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Maintenance treatment for opioid dependence with slow-release oral morphine: A randomized cross-over, non-inferiority study versus methadone


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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.
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Maintenance treatment for opioid dependence with
slow-release oral morphine: a randomized cross-over,
non-inferiority study versus methadone
Thilo Beck1, Christian Haasen2, Uwe Verthein2, Stephan Walcher3, Christoph Schuler4,
Markus Backmund5,6, Christian Ruckes7& Jens Reimer2
Arud Centres for Addiction Medicine, Zurich, Switzerland,1Centre for Interdisciplinar y Addiction Research of Hamburg University, Department of Psychiatry,
University Medical Centre Eppendorf, Hamburg, Germany,2Concept Schwerpunktpraxis Sucht, Munich, Germany,3Praxis Turmstrasse, Berlin, Germany,4
Praxiszentrum imTal,Munich, Ger many,5Ludwig-Maximilians-Universität, Munich, Germany6and Interdisciplinary Centre for Clinical Trials (IZKS), University Medical
Centre of the Johannes Gutenberg University Mainz, Mainz, Germany7
Aims To compare the efficacy of slow-release oral morphine (SROM) and methadone as maintenance medication for
opioid dependence in patients previously treated with methadone. Design 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. Setting Fourteen out-patient
addiction treatment centres in Switzerland and Germany. Participants Adults with opioid dependence in methadone
maintenance programmes (dose 50 mg/day) for 26 weeks. Measurements The efficacy end-point was the propor-
tion of heroin-positive urine samples per patient and period of treatment. Each week, two urine samples were collected,
randomly selected and analysed 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%. Findings 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=0.50, period 2: P=0.19). Overall, safety
outcomes were similar between the two groups. Conclusions Slow-release oral morphine appears to be at least as
effective as methadone in treating people with opioid use disorder.
Keywords Dose–response, maintenance treatment, methadone, opioid addiction, retention rate, slow-release
oral morphine.
Correspondence to: Thilo Beck, Arud Zurich, Konradstrasse 32, 8005 Zurich, Switzerland. E-mail:
Submitted 3 November 2012; initial review completed 11 October 2013; final version accepted 3 November 2013
Medication-assisted maintenance treatment with psy-
chosocial support is suggested to stabilize opioid-
dependent patients [1,2]. All substances with significant
agonistic activity at opioid-μ-receptors, i.e. methadone,
buprenorphine, codeine, diacetylmorphine and mor-
phine, are appropriate for opioid maintenance treatment
(OMT) [3], although methadone is the accepted gold
standard, with established effectiveness [4]. However,
methadone is limited by side effects influencing compli-
ance, resulting in inadequate treatment retention [5,6].
A diversity of OMTs, including diacetylmorphine and
morphine, is required to reach individual treatment
goals [7–9]. Morphine acts as a pure agonist on opioid
receptors; its mode of action differs from that of
methadone and buprenorphine [10,11]. However, its
inherently short elimination half-life limits its practical
use regarding dispensing treatment to patients, and
has resulted in the development of methadone as an
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction. Addiction,109, 617–626
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
alternative [12]. Slow-release preparations of morphine
that result in sustained blood concentrations for 24 hours
after once-daily oral administration therefore represent
an advantage over traditional morphine [13,14].
The clinical utility of slow-release oral morphine
(SROM) for opioid dependence has been reported previ-
ously, and may be associated with reduced opioid craving
and improved tolerability versus methadone [15–20].
However, only one of these studies was a randomized
cross-over trial [18]. Advantages of SROM in patients
intolerant to methadone or with inadequate withdrawal
suppression [21] and those intolerant to supplementary
methadone [22] have been reported. Only one study has
not demonstrated any advantage of SROM over metha-
done [23]. The other available data are based mainly on
trials in which patients were not randomized or without
control, so robust evidence for the clinical utility of SROM
in treating opioid dependence is lacking [24].
The objective of this study was to validate the effec-
tiveness of SROM in opioid-dependent patients treated
previously with methadone in a randomized cross-over
design, aiming to show non-inferiority of SROM over
methadone with flexible dosing. A non-inferiority margin
of 10% was set because differences between SROM and
methadone treatment were expected to be relatively small
[18,25]. A cross-over design was selected, as patients to
be included were already under methadone treatment
and thus in a stable condition. Further, this design, rather
than a parallel group design, allows repeated measure-
ments for each patient during two treatment periods,
minimizes confounding covariates and allows for higher
statistical power with fewer patients [26,27]. Two end-
points were taken into account: (i) weekly urinalyses for
co-consumption of heroin in the same patient independ-
ent of treatment and (ii) in-treatment retention for each
treatment period.
