ArticlePDF Available

Mental Symptoms and Drug Use in Maintenance Treatment with Slow-Release Oral Morphine Compared to Methadone: Results of a Randomized Crossover Study

Authors:

Abstract and Figures

Background: Opioid maintenance treatment is the option of choice to stabilize opioid-dependent patients. Whilst efficacy of methadone and buprenorphine has been studied extensively, fewer data on slow-release oral morphine are available. Aims: This study analyzes the effects of slow-release oral morphine compared to methadone with regard to self-reported mental symptoms, drug use and satisfaction with treatment. Methods: The study was carried out as an open-label randomized crossover trial in 14 treatment sites in Switzerland and Germany. It comprised 2 crossover periods of 11 weeks each. For measuring mental symptoms, the Symptom Checklist-27 (SCL-27) was used. Drug and alcohol use was assessed by the number of consumption days, and treatment satisfaction by a visual analogue scale. Results: A total of 157 patients were included for the analyses (per-protocol sample). Statistically significantly better outcomes for morphine as compared to methadone treatment were found for overall severity of mental symptoms (SCL-27 Global Severity Index), as well as 5 of the 6 syndrome groups of the SCL-27, and for treatment satisfaction. There were no statistically significant differences with regard to drug or alcohol use between groups. Conclusions: This study supports positive effects of slow-release oral morphine compared to methadone on patient-reported outcomes such as mental symptoms and treatment satisfaction with comparable effects on concomitant drug use. Slow-release oral morphine represents a meaningful alternative to methadone for treatment of opioid dependence.
Content may be subject to copyright.
E-Mail karger@karger.com
Research Report
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
Mental Symptoms and Drug Use in Maintenance
Treatment with Slow-Release Oral Morphine
Compared to Methadone: Results of a Randomized
Crossover Study
UweVerthein a ThiloBeck b ChristianHaasen a JensReimer a
a Centre for Interdisciplinary Addiction Research of Hamburg University, Hamburg , Germany;
b Arud Zurich, Zurich ,
Switzerland
tically significant differences with regard to drug or alcohol
use between groups. Conclusions: This study supports pos-
itive effects of slow-release oral morphine compared to
methadone on patient-reported outcomes such as mental
symptoms and treatment satisfaction with comparable ef-
fects on concomitant drug use. Slow-release oral morphine
represents a meaningful alternative to methadone for treat-
ment of opioid dependence. © 2014 S. Karger AG, Basel
Introduction
Opioid maintenance treatment aims to ensure surviv-
al, decrease illicit substance use, and increase patients’
health and functioning
[1] . Opioid agonists used in main-
tenance treatment include methadone, buprenorphine,
levomethadone hydrochloride/levomethadyl acetate, di-
acetylmorphine, (dihydro-)codeine, and (slow-release
oral) morphine. Whilst efficacy in terms of treatment re-
tention and substance use has been studied extensively
for methadone and buprenorphine, there are fewer data
on patient-reported outcomes
[2] . This is particularly
true for diacetylmorphine and slow-release oral mor-
phine, two medications which are increasingly used in
Europe
[3–5] . From a pharmacological perspective, mor-
phine seems to be particularly suitable for opioid mainte-
Key Words
Opioid maintenance treatment · Slow-release oral
morphine · Methadone · Mental symptoms · Concomitant
drug use · Treatment satisfaction
Abstract
Background: Opioid maintenance treatment is the option of
choice to stabilize opioid-dependent patients. Whilst effica-
cy of methadone and buprenorphine has been studied ex-
tensively, fewer data on slow-release oral morphine are
available. Aims: This study analyzes the effects of slow-re-
lease oral morphine compared to methadone with regard to
self-reported mental symptoms, drug use and satisfaction
with treatment. Methods: The study was carried out as an
open-label randomized crossover trial in 14 treatment sites
in Switzerland and Germany. It comprised 2 crossover peri-
ods of 11 weeks each. For measuring mental symptoms, the
Symptom Checklist-27 (SCL-27) was used. Drug and alcohol
use was assessed by the number of consumption days, and
treatment satisfaction by a visual analogue scale. Results: A
total of 157 patients were included for the analyses (per-pro-
tocol sample). Statistically significantly better outcomes for
morphine as compared to methadone treatment were found
for overall severity of mental symptoms (SCL-27 Global Se-
verity Index), as well as 5 of the 6 syndrome groups of the
SCL-27, and for treatment satisfaction. There were no statis-
Received: February 25, 2014
Accepted: September 20, 2014
Published online: November 22, 2014
E
u
r
o
p
e
a
n
Add
i
ct
i
o
n
c
R
e
e
s
a
r
h
Dr. Uwe Verthein
Centre for Interdisciplinary Addiction Research of Hamburg University, CIAR
University Medical Center Hamburg-Eppendorf, Department of Psychiatry and
Psychotherapy , Martinistrasse 52, DE–20246 Hamburg (Germany)
E-Mail u.verthein @ uke.uni-hamburg.de
www.karger.com/ear
© 2014 S. Karger AG, Basel
1022–6877/14/0212–0097$39.50/0
is is an Open Access article licensed under the terms of the
Creative Commons Attribution-NonCommercial 3.0 Un-
ported license (CC BY-NC) (www.karger.com/OA-license),
applicable to the online version of the article only. Distribu-
tion permitted for non-commercial purposes only.
Verthein/Beck/Haasen/Reimer
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
98
nance treatment, as it largely has the same properties as
the substituted drug heroin/diacetylmorphine. The short
half-life of morphine, a therapeutic limitation, has been
overcome by a slow-release formulation
[6, 7] .
In several studies, slow-release oral morphine has been
proven as an efficacious medication for reduction of il-
licit drug use, with effects similar to methadone mainte-
nance treatment
[3, 8–10] . Given the high prevalence rates
of psychiatric comorbidity in opioid-dependent patients,
the effects of substitution medication on these symptoms
in particular are of special interest
[11] . Previous studies
suggest positive effects of slow-release oral morphine on
depression, anxiety or quality of life
[9, 10, 12] . However,
only the study of Eder et al.
[9] had a controlled design,
and it failed to show superior quality of life results for
slow-release oral morphine compared to methadone
[13] .
A recent crossover trial confirmed the noninferiority of
slow-release oral morphine regarding the additional use of
heroin compared to methadone
[8] . This report focuses on
the results of patient-reported outcomes from the study,
which were secondary efficacy-related parameters. The ef-
fects of slow-release oral morphine compared to metha-
done on mental symptoms as well as self-reported drug and
alcohol use and satisfaction with treatment are described.
Methods
An open-label randomized crossover study was conducted in
14 treatment sites in Switzerland and Germany. For study inclu-
sion, patients had to be opioid dependent (F11.2 according to ICD-
10), aged 18 years or older and already participating in methadone
maintenance treatment for at least 26 weeks. The study design is
described in detail elsewhere [see
8 ]. The main part of the study
comprised two crossover periods of 11 weeks each (1 week adjust-
ment phase followed by 10 weeks of treatment; see fig.1 ).
Self-reported outcomes were assessed during the crossover
phase, i.e. at baseline, weeks 2, 6 and 11 during the 1st period and
at weeks 13, 17 and 22 during the 2nd period (see fig.1 ). Mental
symptoms were rated according to the Symptom Checklist-27
(SCL-27), a short form of the SCL-90-R
[14] . This instrument in-
cludes subscales on depressive, vegetative and agoraphobic symp-
toms as well as a global severity index (GSI), which represents an
overall burden of psychiatric symptoms. Drug and alcohol use at
the time of inclusion were assessed according to the European Ad-
diction Severity Index standards
[15] . The number of self-reported
consumption days during the past 30 days at baseline and during
the time span since last assessment (at weeks 2, 6, 11 and 13, 17,
22) was used for analyses. Treatment satisfaction was assessed by
a visual analogue scale (VAS) scoring from 0 (‘not satisfied at all’)
to 10 (‘deeply contented’).
To increase the validity of the study results, stringent criteria
for the per protocol (PP) population were set to include patients
who completed each of the two crossover treatment periods (11
weeks) within a specified time frame of 70 days and 84 days,
who had urinalyses for 9 out of 11 weeks per crossover period and
no discontinuation of study medication for more than 5 consecu-
tive days [see
8 ].
