intervals (CIs). Continuous outcomes were analysed calculating the mean difference (MD) or the standardised mean difference (SMD) with 95% CIs. For outcomes assessed by scales we compared and pooled the mean score differences from the end of treatment to baseline (post minus pre) in the experimental and control group. In case of missing data about the standard deviation of the change, we imputed this measure using the standard deviation at the end of treatment for each group.

Unit of analysis issues

We did not used data presented as number of positive urine tests over total number of tests in the experimental and control group as a measure of substance abuse. This is because using the number of tests instead of the number of participants as the unit of analysis violates the hypothesis of independence among observations. In fact, the results of tests done in each participant are not independent.

If all arms in a multi-arm trial were included in the meta-analysis and one treatment arm was to be included in more than one of the treatment comparisons, we divided the number of events and the number of participants in that arm by the number of treatment comparisons made. This method avoids the multiple use of participants in the pooled estimate of treatment effect while retaining information from each arm of the trial. It compromises the precision of the pooled estimate slightly.

Dealing with missing data

Study authors were contacted to request any data missing from included studies.

Assessment of heterogeneity

Statistically significant heterogeneity among primary outcome studies was assessed using the Chi2 test and I2 statistic (Higgins 2011). A significant Chi2 (P value < 0.10) and I2 statistic of at least 50% were considered as statistical heterogeneity.

Assessment of reporting biases

Funnel plots (plot of the effect estimate from each study against the sample size or effect standard error) were planned to be used to assess the potential for bias related to the size of the trials, which could indicate possible publication bias. Only four studies were retrieved so the funnel plot could not be used.

In order to grade the quality of the evidence, the Grading of Recommendation, Assessment, Development, and Evaluation Working Group (GRADE) (a system for grading the quality of evidence (GRADE Working Group 2004; Guyatt 2008; Guyatt 2010; Schünemann 2006) that takes into account issues not only related to internal validity but also to external validity such as directness of results) was planned to be used. The overall quality of the evidence for each outcome of this review was assessed using the GRADE system. The 'Summary of findings' tables present the main findings of a review in a transparent and simple tabular format. In particular, they provide key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the main outcomes.

The GRADE system uses the following criteria for assigning grade of evidence:

  • high = further research is very unlikely to change our confidence in the estimate of effect;

  • moderate = further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate;

  • low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;

  • very low = any estimate of effect is very uncertain.

Decrease grade if:

  • serious (-1) or very serious (-2) limitation to study quality;

  • important inconsistency (-1);

  • some (-1) or major (-2) uncertainty about directness;

  • imprecise or sparse data (-1);

  • high probability of reporting bias (-1).

Increase grade if:

  • strong evidence of association:- significant RR of greater than 2 (< 0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1);

  • very strong evidence of association: significant RR of greater than 5 (< 0.2) based on direct evidence with no major threats to validity (+2);

  • evidence of a dose-response gradient (+1);

  • all plausible confounders would have reduced the effect (+1).

Because of the paucity of retrieved studies and the fact that results were not pooled, 'Summary of finding' table was not done.

Data synthesis

Given the expected heterogeneity of the results among studies due to differences in the populations, types of control interventions, and setting dosages and duration of treatment intervention, the outcome measures from the individual trials were planned to be combined through meta-analysis when possible (clinical comparability of intervention and outcomes between trials) using a random-effects model. Only four studies with different outcomes were found so meta-analyses were not judged to be appropriate.

Sensitivity analysis

To incorporate assessment in the review process we planned to first plot intervention effects estimates stratified for risk of bias for each relevant domain. If differences in results among studies were identified at different risk of bias, we planned to perform sensitivity analysis excluding from the analysis studies with high risk of bias. We also planned to perform subgroup analysis for studies with low and unclear risk of bias. Meta-analyses were not performed for the reason explained above, and consequently the planned sensitivity analysis was not possible.

Results

Description of studies

Results of the search

After removing duplicates, the electronic search identified 1702 unique records. Through the screening of titles and abstracts, 1692 records were excluded as obviously irrelevant. The full-text reports of the remaining 10 records were examined. Two further titles (Fischer 1996; Sherman 1996) were found on already published reviews and full text of these articles were searched but not yet found, we classified them as awaiting assessment. Twelve titles relating to eight original studies were assessed for inclusion. Five studies were excluded after full-text examination. Three studies (five articles) were finally included. The study flow diagram of the search is shown in Figure 1.

