Slow-release oral morphinefor opioid maintenancetreatment: a systematicreviewJeremie Jegu,1,2 Adeline Gallini,1 Pauline Soler,2

Jean-Louis Montastruc1,3 & Maryse Lapeyre-Mestre1,3

1Department of Medical and Clinical Pharmacology, Centre d’Evaluation et d’Information sur la

Pharmacodépendance Addictovigilance (CEIP-A), University Hospital of Toulouse, 31000 Toulouse,

France, 2Department of Epidemiology, University Hospital of Toulouse, Faculté de Médecine, 31000

Toulouse, France and 3INSERM 1027, Pharmacoepidemiology Research Team, University of Toulouse,

Faculté de Médecine, 31000 Toulouse, France

CorrespondenceDr Jeremie Jegu, Laboratoired’Epidémiologie et de Santé Publique,Faculté de Médecine, Université deStrasbourg, 4 rue Kirschleger, 67000Strasbourg, France.Tel.: +33 3 68 85 32 02Fax: +33 3 68 85 31 89E-mail: jeremie.jegu@unistra.fr----------------------------------------------------------------------

Keywordsmorphine, opiate alkaloids, opioid-relateddisorders/rehabilitation, review,substance-related disorders, therapeutics----------------------------------------------------------------------

Received1 October 2010

Accepted18 January 2011

Accepted Article25 January 2011

This review article summarizes the results of all available clinical trials considering the use of slow-release oral morphine (SROM) foropioid maintenance treatment (OMT). All studies published up to October 2010 and assessing SROM for OMT in adult patients areincluded. Three independent reviewers assessed the selected articles using a standardized checklist. Study design, study length andnumber of subjects included were recorded. Data about retention rate (proportion of participants remaining under maintenancetreatment at the end of the study), quality of life, withdrawal symptoms, craving, additional drug consumption, driving capacity andadverse events were collected. We identified 13 articles corresponding to nine clinical trials considering the use of SROM for OMT.Among them, only one was a randomized trial and one was a controlled not randomized trial. All other studies were uncontrolled.Retention rates were good (from 80.6 to 95%) with SROM maintenance, but similar retention rates were obtained with methadone.Most of the studies showed that quality of life, withdrawal symptoms, craving and additional drug consumption improved with SROM.However, there was no comparison with other maintenance drugs. As most of the studies assessing SROM efficacy were uncontrolled,there is no definite evidence that SROM is an effective alternative to methadone for OMT.

Objectives

United Nations Office on Drugs and Crime estimated thatbetween 15 and 21 million people around the world wereopiate users in 2007 [1]: 1.3 million in North America and3.4–4 million in Europe. In Europe and Asia, opiate depen-dence remains the main drug problem as reflected in thenumber of treatments provided.

Opioid dependence represents a chronic relapsingcondition that may require long-term maintenance treat-ment with oral synthetic opioid [2], as well as psychosocialinterventions to re-establish social integration. Researchhas shown that heroin users in opioid maintenance treat-ment (OMT) buy less street heroin, consume fewer psycho-active drugs, have a reduced risk of HIV infection, need lessincome from crime to support their habit and are in lessdanger of fatal overdose, compared with an untreatedsample [1, 3–5]. Unfortunately, only a small proportion of

addicts receive OMT treatment for their opioid depen-dence. In the US and Europe, this is believed to be around20% [1, 6].

Psychopharmacological drugs play an important role inrehabilitating patients and deserve special attention. Theprimary aim of pharmacological intervention is to reducethe number of relapses and to prolong the time betweenrelapses. Maintaining quality of life and optimizing thepatient’s well-being are also of major importance and mayneed the use of more than one pharmacological agent.Evaluated drugs for OMT include methadone, buprenor-phine and buprenorphine–naloxone combination [7]. Theuse of other opioid agonists as OMT has also beeninvestigated with conflicting results [e.g. levo-a-acetylmethadol, prescribed heroin, codeine and slow-release oral morphine (SROM)].

The number of European countries where SROMis available as an alternative to standard methadone

British Journal of ClinicalPharmacology

DOI:10.1111/j.1365-2125.2011.03923.x

832 / Br J Clin Pharmacol / 71:6 / 832–843 © 2011 The AuthorsBritish Journal of Clinical Pharmacology © 2011 The British Pharmacological Society

maintenance treatment is increasing: Austria (1998), Slova-kia (2005), Slovenia (2005), Bulgaria (2006) and Luxem-bourg (2006) [8]. In France, where SROM can exceptionallybe prescribed in the case of failure of methadone orbuprenorphine previous maintenance treatment, theNational Commission of Narcotics and Psychotropic Drugsfailed to achieve a consensus decision about the use ofSROM in OMT [9].

Therefore, the aim of this systematic review was togather the results of all available clinical trials consideringthe use of SROM for OMT in order to summarize the scien-tific knowledge about this controversial subject.

Methods

All study types about SROM maintenance treatment wereincluded (randomized controlled trial, controlled trial, pro-spective uncontrolled study and cross-sectional studies).There was no geographical or period restriction. Weincluded articles in English, German or French publishedup to October 2010.

Different information sources were searched: PubMed,Cochrane Database of Systematic Reviews, CochraneCentral Register of Controlled Trials, Cochrane Drugs andAlcohol Group, Clinical trial.gov, National Institute onDrug Abuse, United Nations Office on Drugs and Crime,and European Monitoring Centre for Drugs and DrugAddiction.