For statistical analyses regarding the PP population, the results
of the 3 assessments of each criterion were pooled by calculating
a mean score per period for both treatment conditions. With re-
gard to drug (heroin, cocaine, benzodiazepines) or alcohol use,
overall sum scores of consumption days per period were calcu-
lated. These scores were compared by multifactorial analysis of
variance with factors for treatment, sequence and period. Equal-
ity of the carry-over effect was tested by a two-sample t test. Sta-
tistical analyses were performed using SPSS, version 19
[16] . For
the statistical analyses in the intention to treat (ITT) population,
the mean values from available data were calculated for each pe-
riod of treatment.
This study was approved by the national and regional ethics
committees and conducted in accordance with the Declaration of
Helsinki, the International Conference on Harmonisation Guide-
line for Good Clinical Practice, and the European Union Clinical
Trials Directive 2001/20/EC. This clinical trial has been registered
with ClinicalTrials.gov, No. NCT01079117, and EudraCT, No.
2008-002185-60.
Results
A total of 276 patients (ITT sample) were recruited and
randomly assigned to a treatment sequence starting either
with morphine and followed by methadone (group 1) or
Methadone
Methadone
Morphine
R
Week
Assessments
0 1 11 12 22 47
Methadone
Morphine
Morphine
Extension phasePeriod 2Period 1
Fig. 1. Crossover study design over 47
weeks (R= randomization); assessments at
week 0 (baseline), 2, 6, 11, 13, 17 and 22.
Mental Symptoms in Treatment with
Slow-Release Oral Morphine
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
99
methadone followed by morphine (group 2). Retention in
treatment during crossover was high without any differ-
ences between treatments or periods [group 1: 110 of 141
patients (78%); group 2: 101 of 135 patients (75%)]
[8] .
One hundred and fifty-seven patients qualified for the PP
population: 84 patients in group 1 (morphine-methadone)
and 73 patients in group 2 (methadone-morphine) [see
8 ].
Sample Characteristics
Most patients in the PP sample were male, single and
unemployed, and mean age was 39 years. The average
length of methadone substitution treatment before study
entry was 3.6 years. Although some differences in the
baseline characteristics between study populations were
recorded, e.g. rates of hepatitis C virus infection, cocaine
use and psychiatric comorbidity ( table1 ), they were con-
sidered not to be relevant confounders when comparing
the two treatment groups.
Mental Symptoms
Mental symptoms as rated by SCL-27 had a different
time course during the two sequences of treatment. Base-
line values were similar in both treatment arms (sequenc-
es). Symptom severity (as measured by GSI) decreased in
the methadone-morphine arm after the medication
switch, whereas it increased in the morphine-methadone
arm ( fig.2 , left side). Similar results were obtained for de-
pressive symptoms (as measured by the relevant SCL-27
subscale); whilst under morphine treatment, patients re-
ported fewer symptoms compared to the methadone
treatment period ( fig.2 , right side).
Overall severity of mental symptoms (GSI) was lower
under morphine compared to methadone treatment, and
the difference was statistically significant in the PP popu-
lation ( table2 ) as well as in the ITT population (0.60 ± 0.60
under morphine vs. 0.67 ± 0.63 under methadone; p <
0.05). In addition, 5 of the 6 syndrome groups represented
by subscales of SCL-27 showed better outcomes for mor-
phine as compared to methadone treatment. Differences
between treatment groups were most prominent for de-
pressive and dysthymic symptom subscales ( table2 ). Gen-
erally, patients under oral morphine treatment displayed
Table 1. Sample characteristics at baseline
Characteristic ITT
sample
PP
sample
Males, % 81.5 84.1
Age, years 38.1±7.6 38.9±7.4
Civil status, single, % 74.6 77.7
Employed, working
(part-time or full-time), % 23.2 17.8
Length of prior substitution treatment,
years 3.9±4.4 3.6±4.4
Pre-treatment: last methadone dose, mg 98.0±40.0 92.0±30.8
Alcohol use: EuropASI composite score 0.12±0.17 0.12±0.18
Drug use: EuropASI composite score 0.31±0.14 0.31±0.15
Age at first heroin use, years 20.3±5.1 20.5±5.1
Cocaine use, % 48.2 68.8
Body mass index, kg/m225.2±4.4 24.8±4.2
HIV positive, % 3.6 4.5
Hepatitis C positive, % 57.7 67.3
Psychiatric comorbidity, % 69.2 57.3
GSI (SCL-27) 0.72±0.63 0.71±0.61
Total 276 157
Values are expressed as mean ± SD unless otherwise indicated.
0
0.4
0.2
0.6
0.8
1.0
1.2
GSl, SCL-27
Baseline
2
6
11
13
17
22
1
2
Week (P1) Week (P2) Period
GSl
Mo-Me (PP = 84)
GSl
Me-Mo (PP = 73)
Crossover
0
0.4
0.2
0.6
0.8
1.0
1.2
Depression, SCL-27
Baseline
2
6
11
13
17
22
1
2
Week (P1) Week (P2) Period
Depression
Mo-Me (PP = 84)
Depression
Me-Mo (PP = 73)
Crossover
Fig. 2. Mental symptoms (SCL-27) over 22 weeks per period by study arm.
Verthein/Beck/Haasen/Reimer
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
100
Table 2. Mental symptoms (SCL-27), drug and alcohol use (number of days, self-reported) and treatment satis-
faction (VAS, 0–10) by treatment, controlled for sequence, period and carry-over effect
Morphine Methadone Significance
F v alue p value t value
Mental symptoms (SCL-27)
GSI 0.61±0.56 0.68±0.60 6.91 <0.01
Sequence effect 3.90 0.050
Period effect 1.44 0.233
Carry-over effect 0.582 –0.551
Depression 0.62±0.69 0.70±0.75 5.07 <0.05
Sequence effect 0.03 0.858
Period effect 1.54 0.216
Carry-over effect 0.957 0.055
Dysthymic symptoms 0.77±0.70 0.86±0.77 4.97 <0.05
Sequence effect 3.89 0.050
Period effect 3.84 0.052
Carry-over effect 0.495 –0.685
Vegetative symptoms 0.61±0.56 0.69±0.61 4.41 <0.05
Sequence effect 0.00 0.954
Period effect 0.36 0.551
Carry-over effect 0.980 0.025
Agoraphobic symptoms 0.32±0.46 0.37±0.54 4.99 <0.05
Sequence effect 4.19 <0.05
Period effect 3.20 0.076
Carry-over effect 0.538 –0.617
Sociophobic symptoms 0.59±0.69 0.64±0.72 4.17 <0.05
Sequence effect 28.84 <0.001
Period effect 0.00 0.943
Carry-over effect 0.206 –1.269
Symptoms of mistrust 0.83±0.82 0.89±0.85 3.28 0.072
Sequence effect 5.05 <0.05
Period effect 0.00 0.983
Carry-over effect 0.596 –0.531
Substance use
Heroin 6.4±11.7 6.4±11.3 0.01 0.936
Sequence effect 2.19 0.141
Period effect 0.41 0.521
Carry-over effect 0.544 –0.608
Cocaine 2.4±6.0 2.2±6.2 0.49 0.483
Sequence effect 9.38 <0.01
Period effect 0.24 0.626
Carry-over effect 0.289 –1.063
Benzodiazepines 8.2±17.4 7.4±15.8 1.18 0.279
Sequence effect 3.21 0.075
Period effect 0.51 0.477
Carry-over effect 0.611 –0.509
Alcohol 14.5±21.7 14.5±20.8 0.00 0.995
Sequence effect 7.15 <0.01
Period effect 0.03 0.864
Carry-over effect 0.377 –0.886
Treatment satisfaction
Satisfaction 7.6±1.8 6.0±2.2 44.37 <0.001
Sequence effect 0.05 0.824
Period effect 9.63 <0.01
Carry-over effect 0.813 –0.237
Total 157 157
Values are expressed as mean ± SD.