Figure 1.

Study flow diagram.

Included studies

Three studies were included with 195 people (Clark 2002; Eder 2005; Giacomuzzi 2006).

For one study, only a conference abstract was available (Clark 2002). The study was an open-label cross-over study enrolling 11 people administered methadone or SROM for six week each.

Giacomuzzi 2006 compared physical symptoms, quality of life and urine analysis of participants at admission for maintenance treatment with people already in treatment. The three treatments compared were: oral methadone, sublingual buprenorphine and SROM given for six months. A total of 120 people were randomised to the three treatments.

Eder 2005 was a double-blind, double-dummy cross-over trial comparing SROM with methadone for seven weeks in 64 people.

Two studies were conducted in Austria (Eder 2005; Giacomuzzi 2006) and the third in Australia (Clark 2002).

Excluded studies

Five studies were excluded after full-text examination. Reasons for exclusions were: the type of intervention not in the inclusion criteria (i.e. SROM used for detoxification rather than maintenance treatment) (one study) (Madlung-Kratzer 2009); study design not in the inclusion criteria, as four studies were non-randomised or uncontrolled studies (Mitchell 2003; Mitchell 2004; Mitchell 2006; Moldovanyi 1996).

Risk of bias in included studies

See Figure 2; Figure 3.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Only one study was judged as a low risk of bias for selection bias (adequate random sequence generation and allocation concealment) (Eder 2005). The other two studies did not provide a description for this item and were judged to be at unclear risk of bias.

Blinding

Only one study was double-blinded, double-dummy (Eder 2005). The other two were open label (Clark 2002; Giacomuzzi 2006)

Incomplete outcome data

All the studies were judged at low risk of bias for this outcome.

Selective reporting

All the studies were judged at low risk of bias for this outcome.

Effects of interventions

Retention in treatment

In Clark 2002, nine participants out of 11 (81.8%) completed the study. It was not reported whether dropout occurred during the methadone or the SROM phase.

In Eder 2005, five out of 32 participants dropped out during the SROM phase and four out of 32 during the methadone phase (14%).

In Giacomuzzi 2006, no information was reported on dropout but it seems that all participants remained in treatment until the end of the study.

Use of primary substance of abuse

In Clark 2002, it was reported that among the participants completing the study, there were no clinically or statistically significant differences in heroin use.

In Eder 2005, six participants (10%) during treatment with SROM and 11 participants (19%) during treatment with methadone had evidence of
fresh needle marks to indicate concomitant intravenous drug abuse.

In Giacomuzzi 2006, no data were reported on use of heroin. The only available information was that "post hoc paired group comparisons showed statistically significant differences between clients at admission and SROM maintenance treatment in opioid consumption p<0.001) in which participants in the SROM group showed the more favourable values".

Use of other substances

In Clark 2002, it was reported that of those who completed, there were no clinically or statistically significant differences in other drug use.

In Eder 2005, cocaine usage increased significantly over time in both treatment groups (P value < 0.001). Benzodiazepine urinalysis results remained stable throughout the study. Concomitant amphetamine consumption never exceeded 2%. There was no significant difference between treatment groups or medications (data shown only in figure).

In Giacomuzzi 2006, the only available information was that "post hoc paired group comparisons showed statistically significant differences between clients at admission and SROM maintenance treatment in cocaine consumption p<0.001) in which participants in the SROM group showed the more favourable values".

Social functioning and participant satisfaction

In Clark 2002, it was reported that among completing participants, there were no clinically or statistically significant differences in severity of dependence or mental health/social functioning. There was a trend for less severe opiate withdrawal symptoms between doses among people taking morphine than those taking methadone (withdrawal score 2.2 vs. 4.8, P value = 0.06). Morphine was generally well tolerated and was preferred by seven out of nine subjects. No participants complained that morphine did not "hold" for the 24-hour dosing interval.

In Eder 2005, a statistically significant interaction between time and group was apparent for heroin (P value = 0.037) and alcohol (P value = 0.013) craving with craving reduced more during SROM treatment (data shown only in figure). A decrease in depressive symptoms (measured by Beck Depression Inventory (BDI)) and physical
complaints (measured using the Beschwerde-Liste (BL)) was achieved at the time of cross-over with a significant difference (P value < 0.001) in the second period in favour of SROM and a significant increase for people treated with methadone in the second study period. Similarly, there was a statistically significant time effect for anxiety scores (State-Trait Anxiety Inventory (STAI)) (P value = 0.008) and a statistically significant interaction for time and group (P value = 0.003) in favour of morphine (data shown only in figure). For quality of life at cross-over (week 7) and at the end of the study phase (week 14), no significant differences between groups were found in any of the six QoL domains.