Research equations used for searching each databaseare presented in Table 1. A Medline research equation wasconstructed using the following MeSH terms: publicationtype, type of maintenance drug (methadone, buprenor-phine and morphine), substance related disorder andopiate alkaloids. Articles dealing with morphine analgesiawere excluded by the research equation. Results were notlimited to humans in order to avoid the risk of excludingrelevant references without the assignment of ‘humans’ or‘animals’ as an indexing term [10]. Other database searcheswere mainly performed using the keywords morphine andmaintenance. Unpublished articles and congress presenta-tions were not included. Finally, the references cited inselected articles were checked in order to include studiesnot found in any database.

The process of article selection was conducted by twoindependent reviewers (J. J. and M. L.-M.). Articles were firstselected considering their title. Articles mentioning in theirtitle ‘morphine’ or ‘maintenance treatment’ without furtherprecision were selected. The abstracts of the remainingarticles were then assessed. Experimental studies orstudies not dealing with morphine were then excluded.The full text of remaining articles was assessed, and onlyarticles about SROM maintenance treatment in nonpreg-nant addict patients were included in the analysis.

Three independent reviewers (J. J., A. G. and P. S.)assessed the selected articles using a standardized check-

list. Article methodological quality was assessed using theCONSORT [11] or STROBE [12] checklist depending on thestudy design. Data about study design, duration andgeographical location were collected. Participant charac-teristics (mean age, percentage of men and previous main-tenance treatment), type of intervention and comparisongroup studied were recorded. Data about retention rate(proportion of participants remaining under maintenancetreatment at the end of the study), quality of life, with-drawal symptoms, craving, additional drug consumption,driving capacity and adverse events were collected.

Risk of bias in individual studies was assessed by col-lecting data about study design and participant character-istics and by completing CONSORT and STROBE checklists.Study type and sample size were mentioned in data syn-thesis.

Because of methodological heterogeneity and the verylow number of randomized controlled studies available,results were not combined, leading us to perform a quali-tative systematic review. This review was conducted fol-lowing the recommendations of the PRISMA statement(Preferred Reporting Items for Systematic Reviews andMeta-Analyses) [13].

Results

A total of 1088 studies were identified through databasesearching. Figure 1 details the number of studies screened,

Table 1Research strategy

Database Research term

PubMed 1. ‘Randomized controlled trial’ [PublicationType] OR ‘controlled clinical trial’[Publication Type] OR ‘comparative study’[Publication Type]

2. ‘Buprenorphine’ [Mesh] OR ‘methadone’[Mesh] OR ‘morphine’ [Mesh:noexp] NOT‘analgesia’ [Mesh])

3. ’Substance-related disorders’ [Mesh] AND‘opiate alkaloids’ [Mesh]

4. 1 AND 2 AND 3Cochrane Database of

Systematic ReviewsMorphine

Clinical trials.gov (Morphine NOT analgesia NOT pain) AND PhaseIII IV

Cochrane Central Registerof Controlled Trials

Morphine AND maintenance

Cochrane Drugs andAlcohol Group

Morphine – analgesia – pain

National Institute on DrugAbuse

Morphine AND maintenance

United Nations Office onDrugs and Crime

Morphine

European MonitoringCentre for Drugs andDrug Addiction

Morphine

Slow-release oral morphine for opioid maintenance treatment

Br J Clin Pharmacol / 71:6 / 833

assessed for eligibility and included in the review. Finally,13 articles were included in our analysis [14–26].

Designs of included studies are summarized in Table 2.In fact, only nine different studies corresponded to the 13selected articles; it appeared that different analyses wereperformed using the same data set (same study size, par-ticipants and intervention) for article numbers 2 and 6 [15,19]; 3, 8 and 9 [16, 21, 22]; and 5 and 7 [18, 20]. Of these ninestudies,only one was a randomized controlled trial, leadingto two different articles [15, 19].

Synthesis of the main results is presented in Table 3.Retention rate was available in six studies of the nineincluded. It varied from 95% at 6 months [25] to 80.6% at 4weeks [14], and was similar to the retention rate observedwith methadone in the sole available comparative study

(84.4% at 7 weeks with SROM vs. 90.6% with methadone)[19].

In almost all uncontrolled studies, quality of life, with-drawal symptoms, craving and additional drug consump-tion were improved with SROM maintenance treatment. Incontrolled studies, similar improvements were obtainedwith methadone [15, 19].

Considering quality of life, well-being was improvedwith SROM [14, 25]. In addition, SROM was associated withhigher SF-36 Social Functioning scores than methadone(mean SF-36 Social Functioning score of 78 � 18 vs. 58 �25) [21]. In the comparative study, however, no statisticallysignificant difference was found in any quality of lifedomain of the Berlin Quality of Life Profile between SROMand methadone [15].

1088 records identified through database searching

8 additional records identified through other sources

1096 records after duplicates removed

55 records screened 22 recordsexcluded

33 full-text articles assessed for eligibility

20 full-text articles excluded

13 articles included in qualitative synthesis

Reasons (number of study excluded) - Opioid withdrawal control, detoxification (4)- Opioid detoxification (1) - Neonatal abstinence syndrome treatment (3) - Transition between methadone and buprenorphine (1) - Study about opioid medication abuse prescription (1) - Maintenance with buprenorphine (1) - Pupillary diameter and pupillary reactions (1) - Type of Heroin administration (1) - Intravenous morphine (2) - Pregnant addicts (2) - Experimental study about morphine or effects of other drugs (1) - Congress abstract (1) - Few data about SROM maintenance (1) [27]

Reasons (number of study excluded) - Morphine not studied (11) - Experimental study about morphine or effects of other drugs (5) - Long-term opioid drug consumption and pain control (1) - Study on animal (2) or in vitro (1) - Article in Swedish (1) - Wrong publication type: Editorial (1)

Figure 1Flow diagram of number of studies screened, assessed for eligibility and included. SROM, slow-release oral morphine

J. Jegu et al.

834 / 71:6 / Br J Clin Pharmacol

Withdrawal symptoms were particularly reducedduring the first 20 days of SROM maintenance [14, 23–25].However, a switch between maintenance drugs in com-parative studies led to a short recurrence of withdrawalsymptoms [19, 21].