Mental Symptoms in Treatment with
Slow-Release Oral Morphine
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
101
better mental health than when under methadone treat-
ment. In some of the subscales, e.g. those related to symp-
toms of agoraphobia, sociophobia and mistrust, an inter-
fering effect of sequence was observed, indicating differ-
ent symptom levels between group 1 and group 2, i.e.
generally higher scores in the methadone-morphine arm,
as represented by the GSI scores (see fig.2 ). The tests for
a possible carry-over effect regarding SCL-27 GSI and
subscales did not show statistical significance.
Drug and Alcohol Use
The highest number of consumption days was found
for alcohol, followed by benzodiazepines, heroin and co-
caine. There were no statistically significant differences in
substance use according to the treatment condition (mor-
phine vs. methadone). Switching from morphine to meth-
adone or vice versa had no effect on substance use, except
for an increase in benzodiazepine use in the methadone-
morphine arm ( fig.3 ). The average number of consump-
tion days of heroin, cocaine, benzodiazepines and alcohol
remained similar in both study periods. However, patients
starting with methadone and switching to morphine had
generally higher consumption levels in both periods.
This stable consumption pattern is reflected in the sta-
tistical analyses of the comparison of the mean number of
consumption days between the treatment conditions.
The comparison for treatment groups did not reveal a
statistically significant difference for any substance ( ta-
ble2 ). For the use of cocaine and alcohol, a significant
sequence effect was detected. This finding corresponds to
an overall higher consumption in the methadone-mor-
phine subsample in both study periods. Again, the tests
for possible carry-over effects yielded no statistically sig-
nificant differences.
Satisfaction with Treatment
Initially, treatment satisfaction increased under both
treatment conditions (morphine and methadone). How-
ever, after switching from morphine to methadone, treat-
ment satisfaction decreased, whereas it increased further
in patients who switched from methadone to morphine.
In both periods, patients described higher treatment sat-
isfaction under treatment with morphine compared to
methadone ( fig.4 ).
Treatment satisfaction was statistically significantly in
favor of morphine ( table2 ). Furthermore, the period ef-
fect reached statistical significance, which is reflected by
an overall higher treatment satisfaction in the first period
(see fig.4 ). There was no significant carry-over effect re-
garding treatment satisfaction. Higher satisfaction under
morphine treatment was also reported in the ITT popula-
tion (7.66 ± 2.21 under morphine vs. 6.01 ± 2.50 under
methadone; p< 0.001).
Discussion
In this open-label, randomized, crossover trial, the ef-
fects of morphine substitution treatment were analyzed
using a robust methodology with regard to self-reported
mental symptoms, drug use and treatment satisfaction.
Treatment with slow-release oral morphine was associ-
0
2
4
6
8
10
12
14
16
18
Number of days
Period 1 Period 2
Heroin
Period 1 Period 2
Cocaine
Period 1 Period 2
Benzodiazepines
Period 1 Period 2
Alcohol
Mo-Me (PP = 84)
Me-Mo (PP = 73)
Fig. 3. Drug and alcohol use per period by
study arm; mean number of self-reported
consumption days (sum of consumption
days per period).
Verthein/Beck/Haasen/Reimer
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
102
ated with less overall severity of mental symptoms, as well
as less severity for specific mental health outcomes such
as depression, dysthymic symptoms, vegetative symp-
toms, agoraphobic symptoms and sociophobic symp-
toms compared to methadone treatment. Furthermore,
treatment satisfaction was significantly better under mor-
phine treatment compared to methadone. Advantages of
morphine over methadone were evident not only in the
PP but also in the ITT population. Similar differences in
treatment effects were observed in patients who previ-
ously received methadone and were switched to slow-re-
lease oral morphine
[10] .
No significant differences between morphine and
methadone treatment were noted with regard to co-con-
sumption of heroin, cocaine, benzodiazepines or alcohol.
Previous findings have suggested the efficacy of metha-
done in reducing opioid cravings over 24 h, but without
sufficient stabilization of mood disturbances over this
time period. This finding was related to the pharmacoki-
netic properties of methadone and its differential effects
on mood and withdrawal suppression
[17] . In a compar-
ative study, slow-release oral morphine produced a later
plasma peak than methadone, which could explain the
better subjective efficacy with respect to withdrawal and
mental symptoms over a 24-hour period
[7] . However, in
this study the dose level of morphine was comparatively
low (methadone/morphine conversion factor 1:
4.6) in
order to reach an adequate substitution effect. Advantag-
es of morphine over methadone in terms of depression,
anxiety and quality of life have been described before
[9,
13] , but only one study followed a controlled design [9] .
However, that study failed to find superior quality of life
outcomes in the morphine group, likely due to the small
sample size and low statistical power. Our study provides
additional clinical evidence for a superior effect of slow-
release oral morphine on improvement of psychiatric
symptoms compared to methadone, and was conducted
using a relatively large and controlled study design. Since
a flexible dose regimen was used in both treatment condi-
tions and average doses of morphine and methadone
(based on a ratio of about 7.6:
1) were similar [see 8 ], the
observed effects may be associated with the intrinsic
pharmacological profile of the treatments.
Treatment goals have seen a shift from a paternalistic
model of delivery of care to a more patient-centered ap-
proach in recent years
[18] . In this context, the concept of
shared decision making and patient satisfaction has be-
come even more important. Whilst in addiction medi-
cine, shared decision making faces some disease-inherent
and legal boundaries, satisfaction with treatment as a
preference for specific substitution medication should be
considered in daily practice in order to improve the
chances of achieving treatment goals in this difficult-to-
treat population. In our study, patient satisfaction was
considerably higher with slow-release oral morphine as
compared to methadone.
0
6
5
4
3
2
1
7
8
9
10
Treatment satisfaction (0–10)
Baseline 2 6 11 13 17 22 1 2
Week (P1) Week (P2)
Crossover
Period
Satisfaction
Mo-Me (PP = 84)
Satisfaction
Me-Mo (PP = 73)
Fig. 4. Satisfaction with treatment (VAS)
over 22 weeks per period by study arm.
Mental Symptoms in Treatment with
Slow-Release Oral Morphine
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
103
Some limitations should be mentioned. Although pa-
tients enrolled in this study were already under metha-
done maintenance treatment, motives for treatment
switch were not evaluated. Patients may have been either
dissatisfied by ongoing (methadone) treatment or were
curious to experience an alternative treatment which is
currently under clinical evaluation. The SCL-27 scale – a
short form of the well-established symptom check list
SCL-90
[14, 19] – was used because of the availability of
a validated translation into German and the fact that the
short version is less burdensome to administer without
loss of sensitivity of change
[20] . The SCL-27 has accept-
able psychometric properties which were found for the
overall GSI score as well as for the subscales in studies
with clinical and nonclinical samples
[21, 22] (which is
also true for the further developed version SCL-27-plus
[23] ). Other instruments for assessing psychological dis-
tress are not well established in the target population of
opioid-dependent persons. Treatment satisfaction as-
sessed by VAS may have some limitations, but has the
advantage of providing a clear and simple measure. Alter-
native instruments, e.g. the Treatment Satisfaction Ques-
tionnaire for Medications-9, are more general as they
combine effectiveness, side effects, convenience and
global satisfaction. Although the latter dimension in this
questionnaire is based on three items, one may question
their power compared to a simplified unbiased and
straightforward VAS
[24] .
A sequence effect was observed with regard to mental
symptoms as well as to cocaine and alcohol consumption,
with a stronger symptom load and more substance use in
the methadone-morphine arm (group 2). Wide standard
deviations in comparison to the means suggest that these
effects may have mathematical rather than clinical rele-
vance. With regard to self-reported cocaine use, no chang-
es were seen in the methadone-morphine sequence (group
2) and there was some reduction of use in the morphine-
methadone sequence (group 1). Higher use of alcohol was
reported in both sequences of treatment, although levels
were highest in the methadone-morphine sequence
(group 2). A period effect was seen, such that an overall
decrease in treatment satisfaction was apparent as the
time in study progressed. Despite some inconsistent ef-
fects regarding sequences and periods, no statistically sig-
nificant carry-over effects were seen in any parameter test-
ed. This confirms the validity of the findings of this study.