In Giacomuzzi 2006, people on SROM generally showed less favourable values in QoL score than people on methadone or sublingual buprenorphine. Methadone and buprenorphine maintained group showed significantly more favourable values for finances (4.4 and 4.2 vs. 2.6, P value < 0.010), family (5.8 and 5.1 vs. 3.6, P value < 0.044), and overall satisfaction (5.3 and 4.9 vs. 4.1, P value < 0.031) compared to people maintained on SROM. The methadone group showed more favourable value for leisure time (5.4 vs. 3.7, P value < 0.001), housing (6.1 vs. 4.7, P value < 0.023), partnership (5.7 vs. 4.2 , P value = 0.034), friends and acquaintances (5.6 vs. 4.4, P value = 0.003), mental health (5.0 vs. 3.4, P value = 0.002) and self esteem (8.2 vs. 5.7, P value = 0.002) compared to people on SROM. A statistically significant difference between buprenorphine and SROM was found for physical health in favour of buprenorphine (4.8 vs. 3.3, P value = 0.043).

Medical adverse events

In Eder 2005, at least one side effect was reported by 82% of participants receiving morphine and 76% of those receiving methadone. The most commonly reported adverse event for morphine capsules was toothache (26%), followed by headache (23%), constipation (11%) and influenza (11%). The most commonly reported adverse events for methadone solution were: toothache (22%), vomiting (17%), headache (14%) and stomach ache (12%). Sleep disturbance and insomnia were commonly reported with methadone (15% of people) but not with morphine. None of these adverse events were rated as serious or considered to be treatment-related. One person receiving SROM was withdrawn from the study because of aggravation of depression and required hospital treatment a few days after discontinuing the study.

In Giacomuzzi 2006, it was reported that buprenorphine- and methadone-treated participants showed significantly more favourable values than the group maintained on SROM for stomach cramps (17% and 13% vs. 47%, P value < 0.013), fatigue or tiredness (50% and 30% vs. 80%, P value < 0.015), general aches and pain (13% and 20% vs. 33%, P value < 0.001) and insomnia (40% and 40% vs. 68%, P value < 0.023). People treated with methadone had fewer problems in falling asleep compared with people treated with SROM (36% vs. 70%, P value = 0.009) and people treated with sublingual buprenorphine experienced less depression than people treated with SROM (37% vs. 68%, P value = 0.023).

Discussion

Summary of main results

The studies currently available do not allow evaluation of the effectiveness of SROM as an alternative substitution intervention for opioid dependence over the commonly adopted measures of outcomes because of the weakness of study design (cross-over studies with small sample size and very short follow-up). Nevertheless they provided some useful insights that can serve as basis for further investigation.

The available studies did not identify differences in terms of retention in treatment among the periods in which participants were taking SROM and those when they were on methadone. When looking at the concomitant use of opioids during treatment, in one of the three studies included, a lower percentage of participants in the SROM period had signs of injections indicating intravenous drug use. Use of other substances was measured in two studies and none of them identifying any significant difference.

SROM gave better results than methadone for depressive symptoms, physical complaints and anxiety scores but no differences were observed at cross-over or at the conclusion in one study that measured QoL. Nevertheless in a further study measuring QoL with the same scale, SROM gave less favourable results than methadone and sublingual buprenorphine.

The measures related to social functioning gave better results for people in methadone and sublingual buprenorphine than those on SROM, but, in a small study, SROM was preferred by seven out of nine participants.

As far as the safety of the drug was concerned, two of the three included studies reported medical adverse effects and people treated with SROM consistently reported more health problems than people treated with buprenorphine and methadone; symptoms included stomach cramps, headache, toothache, constipation, vomiting and insomnia.

Overall completeness and applicability of evidence

SROM is currently provided as an alternative drug for substitution treatment for opioid dependence in some European countries such as Bulgaria, Austria, Slovenia, Slovakia and, only occasionally, in France (EMCDDA 2011) and Australia. it is, therefore, important to understand its specific role in the offer of substances for substitution treatment in opioid dependence. Nevertheless the available experimental studies do not provide sufficient evidence to support or discard the use of such a medicine to stabilise opioid-dependent people.

