cochrane database of systematic reviews (reviews) || slow-release oral morphine as maintenance...

Slow-release oral morphine as maintenance therapy for

opioid dependence (Review)

Ferri M, Minozzi S, Bo A, Amato L

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2013, Issue 6

http://www.thecochranelibrary.com

Slow-release oral morphine as maintenance therapy for opioid dependence (Review)

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iSlow-release oral morphine as maintenance therapy for opioid dependence (Review)


[Intervention Review]

Slow-release oral morphine as maintenance therapy foropioid dependence

Marica Ferri1, Silvia Minozzi2 , Alessandra Bo1, Laura Amato2

1Interventions, Best Practice and Scientific Partners, European Monitoring Centre for Drugs and Drug Addiction, Lisbon, Portugal.2Department of Epidemiology, Lazio Regional Health Service, Rome, Italy

Contact address: Marica Ferri, Interventions, Best Practice and Scientific Partners, European Monitoring Centre for Drugs and Drug

Addiction, Cais do Sodre’ 1249-289 Lisbon, Lisbon, Portugal. [email protected].

Editorial group: Cochrane Drugs and Alcohol Group.

Publication status and date: New, published in Issue 6, 2013.

Review content assessed as up-to-date: 24 August 2012.

Citation: Ferri M, Minozzi S, Bo A, Amato L. Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane

Database of Systematic Reviews 2013, Issue 6. Art. No.: CD009879. DOI: 10.1002/14651858.CD009879.pub2.


A B S T R A C T

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.

1Slow-release oral morphine as maintenance therapy for opioid dependence (Review)


mailto:[email protected]

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.

P L A I N L A N G U A G E S U M M A R Y

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, buprenor-

phine, 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.



B A C K G R O U N D

Description of the condition

Opioid dependence remains associated with public health and so-

cial 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 pop-

ulation 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 world-

wide (UNODC 2011). According to the estimates by the United

Nations, most opioid users are concentrated in the Americas (par-

ticularly in North America), followed by Asia and Europe. How-

ever, heroin and opium users are mainly in Asia, followed by Eu-

rope and Africa, while, in the Americas and Oceania (New Zealand

and Australia), prescription opioids appear to be the main prob-

lem. 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 in-

clude 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 in-

terchangeably 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 mar-

keted 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 concen-

trations 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 treat-

ments 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 re-

sults (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 opi-

oids. 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 clar-

ify 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.

O B J E C T I V E S

To evaluate the efficacy of SROM as an alternative maintenance

pharmacotherapy for the treatment of opioid dependence.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled studies (RCTs) and controlled clinical tri-

als (CCTs).



Types of participants

Adults (aged ≥ 18 years) dependent on heroin according to Diag-

nostic 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 re-

lating 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:

• ClinicalTrials.gov (www.clinicaltrials.gov);

• World Health Organization (WHO) International Clinical

Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/);

• Current Controlled Trials (www.controlled-trials.com/);

• EU Clinical Trials Register (www.clinicaltrialsregister.eu);

• Osservatorio Nazionale sulla Sperimentazione Clinica dei

Medicinali (oss-sper-clin.agenziafarmaco.it);

• Trials (www.trialsjournal.com).

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 consid-

ered 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 poten-

tially 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.



http://www.clinicaltrials.gov

http://apps.who.int/trialsearch/

http://apps.who.int/trialsearch/

http://www.controlled-trials.com/

http://www.controlled-trials.com/

http://www.clinicaltrialsregister.eu

http://oss-sper-clin.agenziafarmaco.it



http://www.trialsjournal.com

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 genera-

tion and allocation concealment (selection bias), blinding of par-

ticipants 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 re-

ported 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 judge-

ments, we used the criteria indicated by the Cochrane Handbook for

Systematic Reviews of Interventions adapted to the addiction field.

See Table 1 for details.

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 (avoid-

ance of performance bias and detection bias) were considered sep-

arately 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 rela-

tionship).

Incomplete outcome data (avoidance of attrition bias) were con-

sidered for all outcomes except for the dropout from the treat-

ment, 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 ex-

pressed by their 95% confidence intervals (CIs). Continuous out-

comes 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 differ-

ences 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 indepen-

dent.