In the context of patient-centered medicine, our data
support a positive effect of slow-release oral morphine
compared to methadone on patient-reported outcomes
such as mental symptoms and treatment satisfaction,
with similar effects on concomitant drug use. Slow-re-
lease oral morphine therefore represents a meaningful al-
ternative to methadone for the treatment of chronic opi-
oid dependence.
Acknowledgement
We thank patients and staff who participated in the study for
their support. This study was sponsored by Mundipharma Medical
Company, Basel, Switzerland.
Disclosure Statement
The authors report no conflicts of interest. The clinical trial was
designed and financed by Mundipharma Medical Company, Basel,
and conducted by qualified investigators under the sponsorship of
Mundipharma Medical Company. All authors are independent of
any significant financial or other relationship to the sponsor, ex-
cept for appropriate compensation for the conduct of this study
and related expenditure.
References
1 WHO/UNDOC/UNAIDS position paper.
www.who.int/substance_abuse/publications/
en/PositionPaper_flyer_English.pdf, 2004.
2 Mattick RP, Kimber J, Breen C, Davoli M: Bu-
prenorphine maintenance versus placebo or
methadone maintenance for opioid depen-
dence. Cochrane Database Syst Rev 2008;2 :
CD002207.
3 Jegu J, Gallini A, Soler P, Montastruc J-L, La-
peyre-Mestre M: Slow-release oral morphine
for opioid maintenance treatment: a system-
atic review. Br J Clin Pharmacol 2011;
71: 832–
843.
4 Ferri M, Davoli M, Perucci CA: Heroin main-
tenance for chronic heroin-dependent indi-
viduals. Cochrane Database Syst Rev 2011;12
:
CD003410.
5 Ferri M, Minozzi S, Bo A, Amato L: Slow-re-
lease oral morphine as maintenance therapy
for opioid dependence. Cochrane Database
Syst Rev 2013; 6 : CD009879.
6 Broomhead A, West R, Eglinton L, Jones
M, Bubner R, Sienko D, Knox K: Compara-
tive single-dose pharmacokinetics of sus-
tained-release and modified-release mor-
phine sulphate capsules under fed and fast-
ing conditions. Clin Drug Investig 1997;
13:
162–170.
7 Mitchell TB, White J, Somogyi AA, Bochner
F: Comparative pharmacodynamics and
pharmacokinetics of methadone and slow-re-
lease oral morphine for maintenance treat-
ment of opioid dependence. Drug Alcohol
Depend 2003;
72: 85–94.
8 Beck T, Haasen C, Verthein U, Walcher S,
Schuler C, Backmund M, Ruckes C, Reimer J:
Maintenance treatment for opioid depen-
dence with slow-release oral morphine: a ran-
domized cross-over study versus methadone.
Addiction 2014;
109: 617–626.
9 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: 1101–1109.
Verthein/Beck/Haasen/Reimer
Eur Addict Res 2015;21:97–104
DOI: 10.1159/000368572
104
10 Kastelic A, Dubajic C, Strbad E: Slow-release
oral morphine for maintenance treatment of
opioid addicts intolerant to methadone or
with inadequate withdrawal suppression. Ad-
diction 2008;
103: 1837–1846.
11 Reimer J, Verhein U, Karow A, Schäfer I, Na-
ber D, Haasen C: Physical and mental health
in severe opioid-dependent patients within a
randomized controlled maintenance trial.
Addiction 2011;
106: 1647–1655.
12 Vasilev GN, Alexieva DZ, Pavlova RZ: Safety
and efficacy of oral slow-release morphine for
maintenance treatment in heroin addicts: a
6-month open noncomparative study. Eur
Addict Res 2006;
12: 53–60.
13 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 metha-
done treatment. Eur Addict Res 2008;
14: 99–
105.
14 Hardt J, Egle UT, Kappis B, Hessel A, Brähler
E: Die Symptom-Checkliste SCL-27 – Ergeb-
nisse einer deutschen Repräsentativbefra-
gung. Psychother Psychosom Med Psychol
2004;
54: 214–223.
15 Kokkevi A, Hartgers C: EuropASI: European
adaptation of a multidimensional assessment
instrument for drug and alcohol dependence.
Eur Addict Res 1995;
1: 208–210.
16 SPSS Inc: IBM SPSS Statistics 19. Core-Sys-
tem-Manual, 1989, 2010.
17 Shiran MR, Lennard MS, Iqbal MZ, Lagun-
doye O, Seivewright N, Tucker GT, Rostami-
Hodjegan A: Pharmacokinetic-pharmacody-
namic modelling of mood and withdrawal
symptoms in relation to plasma concentra-
tions of methadone in patients undergoing
methadone maintenance treatment. J Clin
Psychopharmacol 2012;
32: 666–671.
18 Dwamena F, Holmes-Rovner M, Gaulden
CM, Jorgenson S, Sadigh G, Sikorskii A,
Lewin S, Smith RC, Coffey J, Olomu A: In-
terventions for providers to promote a pa-
tient-centred approach in clinical consulta-
tions. Cochrane Database Syst Rev 2012;12:
CD003267.
19 Maremmani I, Pani PP, Pacini M, Perugi G:
Substance use and quality of life over 12
months among buprenorphine maintenance-
treated and methadone maintenance-treated
heroin-addicted patients. J Subst Abuse Treat
2007;
33: 91–98.
20 Prinz U, Nutzinger DO, Schulz H, Petermann
F, Braukhaus C, Andreas S: Comparative psy-
chometric analyses of the SCL-90-R and its
short versions in patients with affective disor-
ders. BMC Psychiatry 2013;
13: 104.
21 Kuhl HC, Hartwig I, Petitjean S, Müller-
Spahn F, Margraf J, Bader K: Validation of the
Symptom Checklist SCL-27 in psychiatric pa-
tients: psychometric testing of a multidimen-
sional short form. Int J Psychiatry Clin Pract
2010;
14: 145–149.
22 Hardt J, Dragan M, Kappis B: A short screen-
ing instrument for mental health problems:
the symptom checklist-27 (SCL-27) in Poland
and Germany. Int J Psychiatry Clin Pract
2011;
15: 42–49.
23 Kuncewicz D, Dragan M, Hardt J: Validation
of the Polish version of the symptom-chscklist-
27-plus questionnaire. Psychiatr Pol 2014;
48:
345–358.
24 Bharmal M, Payne K, Atkinson MJ, Desro-
siers MP, Morisky DE, Gemmen E: Valida-
tion of an abbreviated Treatment Satisfaction
Questionnaire for Medication (TSQM-9)
among patients on antihypertensive medica-
tions. Health Qual Life Outcomes 2009;
7: 36.
... Retention rates were similar, and both substances had a comparable safety profile (Beck et al., 2014;Hämmig et al., 2014). Secondary analyses showed statistically significant benefits of SROM over methadone treatment in terms of mental health symptoms, treatment satisfaction, and heroin craving (Falcato et al., 2015;Verthein et al., 2015). Compared to racemic methadone, patients seem to tolerate SROM slightly better tolerance, it has fewer side effects, and a slightly more favorable cardiogenic risk profile due to longer mean QTc intervals occurring in racemic methadone-treated patients (Hämmig et al., 2014). ...
... The study based sample size calculation on the cross-over study in which an improvement of 5% in mental health symptoms was found after switching from methadone to morphine (Beck et al., 2014;Verthein et al., 2015). Since this study consisted of a longer period compared to the cross-over study, the current study expected an improvement of 10% in mental health symptoms between baseline and t12. ...
... The larger sample leads to a higher statistical power and increases the probability of a significant result. Previous experimental studies have also shown the positive effect of SROM on mental health symptoms (Eder et al., 2005;Verthein et al., 2015). Our study confirms and underlines the findings that SROM treatment leads to a significant improvement in mental health in OAT patients. ...