Generalisation of results based on 195 people would be inappropriate due to heterogeneity of this small sample. For instance, Eder 2005 excluded people who were already in maintenance therapy, whereas Giacomuzzi 2006 enrolled people who had been in treatment for at least six months with methadone, buprenorphine or SROM. As each study design answered a different question and other studies that are not included in the present review are available, it was useful to put together the results from the existing experimental studies to assess the effectiveness of SROM for maintenance therapy; however, the present review could not reach conclusions due to the small number of existing studies.

Quality of the evidence

Overall, the quality of the evidence can be judged to be low: only one out of three studies had adequate protection against selection, performance and detection bias for subjective outcomes (Eder 2005). Two out of three studies were cross-over studies with the main aim to assess acceptability and adverse effects of treatments (Clark 2002; Eder 2005). The third study (Giacomuzzi 2006) compared physical symptoms, QoL and urinalysis of people at admission for maintenance treatment with people already having treatment and did not provide information on how people already having treatment were randomised to different treatment options.

Potential biases in the review process

A comprehensive literature search was undertaken looking for both published and unpublished trials. Authors with an expertise in the field were contacted in order to retrieve any further articles missed by the electronic search. Even though it was not possible to produce a funnel plot to investigate the possibility of publication bias due to the small number of included studies, we are confident that we have not missed relevant RCTs on SROM.

Agreements and disagreements with other studies or reviews

A comprehensive review was published by Jegu and colleagues that included all the available studies on SROM for maintenance therapy irrespective of the design, which identified only one of the three RCTs included in the present review (Jegu 2011). Notwithstanding, the authors reached the same conclusions as ours that the presently available evidence is insufficient to assess the effectiveness of SROM for opioid maintenance therapy. van den Brink in his overview of pharmacological interventions for the treatment of substance use disorders and pathological gambling, described the results of four studies on the acceptability of the intervention (excluded by the present review because of study design) but no conclusions were drawn about SROM (van den Brink 2012). Soyka and colleagues developed a Guidelines for the Biological Treatment of Substance Abuse and related disorders whose literature review includes one acceptability study and one non-randomised studies (both excluded by the present review because of study design not in the inclusion criteria) but no specific recommendations addressed SROM (Soyka 2011). In a recent study SROM was prescribed to substitute complementary methadone in a group of 12 patients attending a supervised injecting clinic for prescribed injectable diamorphine, and intolerant to methadone, giving promising results (Bond 2012).

Authors' conclusions

Implications for practice

No implication for practice could be drawn by this review as not enough experimental studies were available.

Implications for research

Further studies may enrol participants who proved to be intolerant to methadone (or in need of suspending it) and this would justify the use of a substance that may have a higher level of adverse effects. Those studies should be empowered to identify possibly significant differences in terms of retention in treatment. An accurate and objective measure of non-prescribed opioid use during treatment would further explore the potential of SROM for reducing this habit.

Parallel group RCTs with adequate sample size comparing SROM with methadone or buprenorphine maintenance treatment with long follow-up and assessing retention in treatment and use of primary substance of abuse are strongly recommended before SROM is used in routine clinical practice.

Measure of participant and carer preferences should also be accurately collected in order to identify the role that each substitution substance may play in the global offer of pharmacological treatment for opioid addiction, taking into account the trade-off between benefits and risks (i.e. possible risks of diversion (Beer 2010)).

Acknowledgements

We thank Zuzana Mitrova for her help in preparing the search strategy.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. PubMed search strategy

  1. "Opioid-Related Disorders"[Mesh]

  2. (opiat*[tiab] or opioid*[tiab] or heroin*[tiab] or narcot*[tiab] or methadone[tiab] buprenorphine[tiab])

  3. #1 or #2

  4. (withdraw*[tiab] or abstinen*[tiab] or abstain*[tiab] or abuse*[tiab] or abusing[tiab] or  dependen*[tiab] or addict*[tiab] or overdos*[tiab] or "over-dose"[tiab] or intoxicat*[tiab] )

  5. #3 AND #4

  6. "Morphine"[Mesh]

  7. morphine[tiab]

  8. #6 or #7

  9. randomized controlled trial [pt]