Craving for heroin was reduced significantly with SROM[14, 21, 23–25]. In the randomized controlled trial (metha-done vs. SROM), craving for heroin decreased andremained low in both groups [19].

Some studies reported that SROM was associated withfewer and less serious adverse events, particularly inpatients with significant adverse events related to metha-done, but this applied mainly to open-label crossoverstudies [21].

Tables 4 and 5 detail the characteristics and the resultsof each of the included studies (study size, participants,intervention, comparison, outcomes, study design,follow-up period and main results, including P-values).

Discussion

Data about SROM efficacy are scarce in the literature. Fewstudies considering the use of SROM for OMT are available,and most of them were uncontrolled or not randomized.Moreover, it is not possible to conclude that SROM isequivalent to methadone in enhancing quality of life,reducing craving, controlling withdrawal symptoms ordecreasing additional drug consumption.

Our systematic review suffers from several mandatorylimitations. First, a reporting bias is possible. In order tominimize this risk, an active search was performed to findall studies dealing with SROM for OMT, multiple databaseswere searched and references cited in selected articleschecked. One study providing preliminary data aboutSROM for OMT in patients intolerant to methadone was

not included in qualitative analyses because only thosepatients completing the maintenance programme wereassessed (16 patients, retention rate of 100%) and becauseno standardized measuring instruments were used toassess psychopathological features [27]. However, thisstudy showed that adverse events related to methadonecould be ameliorated after the switch to SROM mainte-nance (particularly weight gain).Second,a selective report-ing of complete studies or outcomes within studies is alsopossible (publication bias). In order to limit the risk ofmissing data about outcomes within studies, a comparisonof outcomes listed in the methods section of the publishedreports was made with those for which results were pre-sented. Finally, risk of publication bias of nonsignificantfindings or uncompleted studies was limited by requestingtrials registries (Clinical Trial.gov, Cochrane Central Registerof Controlled Trials).No supplementary study was retrievedby this method.

Compared with methadone or buprenorphine, SROMmaintenance efficacy is not well documented, and theavailable studies are too heterogeneous to be analysedtogether. A meta-analysis published in 2008 comparingmethadone and buprenorphine maintenance included 24randomized and controlled clinical trials [28]. We foundonly one randomized controlled study with a crossoverdesign comparing SROM with methadone [19].

Because of the lack of control groups in most of thestudies, it is difficult to know which part of the measuredeffect is because of the drug or of the psychosocial andpsychotherapeutic interventions. Psychosocial and psy-chotherapeutic interventions combined with pharmaco-therapy have been shown to be effective in treatmentoutcome studies [29]. These approaches aim to increasetreatment motivation, prevent relapse and reduce harm. Inaddition, they may provide advice and practical support topatients who have to address their housing, employment

Table 2Articles included: summary of study design

Study design Number of study Article Notes

Randomized controlled trial 1 2. Winklbaur et al. (2008) [15]6. Eder (2005) [19]

CrossoverSame data set for articles 2 and 6

Controlled trial 1 3. Mitchell et al. (2006) [16]8. Mitchell et al. (2004) [21]9. Mitchell et al. (2003) [22]

CrossoverSame data set for articles 3, 8 and 9

Prospective uncontrolled study 5 1. Kastelic et al. (2008) [14]12. Vasilev et al. (2006) [25]11. Kraigher et al. (2005) [24]10. Kraigher et al. (2002) [23]13. Rao et al. (2005) [26]

–

Cross-sectional study 2 4. Giacomuzzi et al. (2006) [17]5. Giacomuzzi et al. (2005a) [18]7. Giacomuzzi et al. (2005b) [20]

Same data set for articles 5 and 7

Slow-release oral morphine for opioid maintenance treatment

Br J Clin Pharmacol / 71:6 / 835

Table 3Synthesis of results

Outcome/article nStudytype/duration Effects estimated – 95% CI†

Retention rate6. Eder et al. (2005) [19] 64 RCT/7 weeks SROM: 84.4% (67.2%–94.7%)/methadone: 90.6% (75%–98%)

11. Kraigher et al. (2005) [24] 110 PUS/3 weeks SROM: 93.6% (87.3%–97.4%)1. Kastelic et al. (2008) [14] 67 PUS/4 weeks SROM: 80.6% (69.1%–89.2%)

10. Kraigher et al. (2002) [23] 67 PUS/3 weeks SROM: 94% (85.4%–98.4%)13. Rao (2005) [26] 74 PUS/4 weeks SROM: 44.6% (33%–56.6%)12. Vasilev et al. (2006) [25] 20 PUS/6 months SROM: 95% (75.1%–99.9%)

Quality of life2. Winklbaur et al. (2008) [15] 64 RCT/14 weeks Berlin Quality of Life Profile (BQLP): no statistically significant difference in any quality of life domain8. Mitchell et al. (2004) [21] 18 CT/6 weeks SROM was associated with higher SF-36 Social Functioning scores than methadone (mean score of 78 � 18

vs. 58 � 25)1. Kastelic et al. (2008) [14] 67 PUS/4 weeks Symptom CheckList 27 (SCL-27): enhanced well-being

12. Vasilev et al. (2006) [25] 20 PUS/6 months Improvement of patient well-being4. Giacomuzzi et al. (2006) [17] 240 CSS Berlin Quality of Life Profile, overall satisfaction: methadone 5.3 � 1.5 buprenorphine 4.9 � 1.4 SROM 4.1 �

1.7 no maintenance treatment 3.5 � 1.6

Withdrawal symptoms6. Eder et al. (2005) [19] 64 RCT/7 weeks Significant decrease after week 1, withdrawal recurring during the crossover phase in both groups8. Mitchell et al. (2004) [21] 18 CT/6 weeks Withdrawal severity during the five first days of SROM maintenance was greater than during the resumption

of methadone maintenance11. Kraigher et al. (2005) [24] 110 PUS/3 weeks Withdrawal symptoms decreased (mean Wang scale value of 12.1 at day 1 compared with 0.3 at day 20)1. Kastelic et al. (2008) [14] 67 PUS/4 weeks Decrease in the Short Opiate Withdrawal Scale (SOWS) value (in subgroup A 4.1 � 3.7 at day 0 and 1.6 �

3.0 at day 28, in subgroup B 9.0 � 6.7 at day 0 and 2.9 � 3.5 at day 28)10. Kraigher et al. (2002) [23] 67 PUS/3 weeks Decreased with SROM maintenance (mean Wang scale value of 11.2 at day 1 compared with 1.1 at day 20)12. Vasilev et al. (2006) [25] 20 PUS/6 months SOWS scores reduced markedly in the first 2 weeks and remained low until week 24 (mean value of 16.9 �

6.6 at baseline vs. 6.6 � 5.9 at week 24)Craving

6. Eder et al. (2005) [19] 64 RCT/7 weeks Craving for heroin, cocaine and alcohol decreased and remained low in both groups8. Mitchell et al. (2004) [21] 18 CT/6 weeks SROM was associated with reduced heroin craving compared with methadone [Visual Analogue Scale (VAS):

mean value of 19 vs. 37]11. Kraigher et al. (2005) [24] 110 PUS/3 weeks Reduction in heroin (VAS: mean value of 46 at baseline vs. 15 at day 20) and cocaine craving (25 at baseline

vs. 12 at day 20)1. Kastelic et al. (2008) [14] 67 PUS/4 weeks Decrease in craving for other drugs in both subgroups, especially for heroin and alcohol

10. Kraigher et al. (2002) [23] 67 PUS/3 weeks Reduction in heroin (VAS: mean value of 48 at baseline vs. 15 at day 20) and cocaine craving (24 at baselinevs. 10 at day 20)

12. Vasilev et al. (2006) [25] 20 PUS/6 months Reduction in the craving for heroin (VAS: mean value reduced from 7.7 � 2.0 at baseline to 2.3 � 2.3 atweek 24)

Additional drug consumption6. Eder et al. (2005) [19] 64 RCT/7 weeks Number of injection sites decreased, cocaine usage increased over time and benzodiazepine consumption

remained stable in both groups9. Mitchell et al. (2003) [22] 14 CT/6 weeks Similar for both treatments

11. Kraigher et al. (2005) [24] 110 PUS/3 weeks Decrease in cocaine additional consumption (40% of patients had cocaine consumption at baseline comparedwith 23.3% at day 20)

1. Kastelic et al. (2008) [14] 67 PUS/4 weeks Unchanged10. Kraigher et al. (2002) [23] 67 PUS/3 weeks Reduction in benzodiazepine consumption (52% at day 1 vs. 35% at day 20) but cocaine consumption

remained unchanged12. Vasilev et al. (2006) [25] 20 PUS/6 months Reduction in the illicit use of heroin and methadone13. Rao et al. (2005) [26] 74 PUS/4 weeks Reduction in the heroin consumption (61% of patients reported that they had stopped heroin, 24.2%

reported using heroin only for 5 days over the previous month)4. Giacomuzzi et al. (2006) [17] 240 CSS Lower consumption of cocaine and opioid in all three maintenance groups than in patients at admission

Adverse events6. Eder et al. (2005) [19] 64 RCT/7 weeks SROM 82% (toothache, headache, constipation and influenza) and methadone 76% (toothache, vomiting,

headache, stomachache)8. Mitchell et al. (2004) [21] 18 CT/6 weeks SROM was associated with fewer and less troublesome adverse events than methadone (15 � 25 vs. 62 �

33)12. Vasilev et al. (2006) [25] 20 PUS/6 months Constipation (n = 5), sweating (n = 1)1. Kastelic et al. (2008) [14] 67 PUS/4 weeks Improvement in number of adverse events in subgroup A with significant adverse events related to methadone

(4.2 � 2.7 at day 0 and 2.3 � 3.0 at day 28)13. Rao et al. (2005) [26] 74 PUS/4 weeks Gastritis (n = 3), pruritis (n = 2), constipation (n = 2), sedation (n = 1)

Abbreviations are as follows: CSS, cross-sectional study; CT, controlled trial; PUS, prospective uncontrolled study; RCT, randomized controlled trial; VAS, visual analogue scale. †Exact95% confidence interval assessed by using binomial distribution.

J. Jegu et al.

836 / 71:6 / Br J Clin Pharmacol

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7w

eeks

ofm

etha

done

follo

wed

by

7w

eeks

ofSR

OM

mai

nten

ance

(B)

SRO

M(6

80m

gda

ily)

vs.

met

hado

ne

(85

mg

daily

)

Rete

ntio

nra

te,

with

draw

al

sym

ptom

s,cr

avin

g,ad

ditio

nal

drug

cons

umpt

ion,

depr

essi

on,

anxi

ety,

phys

ical

com

plai

nts,

adve

rse

even

ts

Rand

omiz

edco

ntro

lled

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l.C

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over

desi

gn

14w

eeks

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esa

mpl

eas

2.

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klba

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al.