Article
Introduction Since April 2015, slow-release oral morphine (SROM) has been approved for opioid agonist treatment (OAT) in Germany. Experimental studies show that benefits of SROM over methadone include less heroin craving, better tolerability, and higher patient satisfaction and mental stability. The SROMOS study (Efficacy and Tolerability of Slow-Release Oral Morphine in Opioid Substitution Treatment) aims to investigate the long-term effects (effectiveness and safety) of morphine substitution under routine care in Germany. Material and methods This is a prospective, noninterventional, naturalistic, observational study. Between July 2016 and November 2017, this study recruited patients in OAT who decided to switch to SROM from 23 outpatient addiction treatment centers in Germany. The study collected data on mental health (Brief Symptom Inventory – BSI-18), substance use, somatic health (Opiate Treatment Index Health-Symptoms-Scale – OTI-HSS), opioid craving (visual analogue scale), and withdrawal symptoms (Short Opiate Withdrawal Scale) at baseline (t0) and after 3 (t3), 6 (t6) and 12 (t12) months. Physicians documented side effects as adverse events (AEs) and adverse drug reactions (ADRs). Results Three-quarters of the enrolled study participants (N = 180) were male. The average age was 44.4 years. Patients were opioid-dependent for 23 years and had been in OAT for almost seven years on average. After 12 months, 60.6% were still being treated with SROM. Mental health improved significantly under SROM treatment between t0 and t12. The intention-to-treat (ITT), as well as the per-protocol (PP) analysis, shows a statistically significant improvement of the mean Global Severity Index (GSI) of the BSI-18 value of 20% (ITT) and 24% (PP). Physical health also improved significantly under SROM treatment. There were no statistically significant changes in the use of cannabis, cocaine, amphetamines, and tranquillizers in the past 30 days, but heroin use, intravenous consumption, and the number of drinking days significantly decreased. Conclusions This study provides some of the first long-term data on OAT with SROM under routine care conditions. SROM treatment is an effective alternative for a subgroup of opioid-dependent patients with an unsatisfactory course of OAT or in cases where undesirable side effects due to alternative substances have occurred. Ethical statement The study protocol was approved by the Ethics Committee of the Chamber of Physicians in Hamburg in March 2016 (No. PV5222). The study was conducted by following the Declaration of Helsinki and is registered with the German Register of Clinical Trials (DRKS, ID: DRKS00010712).
... Studies have shown maintenance treatment with slow-release oral morphine a medication with the same active ingredient of OT (i.e. morphine) has fewer physical side events [34,35], lower depression and anxiety scores [34,36], an enhanced sense of feeling 'normal' [35] and higher treatment satisfaction [36] and acceptability [35] as compared to methadone maintenance treatment. Further studies to compare the safety and treatment satisfaction of OT with other opioid pharmacotherapies are warranted. ...
... Studies have shown maintenance treatment with slow-release oral morphine a medication with the same active ingredient of OT (i.e. morphine) has fewer physical side events [34,35], lower depression and anxiety scores [34,36], an enhanced sense of feeling 'normal' [35] and higher treatment satisfaction [36] and acceptability [35] as compared to methadone maintenance treatment. Further studies to compare the safety and treatment satisfaction of OT with other opioid pharmacotherapies are warranted. ...
Article
Introduction In response to a high burden of opioid use disorder (OUD), Iran established a network of opioid agonist treatment (OAT) centres beginning in 2002. To increase treatment diversity, particularly for patients who use opium as their drug of choice, opium tincture (OT)-assisted treatment was introduced to the network. This study aimed to explore factors influencing OT-assisted treatment selection for OUD in Tehran, Iran. Methods We conducted 54 in-depth interviews with patients with OUD (n = 33), family members of patients (n = 9) and drug treatment providers (n = 12). Participants were recruited from 12 drug treatment centres across Tehran, between September and November 2019. All interviews were audio-recorded, transcribed and coded in OpenCode 4.02 software and analysed using thematic analysis. Results Study participants more commonly reported individual-level factors as facilitators (e.g. to reduce harms associated with illicit opioid use, achieve recovery through a gradual dose reduction regimen combined with Congress 60 recovery program) and structural level factors (e.g. low adoption by OAT system and lack of familiarity of treatment providers) as barriers for utilisation of OT-assisted treatment regimens. OT was perceived to produce lower levels of physiological dependence than methadone, but the requirement for twice supervised dosing was restrictive. Low familial and community acceptance were also seen as barriers to access. Discussion and Conclusions This research identified a range of perceived benefits for OT-assisted treatment ranging from harm reduction to an intermediate step to achieve recovery. However, several structural-, individual-, familial- and community-level barriers impede its availability and acceptability.
... Two studies compared SROM with oral methadone in patients with opioid dependence. Polysubstance dependence was an exclusion criteria in one study (26,27), while cocaine use and HBV/HCV was reported for half of the sample at baseline in the other study (28,29). Standardized psychosocial counseling was provided in one study (26), while it was not reported by the other study (28). ...
... Polysubstance dependence was an exclusion criteria in one study (26,27), while cocaine use and HBV/HCV was reported for half of the sample at baseline in the other study (28,29). Standardized psychosocial counseling was provided in one study (26), while it was not reported by the other study (28). After 14-22 weeks of treatment, SROM was superior to methadone on almost all measures of mental health including depressive symptoms, anxiety symptoms, overall mental health, and different subscales of SCL-27 ( Table 1). ...
Article
Background: There is a knowledge gap in systematic reviews on the impact of opioid agonist treatments on mental health. Objectives: We compared mental health outcomes between different opioid agonist treatments and placebo/waitlist, and between the different opioids themselves. Methods: This meta-analysis of randomized clinical trials (RCTs) was pre-registered at PROSPERO (CRD42018109375). Embase, MEDLINE, PsychInfo, CINAHL Complete, and Web of Science Core Collection were searched from inception to May 2020. RCTs were included if they compared opioid agonists with each other or with placebo/waitlist in the treatment of patients with opioid use disorder and reported at least one mental health outcome after 1-month post-baseline. Studies with psychiatric care, adjunct psychotropic medications, or unbalanced psychosocial services were excluded. The primary outcome was overall mental health symptomatology, e.g. Symptom Checklist 90 total score, between opioids and placebo/waitlist. Random effects models were used for all the meta-analyses. Results: Nineteen studies were included in the narrative synthesis and 15 in the quantitative synthesis. Hydromorphone, diacetylmorphine (DAM), methadone, slow-release oral morphine, buprenorphine, and placebo/waitlist were among the included interventions. Based on the network meta-analysis for primary outcomes, buprenorphine (SMD (CI95%) = −0.61 (−1.20, −0.11)), DAM (−1.40 (−2.70, −0.23)), and methadone (−1.20 (−2.30, −0.11)) were superior to waitlist/placebo on overall mental health. Further direct pairwise meta-analysis indicated that overall mental health improved more in DAM compared to methadone (−0.23 (−0.34, −0.13)). Conclusions: Opioid agonist treatments used for the treatment of opioid use disorder improve mental health independent of psychosocial services.
... The most mentioned reasons for the medication switch were expected a decrease in heroin craving, expected better tolerability of the drug and unsatisfying previous course of treatment. These benefits are also remarked in the scientific literature: the advantages of the substitution treatment with SROM versus methadone are less craving for heroin, better tolerability and higher patient satisfaction 36,43,44,48,51 . When the physicians were asked to identify the main reason for the switch the expectation of a stronger suppression of heroin craving ranked first. ...
... The second main reason was the expectation of a better effect on mental comorbidity. SROM indeed appears to reduce depressive and anxiety symptoms 36,43,48 . Other important advantages of SROM versus methadone that were mentioned by the attending physicians are the absence of drug-induced QTc interval prolongation in the ECG 48 and the less interaction with other concomitant medications. ...
Article
Full-text available
Since 2015 slow-release oral morphine (SROM) is approved for opioid substitution treatment (OST) in Germany. The SROMOS study (efficacy and tolerability of slow-release oral morphine in opioid substitution treatment) evaluates the efficacy and safety of SROM in routine care. This article describes the switching process from racemic methadone, levomethadone and buprenorphine to SROM. Between July 2016 and November 2017 180 patients in 23 study centers in Germany were included in the prospective, non-interventional, naturalistic observational study. Patients were already in OST and switched from a previous medication to SROM. The switching process was analyzed during a period of fourteen days. Data were available for 169 participants. The switching process had a different progression depending on premedication and pre dosage. On the fourteenth day of SROM treatment patients switched from racemic methadone took an average dosage of 922.2 mg/day, from levomethadone 801.0 mg/day and from buprenorphine 626.7 mg/day. Average conversion ratio racemic methadone to SROM was 1:11.8, levomethadone to SROM 1:17.4 and buprenorphine to SROM 1:58.0. This study provides the first data on the switching process from buprenorphine to SROM. Average dose ratio racemic methadone to SROM on the fourteenth day of treatment was considerably higher than recommended in the prescribing information.