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 par-

ticipants in the pooled estimate of treatment effect while retaining

information from each arm of the trial. It compromises the preci-

sion 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 Rec-

ommendation, Assessment, Development, and Evaluation Work-

ing Group (GRADE) (a system for grading the quality of ev-

idence (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 di-

rectness 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 for-

mat. 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 interven-

tions, 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 com-

parability 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.

R E S U L T S

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 ran-

domised 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 mainte-

nance treatment) (one study) (Madlung-Kratzer 2009); study de-

sign not in the inclusion criteria, as four studies were non-ran-

domised 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 conceal-

ment) (Eder 2005). The other two studies did not provide a de-

scription 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 com-

pleting 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 metha-

done 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 urinal-

ysis results remained stable throughout the study. Concomitant

amphetamine consumption never exceeded 2%. There was no sig-

nificant 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 dif-

ferences 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 partic-

ipants, there were no clinically or statistically significant differ-

ences in severity of dependence or mental health/social function-

ing. 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). Mor-

phine 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 sig-

nificant 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 main-

tained group showed significantly more favourable values for fi-

nances (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 differ-

ence 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 partic-

ipants 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 ad-

verse events for methadone solution were: toothache (22%), vom-

iting (17%), headache (14%) and stomach ache (12%). Sleep dis-

turbance 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 be-

cause 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 stom-

ach 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 de-

pression than people treated with SROM (37% vs. 68%, P value

= 0.023).

D I S C U S S I O N

Summary of main results

The studies currently available do not allow evaluation of the ef-

fectiveness 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 stud-

ies with small sample size and very short follow-up). Nevertheless

they provided some useful insights that can serve as basis for fur-

ther investigation.

The available studies did not identify differences in terms of reten-

tion 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 symp-

toms, 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 meth-

adone 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 in-

cluded studies reported medical adverse effects and people treated

with SROM consistently reported more health problems than peo-

ple treated with buprenorphine and methadone; symptoms in-

cluded stomach cramps, headache, toothache, constipation, vom-

iting and insomnia.

Overall completeness and applicability ofevidence

SROM is currently provided as an alternative drug for substitu-

tion treatment for opioid dependence in some European countries

such as Bulgaria, Austria, Slovenia, Slovakia and, only occasion-

ally, 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 inappro-

priate 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 treat-

ment 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 avail-

able, it was useful to put together the results from the existing ex-

perimental studies to assess the effectiveness of SROM for main-

tenance therapy; however, the present review could not reach con-

clusions 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 otherstudies or reviews

A comprehensive review was published by Jegu and colleagues that

included all the available studies on SROM for maintenance ther-

apy irrespective of the design, which identified only one of the

three RCTs included in the present review (Jegu 2011). Notwith-

standing, the authors reached the same conclusions as ours that

the presently available evidence is insufficient to assess the effec-

tiveness 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 interven-

tion (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 liter-

ature review includes one acceptability study and one non-ran-

domised studies (both excluded by the present review because of

study design not in the inclusion criteria) but no specific recom-

mendations 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).

A U T H O R S ’ C O N C L U S I O N S

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 pri-

mary substance of abuse are strongly recommended before SROM

is used in routine clinical practice.

Measure of participant and carer preferences should also be ac-

curately collected in order to identify the role that each substi-

tution 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)).

A C K N O W L E D G E M E N T S

We thank Zuzana Mitrova for her help in preparing the search

strategy.

R E F E R E N C E S

References to studies included in this review

Clark 2002 {published data only}

Clark N, Khoo K, Lintzeris N, Ritter A, Whelan G. A

randomised trial of once-daily slow-release oral morphine

versus methadone for heroin dependence. Drug and Alcohol

Dependence 2002;66 Suppl 1:S33.

Eder 2005 {published data only}∗ Eder H, Jagsch R, Kraigher D, Primorac A, Ebner N,

Fischer G. Comparative study of the effectiveness of slow-

release morphine and methadone for opioid maintenance

therapy. Addiction 2005;100(8):1101–9.

Eder H, Kraigher D, Peternel R, Ortner R, Schindler S,

Kasper S, et al.Methadone versus slow-relapse morphine

maintenance for the treatment of opioid dependence. Drug

and Alcohol Dependence 2001;63 Suppl 1:S42.