(200

8)[1

5]

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iaco

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zzi

etal

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005b

)[2

0]

41G

eogr

aphi

cre

gion

:A

ustr

ia

Opi

oid-

depe

nden

tvo

lunt

eers

rece

ivin

gSR

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orm

etha

done

trea

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t

Mea

nag

e:29

.7ye

ars

Perc

enta

geof

men

unkn

own

–M

etha

done

(59.

1m

gda

ily)

vs.

SRO

M(3

48.6

mg

daily

)

Driv

ing

capa

city

Cro

ss-s

ectio

nals

tudy

–Sa

me

sam

ple

as5.

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com

uzzi

etal

.

(200

5a)

[18]

with

diff

eren

tco

mpa

rison

grou

ps

Slow-release oral morphine for opioid maintenance treatment

Br J Clin Pharmacol / 71:6 / 837

Tab

le4

Co

nti

nu

ed

Art

icle

Stu

dy

size

Part

icip

ants

Inte

rven

tio

nC

om

par

iso

nO

utc

om

esSt

ud

yd

esig

nFo

llow

-up

per

iod

No

tes

8.M

itch

ell

etal

.(2

004)

[21]

18G

eogr

aphi

cre

gion

:So

uth

Aus

tral

ia

Opi

oid-

depe

nden

tvo

lunt

eers

rece

ivin

gm

etha

done

mai

nten

ance

trea

tmen

t

Mea

nag

e:36

year

s

50%

mal

e

Switc

hfr

omm

etha

done

(78

�

32m

g)to

SRO

M(3

47�

131

mg)

No

cont

rolg

roup

Qua

lity

oflif

e,w

ithdr

awal

sym

ptom

s,pa

tient

ratin

gof

effic

acy

and

acce

ptab

ility

,

trea

tmen

tpr

efer

ence

,ad

ditio

nal

drug

cons

umpt

ion

Con

trol

led

tria

l.

Cro

ssov

erde

sign

6w

eeks

Rem

uner

atio

nup

on

com

plet

ion

ofth

e

stud

y

9.M

itch

ell

etal

.(2

003)

[22]

14G

eogr

aphi

cre

gion

:So

uth

Aus

tral

ia

Opi

oid-

depe

nden

tvo

lunt

eers

rece

ivin

gm

etha

done

mai

nten

ance

trea

tmen

t

Mea

nag

e:35

year

s

78.6

%m

ale

Switc

hfr

omm

etha

done

(78

�

32m

g)to

SRO

M(3

49�

137

mg)

No

cont

rolg

roup

Phar

mac

odyn

amic

san

d

phar

mac

okin

etic

scr

iteria

,

with

draw

alsy

mpt

oms,

addi

tiona

l

drug

cons

umpt

ion,

trea

tmen

t

pref

eren

ce

Con

trol

led

tria

l.

Cro

ssov

erde

sign

6–10

wee

ksSa

me

sam

ple

as3.

Mitc

hell

etal

.(2

006)

[16]

.

Rem

uner

atio

nup

on

com

plet

ion

ofth

e

stud

y

10.

Kra

igh

eret

al.

(200

2)[2

3]

67G

eogr

aphi

calr

egio

n:A

ustr

ia

Patie

nts

with

anop

ioid

depe

nden

ce

with

out

opio

idm

aint

enan

ce

ther

apy

Mea

nag

e:28

.6ye

ars

61.2

%m

ale

3w

eeks

ofSR

OM

mai

nten

ance

(mea

nda

ilydo

se59

3.4

mg)

No

cont

rolg

roup

Rete

ntio

nra

te,

addi

tiona

ldru

g

cons

umpt

ion,

crav

ing,

with

draw

al

sym

ptom

s

Pros

pect

ive

unco

ntro

lled

stud

y

3w

eeks

–

11.

Kra

igh

eret

al.

(200

5)[2

4]

110

Geo

grap

hica

lreg

ion:

Aus

tria

Patie

nts

with

anop

ioid

depe

nden

ce

with

out

opio

idm

aint

enan

ce

ther

apy

Mea

nag

e:27

.9ye

ars

80%

mal

e

3w

eeks

ofSR

OM

mai

nten

ance

(mea

nda

ilydo

se66

5m

g)

No

cont

rolg

roup

Rete

ntio

nra

te,

with

draw

al

sym

ptom

s,cr

avin

g,ad

ditio

nal

drug

cons

umpt

ion,

som

atic

com

plai

nts

Pros

pect

ive

unco

ntro

lled

stud

y

3w

eeks

–

12.

Vas

ilev

etal

.(2

006)

[25]

20G

eogr

aphi

calr

egio

n:Bu

lgar

ia

Patie

nts

with

anop

ioid

depe

nden

ce

with

out

opio

idm

aint

enan

ce

ther

apy

Mea

nag

e:28

.8ye

ars

80%

mal

e

6m

onth

sof

SRO

Mm

aint

enan

ce

(mea

nda

ilydo

se76

0m

g)

No

cont

rolg

roup

Rete

ntio

nra

te,

with

draw

al

sym

ptom

s,cr

avin

g,ad

ditio

nal

drug

cons

umpt

ion,

patie

nts’

wel

l-bei

ng,

adve

rse

even

ts

Pros

pect

ive

unco

ntro

lled

stud

y

6m

onth

s-

13.