... We measured quality of life using a single-item measure, "how satisfied are you with your QoL at the moment?", that we have previously found psychometrically valid compared to longer measures [4]. Cooccuring mental disorders or higher levels of mental health problems have been found in many samples to be associated with lower treatment satisfaction [5][6][7]. Previous research with the NorComt cohort [4,8,9] has confirmed the strong correlation of mental health and quality of life found in previous research, making the addition of both variables into the regression model inappropriate, as this would introduce multicollinearity. As the HSCL-25 is a more widely used and validated measure than our single-item quality of life measure, we will add the HSCL-25 score at T1 into the regression model, as suggested by Groenwald and colleagues [10]. ...
Method
Introduction: Opioid maintenance treatment (OMT) is increasingly approached as a long-term treatment. As opioid use patterns change over time, patients may be entering treatment with different goals, such as harm reduction or recovery. The evidence base is also increasing as to the importance of self-reported satisfaction with treatment. This study protocol describes our plan to measure incoming OMT patients’ treatment goals, and explore whether these goals are related to treatment satisfaction after one year. We have followed the STROBE checklist for reporting of observational epidemiological studies to the extent possible for a protocol. Methods: This research is part of the Norwegian Cohort of Patients in Opioid Maintenance Treatment and Other Drug Treatment (NorComt) study. NorComt is a multidisciplinary study designed to increase understanding of factors impacting treatment adherence and outcomes, for a nationally representative sample of OMT patients. Baseline self-report data was collected from 14 OMT facilities in Norway during 2012-2016, and again one year later, using a variety of validated tools and single-item questions. We hypothesize that patients declaring a treatment goal of harm reduction will be more satisfied with treatment after one year, than patients aiming for recovery, despite recovery dominating the OMT narrative in Norway. We will use adjusted logistic regression models to explore the association of treatment goal at intake, with treatment satisfaction one year later, controlling for the confounder of mental health when measured one year later. Conclusion: This study will explore the importance of centering substance treatment around patient goals, expectations, and outcomes. We invite critical feedback and input on our analytical plan. Keywords: self-report, patient-reported outcome, satisfaction, recovery, harm reduction, opioid
... However, higher dosages risk precipitating adverse effects and generating patient resistance in treatment adhesion (Coffa and Snyder, 2019). Thus, SROM appears to be an attractive OMT for patients with cardiac disease or intolerance to other OMTs because of the lesser physical side effects and the lack of impact on the QT interval (Klimas et al., 2019;Verthein et al., 2015). Besides, SROM appears to have similar efficacy on the illicit drug consumption as methadone (Beck et al., 2014) and even superior efficacy for craving (Klimas et al., 2019). ...
Article
Full-text available
Craving and impulsivity are addiction components which explain why heroin-dependant individuals (HDI), continue using heroin despite not wanting to do so. Opioid maintenance treatment (OMT), such as slow-release oral morphine (SROM), is the most effective treatment for opioid dependence. However, the impact of SROM on craving and impulsivity remains unclear. In this observational study, 23 HDI receiving SROM, their usual OMT, took part in the experiment. Each of the participants filled in the perceived level of craving with a visual analog scale. Their impulsivity was assessed via three laboratory tasks, the stop-signal reaction time, the Balloon Analogue Risk Task and delay discounting. Each evaluation was performed before and after SROM administration. Craving was significantly reduced after administration of SROM (difference 2.83; P = 0.0010), whereas there were no significant differences in performance in the three laboratory tasks. In the long term, we observed an improvement on delay discounting correlated with the duration and dosage of SROM. The acute impact of SROM appears to significantly reduce craving, without impacting impulsivity. Observation of the correlation between delay discounting and the duration and dosage of OMT is of great interest and should be studied further.
... A mu-opioid receptor agonist SROM guarantees steady blood levels over 24 h [41,42] and can serve as an alternative substitution treatment [43] for patients responding poorly to methadone [44] and other substances available for OST or those individuals suffering from intolerable side effects. Having long-standing experience of prescription of slowrelease morphine (SROM) in OST, Austrian clinicians reported in a cohort analysis of 5165 participants that the retention rate after 1 year of treatment with SROM amounted to 79 % (in comparison retention rate for methadone treatment 59%) [45]. ...
Article
Full-text available
Purpose of Review This article aims to provide an overview of standard and adjunctive treatment options in opioid dependence in consideration of therapy-refractory courses. The relevance of oral opioid substitution treatment (OST) and measures of harm reduction as well as heroin-assisted therapies are discussed alongside non-pharmacological approaches. Recent Findings Currently, recommendation can be given for OST with methadone, buprenorphine, slow-release oral morphine (SROM), and levomethadone. Heroin-assisted treatment using diamorphine shall be considered as a cost-effective alternative for individuals not responding to the afore-mentioned opioid agonists in order to increase retention and reduce illicit opioid use. The modalities of application and the additional benefits of long-acting formulations of buprenorphine should be sufficiently transferred to clinicians and the eligible patients; simultaneously methods to improve planning of actions and self- management need to be refined. Regarding common primary outcomes in research on opioid treatment, evidence of the effectiveness of adjunctive psychological interventions is scarce. Summary Maintaining a harm reduction approach in the treatment of opioid addiction, a larger range of formulations is available for the prescribers. Embedding the pharmacological, ideally individualized treatment into a holistic, structure-giving concept also requires a reduction of fragmentation of ancillary services available, drug policies, and treatment philosophies on a global scale.
... In two of these studies, SROM was associated with reduced cravings compared to methadone, though this outcome was not included in the meta-analysis 30,31 . Other small trials have suggested that, compared to methadone, SROM improves depression, anxiety, and treatment satisfaction, but evidence is mixed on quality-oflife improvements compared to treatment with methadone or buprenorphine [32][33][34][35][36] . As the majority of SROM trials are small and unblinded, further studies are necessary. ...
Article
Amidst the opioid overdose crisis, there are increased efforts to expand access to medications for opioid use disorder (MOUD). Hospitalization for the complications of substance use in the United States (US) provides an opportunity to initiate methadone, buprenorphine, and extended release naltrexone and link high-risk, not otherwise engaged, patients into outpatient care. However, treatment options for patients are quickly exhausted when these medications are not desired, tolerated, or beneficial. As an example, we discuss the case of a man who was hospitalized 27 times over 2 years for complications related to his opioid use disorder (OUD), including recurring methicillin-resistant Staphylococcus aureus vertebral osteomyelitis, increasing antimicrobial resistance, new infections, and multiple overdoses in and out of the hospital. The patient suffered these complications despite efforts to treat his OUD with methadone and buprenorphine while hospitalized, and repeated attempts to link him to outpatient care. We use this case to review evidence-based treatments for refractory OUD, which are not approved in the US, but are available in Canada. If hospitalized in Vancouver, Canada, this patient could have been offered slow-release oral morphine and injectable opioid agonist therapy, as well as access to sterile syringes and injection equipment at an in-hospital supervised injection facility. Each of these approaches is supported by evidence and has been implemented successfully in Canada, yet none are available in the US. In order to combat the multiple harms from opioids, it is critical that we consider every evidence-based tool.