Winklbaur B, Jagsch R, Ebner N, Thau K, Fischer G.

Quality of life in patients receiving opioid maintenance

therapy. A comparative study of slow-release morphine

versus methadone treatment. European Addiction Research

2008;14(2):99–105.

Giacomuzzi 2006 {published data only}

Giacomuzzi S, Kemmler G, Ertl M, Riemer Y. Opioid

addicts at admission vs. slow-release oral morphine,

methadone, and sublingual buprenorphine maintenance

treatment participants. Substance Use and Misuse 2006;41

(2):223–44.

References to studies excluded from this review

Bond 2012 {published data only}

Bond AJ, Reed KDF, Beavan P, Strang J. After the

randomised injectable opiate treatment trial: post-trial

investigation of slow-release oral morphine as an alternative

opiate maintenance medication. Drug and Alcohol Review

2012;31(4):492–8.

Madlung-Kratzer 2009 {published data only}

Madlung-Kratzer E, Spitzer B, Brosch R, Dunkel D, Haring

C. A double-blind, randomised, parallel group study to

compare the efficacy, safety and tolerability of slow-release

oral morphine versus methadone in opioid-dependent in-

patients willing to undergo detoxification. Addiction 2009;

104(9):1549–57.

Mitchell 2003 {published data only}

Mitchell TB, White JM, Somogyi AA, Bochner F.

Comparative pharmacodynamics and pharmacokinetics of

methadone and slow-release oral morphine for maintenance

treatment of opioid dependence. Drug and Alcohol

Dependence 2003;72(1):85–94.


Mitchell TB, White JM, Somogyi AA, Bochner F. Slow-

release oral morphine versus methadone: a crossover

comparison of patient outcomes and acceptability as

maintenance pharmacotherapies for opioid dependence.

Addiction 2004;99(8):940–5.


Mitchell TB, White JM, Somogyi AA, Bochner F. Switching

between methadone and morphine for maintenance

treatment of opioid dependence: impact on pain sensitivity

and mood status. American Journal on Addictions 2006;15:

311–5.

Moldovanyi 1996 {published data only}

Moldovanyi A, Ladewig D, Affentranger P, Natsch C,

Stohler R. Morphine maintenance treatment of opioid-

dependent out-patients. European Addiction Research 1996;

2:208–12.

References to studies awaiting assessment

Fischer 1996 {published data only}

Fischer G, Presslich O, Diamant K, Schneider C, Pezawas L,

Kasper S. Oral morphine-sulfate in the treatment of opiate

dependent patients. Alcoholism 1996;32:35–43.



Sherman 1996 {published data only}

Sherman JP. Managing heroin addiction with a long-acting

morphine product. The Medical Journal of Australia 1996;

165:239.

References to ongoing studies

NCT01079117-SROM {published data only}

Morphine Slow-release Capsules in Substitution Therapy.

Ongoing study October 2006.

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Davoli M, Bargagli AM, Perucci CA, Schifano P, Belleudi

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strength of recommendations. BMJ 2004;328:1490.

Guyatt 2008

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Schünemann HJ. What is ’quality of evidence’ and why is it

important to clinicians?. BMJ 2008;336:995–8.

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Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J,

et al.GRADE guidelines 1. Introduction-GRADE evidence

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for Systematic Reviews of Interventions Version 5.1.0

[updated March 2011]. The Cochrane Collaboration,

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AA, Ernst A, et al.An official ATS statement: grading the

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Moller HJ, Kasper S. The World Federation of Societies of

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Clark 2002

Methods Open-label cross-over randomised controlled trial

Participants 11 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

Outcomes Severity 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

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Quote: “outpatient, open label compari-

son of once daily morphine with metha-

done was conducted using a randomised

crossover design”

Allocation concealment (selection bias) Unclear risk Quote: “outpatient, open label compari-

son of once daily morphine with metha-

done was conducted using a randomised

crossover design”

Blinding of participants and personnel

(performance bias)

objective outcomes

Low risk The outcome was not likely to be influ-

enced by lack of blinding


(performance bias)

subjective outcomes

High risk Open label

Blinding of outcome assessment (detection

bias)