  10. controlled clinical trial [pt]

  11. randomized [tiab]

  12. drug therapy [sh]

  13. randomly [tiab]

  14. trial [tiab]

  15. groups [tiab]

  16. #9 or #10 or #11 or #12 or #13 or #14 or #15

  17. animals [mh] NOT humans [mh]

  18. #16 NOT #17

  19. #5 AND #8 AND #18

Appendix 2. CENTRAL search strategy

  1. MeSH descriptor Opioid-Related Disorders explode all trees

  2. (opiat* or opioid* or heroin* or narcot* or methadone or buprenorphin):ti,ab,kw

  3. (#1 OR #2)

  4. (withdraw* or abstinen* or abstain* or abuse* or abusing or dependen* or addict* or overdos* or "over-dose" or intoxicat*):ti,ab,kw

  5. (#3 AND #4)

  6. SROM:ti,ab

  7. (morphine):ti,ab,kw

  8. MeSH descriptor Morphine explode all trees

  9. (#6 OR #7 OR #8)

  10. (#5 AND #9)

Appendix 3. EMBASE search strategy

  1. 'opiate addiction'/exp

  2. opioid*:ab,ti OR heroin*:ab,ti OR narcot*:ab,ti OR methadone:ab,ti OR buprenorphine:ab,ti

  3. #1 OR #2

  4. (withdraw*:ab,ti OR abstinen*:ab,ti OR abstain*:ab,ti OR abuse*:ab,ti OR abusing:ab,ti OR dependen*:ab,ti OR addict*:ab,ti OR overdos*:ab,ti OR 'over-dose':ab,ti OR intoxicat*:ab,ti)

  5. #3 AND #4

  6. morphine:ab,ti OR

  7. 'morphine'/exp OR

  8. srom:ab,ti

  9. #6 OR #7 OR #8

  10. 'crossover procedure'/exp

  11. 'double blind procedure'/exp

  12. 'single blind procedure'/exp

  13. 'controlled

  14. clinical trial'/exp

  15. 'clinical trial'/exp

  16. placebo:ab,ti OR 'double blind':ab,ti OR 'single blind':ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR volunteer*:ab,ti OR random*:ab,ti OR factorial*:ab,ti OR crossover:ab,ti OR (cross:ab,ti AND over:ab,ti) OR

  17. 'randomized controlled trial'/exp

  18. #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17

  19. #5 AND #9 #18 AND [humans]/lim AND [embase]/lim

Contributions of authors

Designing the review: Ferri, Minozzi, Amato, Bo.

Screening search results, screening retrieved papers against inclusion criteria, extracting data from paper: Ferri, Minozzi.

Writing the review: Ferri, Minozzi, Amato.

Appraising quality of papers: Minozzi.

Analysis of data: Ferri, Minozzi, Amato, Bo.

Providing general advice on the review: Davoli.

Declarations of interest

None known.

Sources of support

Internal sources

  • Department of Epidemiology, Lazio Regional Health Service, Not specified.

External sources

  • EMCDDA, Portugal.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Clark 2002

MethodsOpen-label cross-over randomised controlled trial
Participants11 stable methadone maintained participants using heroin on average once per week
Interventions

Experimental intervention: 6 weeks' morphine

Control intervention: 6 weeks' methadone

No information on dosages available

OutcomesSeverity of opiate withdrawal symptoms, heroin or other drug use, severity of dependence, mental health/social functioning
Notes

9 people completed the trial

Only conference abstract available

Country: Australia

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "outpatient, open label comparison of once daily morphine with methadone was conducted using a randomised crossover design"
Allocation concealment (selection bias)Unclear riskQuote: "outpatient, open label comparison of once daily morphine with methadone was conducted using a randomised crossover design"
Blinding of participants and personnel (performance bias)
objective outcomes
Low riskThe outcome was not likely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias)
subjective outcomes
High riskOpen label
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskHeroin use was measured in the last week of each treatment period by self report and by detection of 6-monoacetymorphine (6-MAM) in hair and urine. No description on how other outcomes were assessed
Incomplete outcome data (attrition bias)
All outcomes
Low risk2 people withdrew from the study
Selective reporting (reporting bias)Low risk 

Eder 2005

Methods14-week randomised, double-blind, double-dummy, cross-over study
Participants

64 participants (56 men, 8 women) with opioid dependence; mean age: 28 yea; men: 75%.