Article
This study aimed to determine whether hydromorphone and codeine can be detected in oral fluid specimens following administration of Substitol™, a slow‐release formulation of morphine. This is of interest for those monitoring treatment compliance using drug testing. Oral fluid specimens collected for compliance assessment in routine clinical practice or as part of a clinical trial were subjected to quantitative analysis of hydromorphone, morphine, codeine, and 6‐acetylmorphine using highly sensitive mass spectrometric methods. Oral fluid was collected using a Greiner Bio‐One saliva collection system. Patients undergoing substitution treatment with Substitol™, methadone, or buprenorphine were included, together with patients undergoing pain treatment with hydromorphone. Hydromorphone was detected in 642 of the 663 (97%) samples from substitol‐treated patients. Concentrations were not higher in methadone‐ and buprenorphine‐treated patients who relapsed into heroin use, or in patients on hydromorphone therapy. Codeine was detected in 29% of the samples. These concentrations were lower than those in patients who had relapsed to heroin use. Clinical administration of morphine can lead to detectable concentrations of both hydromorphone and codeine in oral fluids. This should be taken into consideration when using drug testing in oral fluid samples for compliance assessment in this patient group.
Chapter
Indikationen, Wirkungsweise, Nebenwirkungen und Risiken, Kontraindikationen und Interaktionen werden für die Medikamente zur Behandlung von Abhängigkeit und Entzugssyndromen beschrieben. Der Aufbau dieses Kapitels unterscheidet sich insofern von den anderen Kapiteln als die einzelnen Suchtmittel die Struktur vorgeben.
Article
Full-text available
This open-label, noncomparative, single-center trial evaluated the safety and efficacy of once-daily treatment with slow release oral morphine (SROM) capsules for the maintenance treatment of 20 outpatients with heroin dependency over 6 months at the National Institute for Addictions in Sofia, Bulgaria. Doses were individually titrated up to a mean daily maintenance dose of 760 mg (range 440-1,200 mg). SROM was effective in significantly reducing the signs and symptoms of opioid withdrawal and craving for heroin, with stabilization generally evident within two weeks. Nineteen patients completed 6 months of treatment and illicit opioid use was virtually eliminated. One patient withdrew voluntarily at 22 weeks. Validated questionnaires and tests indicated improvements in patients' well-being from baseline assessments. These included significant improvements with regard to suicidal depression (85%), anxiety and dysphoria (66%), general illness (58%), social dysfunction (54%), sense of hopelessness (34%), attention (25%), and self-reported typical depressive (27%) and disease-related (11%) symptoms. No deaths, serious adverse events, or withdrawals due to adverse events occurred. Five episodes of constipation and one episode of sweating (all nonserious and of mild or moderate severity) were reported. Vital signs were unaffected by SROM and no weight change was evident over the study period. The observations made in this study indicate a promising role for once-daily treatment with SROM in the clinical management of heroin dependency.
Article
Full-text available
Aim: The goal of this research is to evaluate the psychometric qualities of the Polish version of the SCL-27-plus questionnaire in terms of its five factor structure, internal consistency and theoretical accuracy. Method: A total of 1.350 persons of which 62% were males, participated in the study. 651 persons were tested with a paper version, 699 subjects received an electronic version of the questionnaire. 336 (tested with the paper version) were patients with diagnosed psychiatric disorders. Paper version participants also filled out the General Health Questionnaire (GHQ-28). Results: Confirmatory factor analysis validated the five factor structure of SCL-27-plus when some errors terms within subscales are allowed to correlate (Depending on the sample: 1.64 < or = chi2/df < or = 2.46; 0.05 < or = RMSEA < or = 0.06; 0.91 < or = CFI < or = 0.95). Cronbach's Alpha reliability measures for the Global Severity Index was 0.90 to 0.92 and for the particular subscales 0.71 to 0.88. The GSI and symptom subscales for SCL-27-plus correlated with their equivalences in the GHQ-28 moderately to highly (r = 0.38 to 0.68). Strong differences occurred between the "clinical" and "non-clinical" groups in the levels of general and specific symptoms (Cohen's d from 0.42 to 1.15). Conclusions: The Polish version of the SCL-27-plus questionnaire demonstrates good psychometric qualities. It can be used to measure the general intensity of psychopathological impairment as well as the specific subscales.
Article
Full-text available
To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for opioid dependence in patients previously treated with methadone. Prospective, multiple-dose, open label, randomized, non-inferiority, cross-over study over two 11-week periods. Methadone treatment was switched to SROM with flexible dosing and vice versa according to period and sequence of treatment. Fourteen outpatient addiction treatment centers in Switzerland and Germany. Adults with opioid dependence in methadone maintenance programs (dose ≥50 mg/day) for ≥26 weeks. The efficacy endpoint was the proportion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected, randomly selected and analyzed for 6-monoacetyl-morphine and 6-acetylcodeine. Non-inferiority was concluded if the two-sided 95% confidence interval (CI) in the difference of proportions of positive urine samples was below the predefined boundary of 10%. One hundred and fifty-seven patients fulfilled criteria to form the per protocol population. The proportion of heroin-positive urine samples under SROM treatment (0.20) was non-inferior to the proportion under methadone treatment (0.15) (least squares mean difference 0.05; 95% CI: 0.02, 0.08; p>0.01). The 95% CI fell within the 10% non-inferiority margin, confirming the non-inferiority of SROM to methadone. A dose-dependent effect was shown for SROM (i.e. decreasing proportions of heroin-positive urine samples with increasing SROM doses). Retention in treatment showed no significant differences between treatments (period 1/period 2: SROM: 88.7%/82.1%, methadone: 91.1%/88.0%; period 1: p=0.49, period 2: p=0.19). Overall, safety outcomes were similar between the two groups. Slow-release oral morphine appears to be at least as effective as methadone in treating people with opioid use disorder.
Article
Full-text available
Background Despite the widespread application of Symptom Checklist 90-R (SCL-90-R), its psychometric weaknesses have repeatedly been noted. This study aimed to comparatively assess the psychometric properties of the SCL-90-R scales and the scales of its short versions Brief Symptom Inventory (BSI), Symptom Checklist-27 (SCL-27), Brief Symptom Inventory-18 (BSI-18), Symptom Checklist-14 (SCL-14), and Symptom Checklist short version-9 (SCL-K-9) in patients with affective disorders. Methods The data of 2,727 patients within the main treatment group of affective disorders were assessed according to the DSM-IV. Patients completed the SCL-90-R and Beck Depression Inventory (BDI). Results There were no significant differences regarding the internal consistency of the SCL-90-R scales and the scales of the short versions. The dimensional structure was only supported for the short versions BSI-18, SCL-14 and SCL-K-9. The assessment of convergent validity revealed high correlations. With regard to the discriminant validity, there were medium correlations. With regard to the sensitivity of change, no significant differences between the scales were found. Conclusions In summary, the scales of the short versions show mostly satisfactory psychometric properties in comparison to the scales of the SCL-90-R. The results support the application of the short versions as screening instruments, especially the BSI-18, and more economic variants of the SCL-90-R covering a wide range of psychopathological symptoms.
Article
Buprenorphine has recently been reported to be an alternative to methadone and LAAM for maintenance treatment of opioid dependent individuals, differing results are reported concerning its relative effectiveness indicating the need for an integrative review. OBJECTIVES: To evaluate the effects of buprenorphine maintenance against placebo and methadone maintenance in retaining patients in treatment and in suppressing illicit drug use. SEARCH STRATEGY: We searched the following databases up to 2001, inclusive: Cochrane Drugs and Alcohol Review Group Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, Current Contents, Psychlit, CORK [www. state.vt.su/adap/cork], Alcohol and Drug Council of Australia (ADCA) [www.adca.org.au], Australian Drug Foundation (ADF -VIC) [www.adf.org.au], Centre for Education and Information on Drugs and Alcohol (CEIDA) [www.ceida.net.au], Australian Bibliographic Network (ABN), and Library of Congress databases, available NIDA monographs and the College on Problems of Drug Dependence Inc. proceedings, the reference lists of all identified studies and published reviews and authors of identified RCT's were asked about any other published or unpublished relevant RCT. SELECTION CRITERIA: Randomised clinical trials of buprenorphine maintenance compared with either placebo or methadone maintenance for opioid dependence. DATA COLLECTION AND ANALYSIS: Reviewers evaluated the papers separately and independently, rating methodological quality of concealment of allocation; data were extracted independently for meta-analysis and double-entered. MAIN RESULTS: Thirteen studies met the inclusion criteria, all were randomised clinical trials, all but one were double-blind. The method of concealment of allocation was not clearly described in 11 of the studies, otherwise methodological quality was good. Buprenorphine given in flexible doses appeared statistically significantly less effective than methadone in retaining patient in treatment (RR= 0.82; 95% CI: 0.69-0.96). Low dose buprenorphine is not superior to low dose methadone. High dose buprenorphine does not retain more patients than low dose methadone, but may suppress heroin use better. There was no advantage for high dose buprenorphine over high dose methadone in retention (RR=0.79; 95% CI:0.62-1.01), and high dose buprenorphine was inferior in suppression of heroin use. Buprenorphine was statistically significantly superior to placebo medication in retention of patients in treatment at low doses (RR=1.24; 95% CI: 1.06-1.45), high doses (RR=1.21; 95% CI: 1.02-1.44), and very high doses (RR=1.52; 95% CI: 1.23-1.88). However, only high and very high dose buprenorphine suppressed heroin use significantly above placebo. REVIEWER'S CONCLUSIONS: Buprenorphine is an effective intervention for use in the maintenance treatment of heroin dependence, but it is not more effective than methadone at adequate dosages.