All outcomes

Unclear risk Heroin 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



Clark 2002 (Continued)

Incomplete outcome data (attrition bias)

All outcomes

Low risk 2 people withdrew from the study

Selective reporting (reporting bias) Low risk

Eder 2005

Methods 14-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, meth-

adone 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

Notes Country: Austria

Risk of bias



bias)

Low risk Quote: “Research pharmacists conducting

the randomisation based on a computer

program”



Eder 2005 (Continued)

Allocation concealment (selection bias) Low risk Quote: “Randomization was conducted in

the hospital pharmacy, located in the gen-

eral hospital (however, separated from the

drug addiction clinic). Research pharma-

cists conducting

the randomisation based on a computer

program never saw patients”


(performance bias)

objective outcomes

Low risk To maintain the blinding, placebo treat-

ments matched the alternative active

treatment. Placebo methadone oral solu-

tion contained dextromethorphan 30 mg

(Nowak GmbH, Lübeck, Germany) to

simulate the taste of methadone, as used

previously in double-dummy trials


(performance bias)

subjective outcomes

Low risk To maintain the blinding, placebo treat-

ments matched the alternative active

treatment. Placebo methadone oral solu-

tion contained dextromethorphan 30 mg

(Nowak GmbH, Lübeck, Germany) to

simulate the taste of methadone, as used

previously in double-dummy trials


bias)

All outcomes

Low risk Quote: “All people involved in performing

the study were completely unaware of treat-

ment group until the code was broken after

the last patient finished the study”


All outcomes

Low risk 55 people (86%) completed both study

phases


Giacomuzzi 2006

Methods Randomised 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



Giacomuzzi 2006 (Continued)

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

Notes Country: Austria

Risk of bias



bias)

Unclear risk Quote: “patients were randomised to receive methadone

sublingual buprenorphine or slow release oral morphine”

Allocation concealment (selection bias) Unclear risk Quote: “patients were randomised to receive methadone

sublingual buprenorphine or slow release oral morphine”


(performance bias)

objective outcomes

Low risk Open label, but the outcome is not likely to be influenced

by lack of blinding


(performance bias)

subjective outcomes

High risk Open label


bias)

All outcomes

Unclear risk No information provided


All outcomes

Low risk No withdrawn from the study


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.



Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Bond 2012 Study design not in the inclusion criteria

Madlung-Kratzer 2009 Participants willing to undergo detoxification

Mitchell 2003 Cross-over, non-randomised study



Moldovanyi 1996 Uncontrolled study

Characteristics of studies awaiting assessment [ordered by study ID]

Fischer 1996

Methods No available data

Participants No available data

Interventions No available data

Outcomes No available data

Notes

Sherman 1996

Methods No available data

Participants No available data

Interventions No available data

Outcomes No available data

Notes



Characteristics of ongoing studies [ordered by study ID]

NCT01079117-SROM

Trial name or title Morphine Slow-release Capsules in Substitution Therapy

Methods Multicentre, 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

Interventions The 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)



NCT01079117-SROM (Continued)

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 date October 2006

Contact information Mondipharma, Medical Company, Zurick, Switzerland

Notes

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



D A T A A N D A N A L Y S E S

This review has no analyses.

A D D I T I O N A L T A B L E S

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):

Low risk • Blinding of participants and providers and unlikely that the

blinding could have been broken



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

subjective outcomes

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


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


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


7. Incomplete outcome data (attrition bias)

:

for all outcomes except retention in treat-

ment 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)



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

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


(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




C O N T R I B U T I O N S O F A U T H O R S

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.

D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R T

Internal sources

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

External sources

• EMCDDA, Portugal.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Administration, Oral; Delayed-Action Preparations [administration & dosage; adverse effects]; Morphine [∗administration & dosage;

adverse effects]; Narcotics [∗administration & dosage; adverse effects]; Opiate Substitution Treatment [adverse effects; ∗methods];

Opioid-Related Disorders [∗drug therapy]; Quality of Life; Randomized Controlled Trials as Topic

MeSH check words

Humans



cochrane database of systematic reviews (reviews) || slow-release oral morphine as maintenance...

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