Inclusion criteria: 19-60 years of age and had a diagnosis of opioid dependence according to DSM-IV, German version of the EuropASI for current and past history of use

Exclusion criteria: serious psychiatric or somatic illnesses (excluding hepatitis) or already receiving maintenance therapy. Co-dependence on alcohol or
cocaine was not permitted. The misuse of benzodiazepines, assessed according to DSM-IV criteria, was not an exclusion criterion at enrolment but participants were gradually
withdrawn within the first 2 weeks of the study using meprobamate

Interventions

Experimental intervention: 1-week titration and a 6-week fixed-dose treatment phase, morphine was
administered daily under supervised conditions

Control intervention: 1-week titration and a 6-week fixed-dose treatment phase, methadone was
administered daily under supervised conditions

Participants received either SROM capsules followed by methadone oral solution, or vice versa, over two 7-week study phases (a 1-week titration and a 6-week treatment phase)

All participants started on a dose of either SROM 200 mg or oral methadone 40 mg. Dose titration increments to 440, 600 and 800 mg/day were available during induction onto SROM and increments to 70, 85 and 100 mg/day were available during methadone induction. There was no washout
period between the 2 study phases to avoid severe withdrawal symptoms

Outcomes

Retention, use of illicit substances based on urinalysis, extent of drug cravings, withdrawal symptoms
and general well being. Safety was assessed on the basis of adverse events and clinical and physical examination

QoL measured by the Lancashire Quality of Life Profile

NotesCountry: Austria
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Research pharmacists conducting the randomisation based on a computer program"
Allocation concealment (selection bias)Low riskQuote: "Randomization was conducted in the hospital pharmacy, located in the general hospital (however, separated from the drug addiction clinic). Research pharmacists conducting
the randomisation based on a computer program never saw patients"
Blinding of participants and personnel (performance bias)
objective outcomes
Low riskTo maintain the blinding, placebo treatments matched the alternative active treatment. Placebo methadone oral solution contained dextromethorphan 30 mg (Nowak GmbH, Lübeck, Germany) to simulate the taste of methadone, as used previously in double-dummy trials
Blinding of participants and personnel (performance bias)
subjective outcomes
Low riskTo maintain the blinding, placebo treatments matched the alternative active treatment. Placebo methadone oral solution contained dextromethorphan 30 mg (Nowak GmbH, Lübeck, Germany) to simulate the taste of methadone, as used previously in double-dummy trials
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "All people involved in performing the study were completely unaware of treatment group until the code was broken after the last patient finished the study"
Incomplete outcome data (attrition bias)
All outcomes
Low risk55 people (86%) completed both study phases
Selective reporting (reporting bias)Low risk 

Giacomuzzi 2006

  1. a

    DSM-IV: Diagnostic and Statistical Manual of Mental Disorders Version IV; EuropASI: European Addiction Severity Index; QoL: quality of life; SROM: slow-release oral morphine.

MethodsRandomised controlled trial
Participants

120 opioid-dependent people according to DSM-IV criteria and were on methadone, men: 57%; mean age: 27 years

Inclusion criteria: current diagnosis of opioid dependence based on the criteria of DSM-IV at admission or to be in methadone, sublingual buprenorphine or SROM maintenance programme for 6 months, living at a commuting distance to the hospital and be mentally competent to give informed consent

Exclusion criteria: acute medical condition at 6 months of treatment, were currently using antipsychotic medication or where in another trial. Forced discharge criteria were limited to drug trafficking in the clinical centre or aggressive behaviour

Interventions

Experimental intervention: SROM for 6 months (n = 40)

Control 1: methadone for 6 months (n = 40)

Control 2: sublingual buprenorphine for 6 months (n = 40)

During induction: methadone 10-30 mg, SROM 60-180 mg, sublingual buprenorphine 2-8 mg

Outcomes

QoL measured by the Lancashire Quality of Life Profile

Withdrawal symptoms measured by the Opioid Withdrawal Scale

NotesCountry: Austria
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "patients were randomised to receive methadone sublingual buprenorphine or slow release oral morphine"
Allocation concealment (selection bias)Unclear riskQuote: "patients were randomised to receive methadone sublingual buprenorphine or slow release oral morphine"
Blinding of participants and personnel (performance bias)
objective outcomes
Low riskOpen label, but the outcome is not likely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias)
subjective outcomes
High riskOpen label
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo withdrawn from the study
Selective reporting (reporting bias)Low risk 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Bond 2012Study design not in the inclusion criteria
Madlung-Kratzer 2009Participants willing to undergo detoxification
Mitchell 2003Cross-over, non-randomised study
Mitchell 2004Cross-over, non-randomised study
Mitchell 2006Cross-over, non-randomised study
Moldovanyi 1996Uncontrolled study