Rao

etal

.(2

005)

[26]

74G

eogr

aphi

calr

egio

n:In

dia

Patie

nts

with

anop

ioid

depe

nden

ce

Mea

nag

e:un

know

n

Perc

enta

geof

men

unkn

own

At

leas

t4

wee

ksof

SRO

M

mai

nten

ance

(60–

240

mg

daily

dose

)

No

cont

rolg

roup

Rete

ntio

nra

te,

addi

tiona

ldru

g

cons

umpt

ion,

wor

king

activ

ity,

crim

inal

activ

ity(p

ick-

pock

etin

g,

stea

ling)

,ad

vers

eev

ents

Pros

pect

ive

unco

ntro

lled

stud

y

4w

eeks

–

J. Jegu et al.

838 / 71:6 / Br J Clin Pharmacol

Table 5Results of individual studies (ordered by study ID)

Article ID Summary data for each group Effects estimated

1. Kastelicet al. (2008)[14]

SROM maintenanceSubgroup analyses:• Significant side effects related to methadone (A):n = 39, mean age 29.4 � 5.9 years, 71.8% male• Inadequate symptom control despite daily

methadone dose of �90 mg (B): n = 28, meanage 29.8 � 6.7 years, 75% male

Retention rate: 80.6% (54 of 67) at 28 days.Withdrawal symptoms (SOWS): A, 4.1 � 3.7 at day 0 and 1.6 � 3.0 at day 28 (P < 0.001); B, 9.0

� 6.7 at day 0 and 2.9 � 3.5 at day 28 (P < 0.001).Craving: decrease in craving for other drugs in both subgroups, especially for heroin and alcoholQuality of life: SCL27, enhanced well-being in both subgroups. Global WHO QOL-BREF score detail:

A, 52.7 � 17.3 at day -7 and 64.8 � 12 at day 28 (P < 0.001); B, 44.9 � 25.2 at day -7 and54.5 � 17.5 at day 28 (P > 0.05).

Additional drug consumption: unchanged in both subgroups.Adverse events: improvement in number of adverse events in subgroup A: 4.2 � 2.7 at day 0 and

2.3 � 3.0 at day 28 (P < 0.001). No data available for subgroup B.Global rating of efficacy: A, very satisfied 61%, satisfied 21%; B, very satisfied 39%, satisfied

39%.Global treatment preference: 96% (52 of 54) of patients preferred SROM maintenance treatment.

2. Winklbauret al. (2008)[15]

SROM/methadone (A): n = 32, mean age 29.5 �

7.5 years, 84.4% male, duration of heroinconsumption 64.2 � 52.7 months

Methadone/SROM (B): n = 32, mean age 27.9 �

5.6 years, 90.6% male, duration of heroinconsumption 60.2 � 49.2 months

Quality of life (BQLP): comparing group A and group B: no statistically significant difference in anyquality of life domain (P from 0.10 to 0.97). Time effect: improvement in nearly all quality of lifedomains between baseline and week 14 [general well-being (P < 0.001), mental health (P = 0.001),general state of health (P = 0.018), leisure time at home (P = 0.034) and leisure time out of home(P = 0.008)].

3. Mitchellet al. (2006)[16]

Crossover: switch from methadone to SROM(during ~6 weeks) and then switch back tomethadone.

n = 14, mean age 35 years, 78.6% male

Pain sensitivity (cold pressor test, electrical stimulation test): pain responses were nearly identical foreach drug.

Mood status (Profile and Mood States, Morphine Benzedrine Group scale): overall mood disturbancedid not differ between drugs.

4. Giacomuzziet al. (2006)[17]

Methadone: n = 40, mean age 27.3 � 6.4 years,57% male

Buprenorphine: n = 40, mean age 26.3 � 7.5years, 57% male

SROM: n = 40, mean age 27.8 � 4.8 years, 57%male

No maintenance treatment (NMT): n = 120, meanage 25.3 � 7.1 years, 63% male

Quality of life (BQLP) – overall satisfaction, methadone 5.3 � 1.5, buprenorphine 4.9 � 1.4, SROM4.1 � 1.7, NMT 3.5 � 1.6 (P < 0.001).

Withdrawal symptoms (Opiate Withdrawal Scale): both the buprenorphine and the methadonemaintenance group showed less stomach cramp, muscular tension, general pain, feeling ofcoldness, heart pounding, runny eyes and aggression than patients at admission (P < 0.05).

Additional drug consumption: significantly lower consumption of cocaine and opioid in all threemaintenance groups than in patients at admission (P < 0.001).

5. Giacomuzziet al.(2005a) [18]

SROM: n = 14, mean age 29.7 � 6.5 yearsBuprenorphine: n = 13, mean age 31.1 � 7.8

years

Driving capacity: better psychomotor performance in patients with buprenorphine maintenancecompared with SROM within Visual Pursuit Test [correct answers (P = 0.016), working time (P =0.047)].

6. Eder et al.(2005) [19]

SROM/methadone (A): n = 32, mean age 29.5 �

7.5 years, 84.4% male, duration of heroinconsumption 64.2 � 52.7 months

Methadone/SROM (B): n = 32, mean age 27.9 �

5.6 years, 90.6% male, duration of heroinconsumption 60.2 � 49.2 months

Retention rate: A (SROM) 84.4% (27 of 32) at 7 weeks; B (methadone) 90.6% (29 of 32) at 7weeks/odds ratio 1.79–95% confidence interval (0.39–8.22).

Additional drug consumption: the number of injection sites decreased, cocaine usage increasedsignificantly over time in both groups (P < 0.001) and benzodiazepine consumption remainedstable.

Craving: craving for heroin, cocaine and alcohol decreased and remained low in both groups.Withdrawal symptoms (Wang scale): significant decrease after week 1, withdrawal recurring during

the crossover phase.Depression, anxiety and physical complaints: patients receiving slow-release morphine had

significantly lower depression (P < 0.001), anxiety scores (P = 0.008) and fewer physical complaints(P < 0.001).

Adverse events (percentage of patients reporting at least one side effect): SROM 82% (toothache,headache, constipation and influenza), methadone 76% (toothache, vomiting, headache andstomachache).