Article
SCL-90-R, a multidimensional assessment instrument for mental health status, is among the most widely used instruments for the evaluation of therapies and quality management in mental institutions. With 90 items it is rather long and has a high redundancy as can be seen in its highly correlated scales. Thus many short versions have been constructed, among them the SCL-27, which was devised as a screening tool. It has 27 items, retains six of the nine SCL-90 dimensions and has shown a good factor structure. So far it has only been validated in non-psychiatric samples. The aim of this study is to determine validity and other psychometric qualities of the SCL-27, compared to the SCL-90-R within a group of 449 psychiatric patients. The study found a large concordance between the symptom scales of the SCL-27 and the corresponding scales of the SCL-90-R. The SCL-27 further showed good reliability and a sensitivity to change comparable to that of the 90-item version. A confirmatory factor analysis yields an acceptable factor validity which is better than that of the long version. This study concludes that the SCL-27 is suitable as a short assessment instrument for psychological health in psychiatric patients.
Article
Background Injection drug users (IDUs) frequently suffer from somatic and mental co-morbidity. The effects of different opioid maintenance protocols on these parameters have not been systematically studied yet. Methods This study was conducted as a 12-month open-label multi-centre randomised controlled trial to test a heroin- vs. methadone based protocol. Results 515 patients were randomised to the heroin-assisted and 500 to the methadone-assisted treatment program. Baseline scores were as follows: OTI-HSS 19.0 (±5.2), BMI 22.6 (±3.5), pathologic electro-/echocardiogram 20.4% (n=582) / 13.9% (n=491), positive HBV-, HCV- and HIV-serology 65.7% (n=863) / 86.5% (n=855) / 9.2% (n=951), positive tuberculin test 9.1% (n=318), KPS 71.4 (±12.9), Global Severity Index (GSI; SCL-90-R) 69.2 (±10.6), GAF 53.6 (±11.7) (all parameters not significant between treatment groups). Improvement after 12 months of treatment differed significantly between treatment groups (heroin vs. methadone): OTI-HSS 8.1 (±5.2) vs. 10.6 (±6.4), BMI 24.5 (±4.3) vs. 23.7 (±4.1), KPS 78.2 (±12.8) vs. 74.2 (±13.3), GSI 58.6 (±13.7) vs. 62.0 (±13.2), GAF 63.0 (±13.3) vs. 56.2 (±15.0) (ANOVA, all p=.000). The frequency of pathologic echocardiograms after 12 months was significantly lower in the heroin compared to the methadone group. Within the heroin group, completers benefited stronger than drop-outs. The remaining parameters did not differ between baseline and 12 months and between treatment groups. Conclusion Integration of severe injection drug users either in methadone or heroin assisted maintenance treatment has positive effects on most change sensitive physical and mental variables. In this patient group heroin assisted treatment showed superior results compared to methadone.
Article
A randomised, single-dose, open-label, crossover study in 24 healthy male and female volunteers evaluated the pharmacokinetic profile and relative bioavailability under fed and fasting conditions of the 2 oral morphine sulfate formulations, modified-release capsules (MXL™) and sustained-release capsules (Kapanol™). A 60mg dose of study medication was administered 7 days apart after either an overnight fast of 10 hours or after a standard high-fat meal. Blood samples were taken for 48 hours postdose and were analysed for morphine by high-performance liquid chromatography using electrochemical detection. Kapanol™ was bio-equivalent fed and fasting, and under fasting conditions Kapanol™ and MXL™ were bioequivalent. In contrast, MXL™ was not bioequivalent under fed and fasting conditions. Although Kapanol™ and MXL™ showed similar oral bioavailability [area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax)], the time to Cmax (tmax) of Kapanol™ was significantly longer than that of MXL™. Food significantly prolonged the tmax of Kapanol™ but had no effect on the extent of absorption or Cmax. In contrast, both the rate and extent of absorption of morphine from MXL™ were significantly reduced with food. In conclusion, Kapanol™ both fed and fasting has a superior sustained-release pharmacokinetic profile for a formulation designed for once-a-day administration compared with MXL™. Because food does not impair the bioavailability of Kapanol™, it can be taken without regard to meals.
Article
Background: Opioid substitution treatments are effective in retaining people in treatment and suppressing heroin use. An open question remains whether slow-release oral morphine (SROM) could represent a possible alternative for opioid-dependent people who respond poorly to other available maintenance treatments. Objectives: To evaluate the efficacy of SROM as an alternative maintenance pharmacotherapy for the treatment of opioid dependence. Search methods: We searched Cochrane Drugs and Alcohol Group's Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 3, 2013), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013) and reference lists of articles. Selection criteria: Randomised controlled trials (RCTs) and quasi-randomised trials assessing efficacy of SROM compared with other maintenance treatment or no treatment. Data collection and analysis: Two review authors independently selected articles for inclusion, extracted data and assessed risk of bias of included studies. Main results: Three studies with 195 participants were included in the review. Two were cross-over trials and one was a parallel group RCT. The retention in treatment appeared superior to 80% in all the three studies (without significant difference with controls). Nevertheless, it has to be underlined that the studies had different durations. One lasted six months, and the other two lasted six and seven weeks. The use of opioids during SROM provision varied from lower to non-statistically or clinically different from comparison interventions, whereas there were no differences as far as the use of other substances was concerned.SROM seemed to be equal to comparison interventions for severity of dependence, or mental health/social functioning, but there was a trend for less severe opiate withdrawal symptoms in comparison with methadone (withdrawal score 2.2 vs. 4.8, P value = 0.06). Morphine was generally well tolerated and was preferred by a proportion of participants (seven of nine people in one study). Morphine appeared to reduce cravings, depressive symptoms (measured using the Beck Depression Inventory; P value < 0.001), physical complaints (measured using the Beschwerde-Liste (BL); P value < 0.001) and anxiety symptoms (P value = 0.008). Quality of life in people treated with SROM resulted in no significant difference or a worst outcome than in those taking methadone and buprenorphine. Other social functioning measures, such as finances, family and overall satisfaction, scored better in people maintained with the comparison substances than in those maintained with SROM. In particular, people taking methadone showed more favourable values for leisure time (5.4 vs. 3.7, P value < 0.001), housing (6.1 vs. 4.7, P value < 0.023), partnerships (5.7 vs. 4.2, P value = 0.034), friend and acquaintances (5.6 vs. 4.4, P value = 0.003), mental health (5.0 vs. 3.4, P value = 0.002) and self esteem (8.2 vs. 5.7, P value = 0.002) compared to people taking SROM; while people taking buprenorphine obtained better scores for physical health.Medical adverse events were consistently higher in people in SROM than in the comparison groups. None of the studies included people with a documented poor response to other maintenance treatment. Authors' conclusions: The present review did not identify sufficient evidence to assess the effectiveness of SROM for opioid maintenance because only three studies meeting our inclusion criteria have been identified. Two studies suggested a possible reduction of opioid use in people taking SROM. In another study, the use of SROM was associated with fewer depressive symptoms. Retention in treatment was not significantly different among compared interventions while the adverse effects were more frequent with the people given SROM.