Characteristics of studies awaiting assessment [ordered by study ID]

Fischer 1996

MethodsNo available data
ParticipantsNo available data
InterventionsNo available data
OutcomesNo available data
Notes 

Sherman 1996

MethodsNo available data
ParticipantsNo available data
InterventionsNo available data
OutcomesNo available data
Notes 

Characteristics of ongoing studies [ordered by study ID]

NCT01079117-SROM

  1. a

    ALAT: alanine transaminase; ASAT: aspartate aminotransferase; SROM: slow-release oral morphine.

Trial name or titleMorphine Slow-release Capsules in Substitution Therapy
MethodsMulticentre, multinational phase III study. Randomised, open-label cross-over design
Participants

Inclusion criteria:

  • minimum age: 18 years

  • fixed abode

  • at least 26 weeks of treatment (up to date) receiving a minimum dose of methadone 50 mg or levomethadone ≥ 25 mg/day at inclusion. Participants on levomethadone must be informed and agree to be switched to methadone

  • mature and capable of acting responsibly, in possession of all mental faculties

  • women must have a negative urine pregnancy test recorded prior to the first dose of study medication and regular negative urine pregnancy tests every 4 weeks. SUB9001 - Integrated Study Protocol 10/58, 13 June 2009

  • hormonal contraception (oral, transdermal, vaginal, intrauterine or subcutaneous) by women of child-bearing age

  • no intention of reducing the substitute medication during the trial

  • acceptance of the trials rules and regulations

  • acceptance to participate in the study

Exclusion criteria:

  • (desired) pregnancy during the trial

  • breastfeeding

  • grave or acute somatic illnesses (e.g. cardiovascular, serious kidney or liver affection (ALAT or ASAT > 5 x augmented)) or other somatic disorder

  • severe unstable mental health problems

  • taking monoamine oxidase inhibitors

  • intracranial injury

  • intracranial hypertension

  • history of epilepsy

  • severe chronic obstructive lung disease

  • chronic respiratory failure

  • known hypersensitivity to morphine or methadone

  • pancreatitis

  • paralytic ileus

  • baseline QTc interval > 450 mseconds

  • long QT syndrome

  • people who have participated in another clinical research study involving a new chemical entity within 3 months of study entry

  • people with pending imprisonment at the time of inclusion

InterventionsThe participants will be randomised to either 10 weeks of treatment with methadone or SROM. After an adjustment phase of 1 week they first will be medicated for 10 weeks with the treatment to which SUB9001 - Integrated Study Protocol 9/58 13 June 2009 they have been randomised. The cross-over, in which all subjects change to their opposite treatment, will serve for an additional adjustment phase of 1 week. After the second and new adjustment phase they will be treated for 10 weeks with the newly adjusted medication. After the end of week 22 all participants continue with, or switch back to, SROM for another 6 months (weeks 23-47)
Outcomes

The objective of this study is to compare the effectiveness of SROM treatment in people that previously have been treated with methadone. Efficacy is to be assessed by the frequency of by-consumption of illicit substances. The primary efficacy end point in this study will be the proportion of positive urine tests for by-consumption of target substances per person. Target substances are defined as all opioids except the study drug.

The proportions are compared between substitution with methadone and SROM treatment in a cross-over design

The secondary end points will be:

  1. effects of SROM on retention rate

  2. by-consumption of other drugs (cocaine, alcohol, cannabis, benzodiazepines)

  3. occurring psychopathological and somatic symptoms

  4. effect of treatment on the electrocardiogram (QTc prolongation)

  5. group characterisation of participants who are keen to change the medication

  6. change in dosage of treatment over time

  7. self- assessed craving for opioids

  8. self assessed satisfaction with treatment

  9. nature, frequency and severity of occurring adverse events in the 2 treatment groups

  10. assessment of safety parameters

Starting dateOctober 2006
Contact informationMondipharma, Medical Company, Zurick, Switzerland
Notes 

Ancillary