7. Giacomuzziet al.(2005b) [20]

Methadone: n = 27, mean age 29.7 � 6.9 yearsSROM: n = 14, mean age 29.7 � 6.5 years

Driving capacity: better psychomotor performance in patients treated with methadone comparedwith SROM within:

• Vienna Reaction Test System: reaction time (P = 0.004), correct reactions (P < 0.001);• Tachistoscopic Traffic Test Manheim for Screen: more correct answers (P < 0.001);• Cognitrone test: lower working time (P < 0.001), lower time for correct reactions (P < 0.001).

8. Mitchellet al. (2004)[21]

Crossover: switch from methadone to SROM(during ~6 weeks) and then switch back tomethadone.

n = 18, mean age 36 years, 50% male

Quality of life: SROM was associated with higher SF-36 Social Functioning scores than methadone(78 � 18 vs. 58 � 25, P = 0.006).

Withdrawal symptoms: withdrawal severity during the first 5 days of SROM maintenance wasgreater than during the resumption of methadone maintenance (P = 0.02).

Treatment preference: 77.7% of subjects preferred SROM to methadone (14 of 18).Treatment efficacy and acceptability: compared with methadone, SROM was associated with

fewer and less troublesome adverse events (15 � 25 vs. 62 � 33, P = 0.001), greater drug liking(P = 0.01) and reduced heroin.

craving (VAS: mean value of 19 vs. 37, P = 0.03).Additional drug consumption: no other significant differences between methadone and SROM.

Slow-release oral morphine for opioid maintenance treatment

Br J Clin Pharmacol / 71:6 / 839

and family-related problems in parallel with treating theiropioid dependence.

Retention in treatment was the main assessment crite-rion in previous published meta-analyses comparing effi-cacy of different drugs for OMT [28, 30]. In our review,retention rate was available in only six of the nine included.It ranged from 95% at 6 months to 80.6% at 4 weeks. Inaddition, the follow-up period was short in most of thesestudies (between 3 and 7 weeks). Randomized and con-trolled trials assessing methadone and buprenorphineefficacy were longer. For example, trials performed byJohnson et al. [31] and Mattick et al. [32] found, respec-tively, a 17-week retention rate of 73% for high-dosemethadone and 58% for buprenorphine, and a 13-weekretention rate of 59% for methadone and 48% forbuprenorphine.

The demographic characteristics of patients includedin these studies (mean age ranging from 26 [17] to 39 years[26]) were similar to those in the population of opiate usersunder maintenance treatment in Occidental countries. InEurope, the mean age of patients entering outpatienttreatment for primary opioid use is 33 years, and almost allcountries have reported an increase since 2003. Anaverage time lag of about 8 years was reported betweenfirst use of opioids and first drug treatment [6].

While defining pharmacological criteria for the use ofdrugs in the treatment of opioid dependence, Montastrucet al. qualified SROM as a poorly satisfying drug for OMT[33]. In fact, SROM exhibited only two of the six definedcriteria (same pharmacodynamic properties as the drugbeing substituted and compatibility with a socially satisfy-ing quality of life), missing out on four of them (duration of

Table 5Continued

Article ID Summary data for each group Effects estimated

9. Mitchellet al. (2003)[22]

Crossover: switch from methadone to SROM(during ~6 weeks) and then switch back tomethadone.

n = 14, mean age 35 years, 78.6% male

Pharmacodynamics and pharmacocinetics criteria: opioid effects were of a similar overallmagnitude following dosing for each drug and showed an inverse association with plasma drugconcentrations, which peaked later for morphine compared with methadone (P < 0.001).

Opioid withdrawal severity: no significant differences between drugs (P = 0.58).Additional drug consumption: similar for both treatments (P > 0.05).Treatment preference: 85.7% of subjects preferred SROM to methadone (12/14, P = 0.01).

10. Kraigheret al. (2002)[23]

SROM: n = 67, mean age 28.6 years, 61.2%male

Retention rate: 94% (63 of 67) at 3 weeks.Withdrawal symptoms: decreased with SROM maintenance (mean Wang scale value of 11.2 at day

1 compared with 1.1 at day 20).Additional drug consumption: reduction in benzodiazepine consumption (52% at day 1 vs. 35% at

day 20, P < 0.01); cocaine consumption remained unchanged.Craving: reduction in heroin (VAS: mean value of 48 at baseline vs. 15 at day 20, P < 0.0001) and

cocaine craving (24 at baseline vs. 10 at day 20, P < 0.0001).

11. Kraigheret al. (2005)[24]

SROM: n = 110, mean age 27.9 years, 80%male

Retention rate: 93.6% (103 of 110) at 3 weeks.Withdrawal symptoms: decreased at day 20 compared with baseline (mean Wang scale value of

12.1 at day 1 compared with 0.3 at day 20, P < 0.0001).Additional drug consumption: decrease in cocaine additional consumption (40% of patients at

baseline had cocaine consumption compared with 23.3% at day 20, P = 0.0083).Craving: reduction in heroin (VAS: mean value of 46 at baseline vs. 15 at day 20, P < 0.0001) and

cocaine craving (25 at baseline vs. 12 at day 20, P < 0.0001).Somatic complain: the incidence of somatic complaints was reduced (Clinical Self Rating Score of

the Munich Psychiatric Information System: mean value of 21.7 at baseline vs. 12.5 at day 20, P <0.0001).

12. Vasilevet al. (2006)[25]

SROM: n = 20, mean age 28.8 years, 80%male

Retention rate: 95% (19 of 20) at 6 months.Withdrawal symptoms: SOWS scores reduced markedly in the first 2 weeks and remained low until

week 24 (mean value of 16.9 � 6.6 at baseline vs. 6.6 � 5.9 at week 24).Additional drug consumption: reduction in the illicit use of heroin and methadone.Craving: reduction in the craving for heroin (VAS: mean value reduced from 7.7 � 2.0 at baseline to

2.3 � 2.3 at week 24, P < 0.001).Patient well-being: improvement of patient well-being from baseline assessment; improvements

with regard to suicidal depression (85%), anxiety and dysphoria (66%), general illness (58%), socialdysfunction (54%), sense of hopelessness (34%), attention (25%), self-reported typical depressive(27%) and disease-related symptoms (11%).

Adverse events: Five episodes of constipation and one episode of sweating.

13. Rao et al.(2005) [26]

No control groupAfter 4 weeks of SROM maintenance: n = 33,

mean age 39 years, 100% male

Retention rate: 44.6% (33 of 74) at 4 weeks.Additional drug consumption: 61% of patients reported that they have stopped heroin, 24.2%

reported using heroin only for 5 days over the previous month.Working activity: proportion of patients working regularly increased from 21.2 to 57.6%.Criminal activity: decreased from 45 to 3%.Adverse events: gastritis (n = 3), pruritis (n = 2), constipation (n = 2) and sedation (n = 1).

Values are presented as means � SD. SROM, slow-release oral morphine; SOWS, Short Opiate Withdrawal Scale; SCL27, Symptom Check List 27; WHO QOL-BREF, WHO Qualityof Life-BREF; BQLP, Berlin Quality of Life Profile; VAS, visual analogue scale.

J. Jegu et al.

840 / 71:6 / Br J Clin Pharmacol

action �24 h, few euphoric and reinforcing effects, oral orsublingual administration without any special affinity forintravenous routes, clinical randomized comparative trialsand security data allowing a New Drug Application for thedrug as an OMT). This review has confirmed these results,especially concerning the lack of randomized comparativetrials.

However, clinical points of view about SROM mainte-nance differ greatly among physicians. Although success-ful experience in the treatment of heroin-dependentpatients with long-acting morphine was reported [34],other data discuss the real efficacy of SROM as an OMT.Riskof misuse is often discussed; some reports suggest thatmost SROM prescription is diverted to i.v. injecting [35],with the risk of microembolisms because of insoluble con-tents, such as talcum [36]. Moreover, a recent study sug-gested that the number of deaths related to morphinemay have increased after the introduction of SROM as anOMT in the Austrian regions of Tyrol and Vorarlberg [36]. InEurope, expansion in maintenance drugs for opioid-dependent users has been accompanied by increasingreports of misuse of these drugs. This is not only true forSROM but also for buprenorphine and methadone, themost diverted drugs in 2009 [6].

Slow-release oral morphine is one of the most powerfuldrugs available for management of severe and chronicpain. Extending indications of SROM to OMT will increasethe risk of misuse and could compromise legitimate use inpain management. This could partly explain the lack ofpivotal clinical trials to assess SROM efficacy for OMT.However, a recent multicentre, multinational phase IIIstudy with a crossover design is underway, comparing theeffectiveness of SROM vs. methadone maintenance treat-ment in patients who have previously been treated withmethadone [37]. With more than 300 patients followed upover a 6 month period, this study will provide highly rel-evant data about SROM efficacy for OMT.

Slow-release oral morphine was initially studied forOMT of pregnant addicted women, with the hypothesisthat SROM may produce less severe neonatal abstinencesyndrome than methadone [38, 39]. A study conducted byFischer et al. [39] did not find any reduction in the numberof days that neonatal abstinence syndrome was experi-enced by neonates with SROM compared with methadoneand concluded that both drugs were suitable maintenanceagents for pregnant opioid addicts.

A recent randomized controlled trial investigatedSROM efficacy for opioid detoxification [40]. No statisticallysignificant differences were found between SROM andmethadone in terms of completion rate (proportion ofpatients completing the study), signs and symptoms ofopioid withdrawal, craving for opioid or self-reportedsymptoms.

Slow-release oral morphine is now available in severalEuropean countries as an alternative to methadone(Austria, Slovakia, Slovenia, Bulgaria and Luxembourg) [8].

The preparation commonly used is Substitol® (morphinesulfate pentahydrate; Mundipharma AG, Basel, Switzer-land). In Austria, the Narcotics Maintenance Decree revisedin 1998 defined methadone as the first choice. Slow-release oral morphine can be used by specialist clinics foropioid maintenance in the event of strong adverse drugsreactions or in the case of pregnancy or HIV infection [35].In France, methadone and buprenorphine are two drugsfully approved for maintenance therapy. Slow-release oralmorphine can be prescribed exceptionally in cases ofmethadone or buprenorphine failure [9]. More scientificdata about SROM efficacy are needed in order to reviselegislation about SROM in France.

Conclusion

In conclusion, as most of the studies assessing SROM effi-cacy were uncontrolled, there is now no definite evidenceshowing that SROM is an effective alternative to metha-done for OMT. Further research should be planned in orderto investigate the clinical utility of this drug for this kind ofindication.

Competing Interests

There are no competing interests to declare.The authors would like to acknowledge Prof. Laurent

Schmitt (Department of Psychiatry, University of Toulouse),Prof.Thierry Lang and Prof. Jean Ferrières (Department of Epi-demiology and Public Health, Inserm U558, University of Tou-louse) for their comments and suggestions to improve thisreview.

No specific funding was obtained to perform this review;the present work was carried out in the context of the researchactivity of the CEIP-A (University Hospital of Toulouse) and theINSERM 1027, Pharmacoepidemiology Research Team (Uni-versity of Toulouse), annually funded by the French Ministry ofResearch.

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