Patient population
Patients were recruited between July 2007 and August
2010 at four out-patient treatment centres in Switzer-
land and 10 in Germany. All patients with a diagnosis of
opioid-dependence according to the Diagnostic and Statis-
tical Manual of Mental Disorders, 4th edition, text revision
(DSM-IV 4.9) were eligible. Independent adults (age 18
years) participating in a methadone maintenance pro-
gramme for 26 weeks with a permanent residence were
eligible for inclusion. Other inclusion criteria were:
methadone dose of 50 mg/day at time of inclusion,
capability to act responsibly and no intention of dose
reductions aiming for abstinence during the trial. Women
were required to have a negative urine pregnancy test
prior to initial dose of study medication and every 4
weeks during the study and, if of child-bearing potential,
were required to use hormonal contraception. Patients
were excluded if they had acute somatic illnesses or other
clinically significant somatic disorders, serious unstable
mental health problems, known contraindications for
opioids, pending imprisonment at the time of inclusion,
baseline QTc-interval >450 msec or long QT-syndrome or
were pregnant/breastfeeding. Treatment-naive patients
or patients unsatisfied with pre-treatment due to insuffi-
cient control of drug-seeking and/or tolerability were
also excluded.
The protocol and informed consent forms were
reviewed and approved by the national and regional
ethics committees and national health authorities com-
petent for the respective trial sites. The study was con-
ducted according to the Declaration of Helsinki, the
International Conference on Harmonization (ICH) Guide-
line for Good Clinical Practice, the European Union Clini-
cal Trials Directive 2001/20/EC and relevant national
narcotics laws.
Study design
This was a multiple-dose, open-label, randomized, cross-
over, non-inferiority study. At study entry, patients were
randomized to receive one of two sequences of treatment
with methadone oral solution or SROM for 11 weeks per
period. To minimize the potential for withdrawal symp-
toms, there was no wash-out period. Instead, each period
consisted of a 1-week adjustment phase followed by a
10-week treatment phase with the study drug. During
the 10-week treatment phase, flexible dosing was permit-
ted depending on a patient’s individual needs. The total
duration was 47 weeks: 22 weeks with a two-way cross-
over followed by 25 weeks of extension with SROM treat-
ment. This publication reports the findings from the
cross-over phase. Results from the extension phase will be
submitted for separate publication.
Assignment to treatment was printed onto individual-
ized case report forms (CRFs) per patient and site and
used by increasing order of patient number per site. Selec-
tion for a sequence-group was determined by a computer-
generated randomization list with a 1:1 ratio of test and
reference treatment and permuted blocks of six without
stratification factors (SPSS version 15.0.1.; SPSS, Inc.,
Chicago, IL, USA). The randomization sequence was
checked based on the day of randomization.
SROM was provided as capsules (Bard Pharmaceuti-
cals, Cambridge, UK; Mundipharma Gesellschaft m.b.H.,
Vienna, Austria); daily doses were prepared using the
appropriate number of capsules containing 60, 120 or
200 mg morphine sulphate. Methadone solution was
provided in Switzerland as 1% solution (Amino AG,
618 Thilo Beck et al.
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
Neuenhof, Switzerland) and in Germany as 0.5% solu-
tion (Eptadone oral solution; Molteni Farmaceutici,
Scandicci, Italy). Methadone oral solution and SROM
capsules were administered orally once daily. Methadone
was switched to SROM in a ratio of 1:6–1:8 of the previ-
ous methadone dose. SROM was switched to methadone
in a ratio of 8:1–6:1 of the previous SROM dose. During
treatment phases, supervised intake of study medication
was scheduled for at least 3 days per week.
Study assessments
The primary efficacy end-point was the proportion of
positive urine samples per patient and per treatment for
co-consumption of heroin. Weekly urine samples were
collected. To fulfil criteria for random urine sampling,
based on a Mersenne Twister random number generator
taking into account the take-home schedule for each
week (statistical package SPSS version 15.0.1), each CRF
contained a pre-defined schedule indicating the 2
working days per week on which urine samples had to be
collected and shipped for analysis. Each trial site used a
different random number seed [28]. Staff members at the
trial sites were not permitted to disclose the schedule of
urine sampling to patients.
Urine samples were analysed by a central laboratory
(University Hospital Basel, Switzerland) under blinded
conditions for 6-monoacetyl-morphine (6-MAM) and
6-acetylcodeine (6-A-cod), using liquid chromatography–
mass spectrometry (LCMS) [29]. A urine sample was
deemed positive if the 6-MAM and/or 6-A-cod concentra-
tions exceeded 10 ng/ml. For each patient the extent of
heroin use was defined as proportions and calculated by
dividing the number of the patient’s heroin-positive urine
samples by the number of their weekly urine samples
selected for urinalysis per cross-over period. Urine samples
were also analysed semiquantitatively by immunoassay
(CEDIA® and DRI®; Thermo Fisher Scientific Inc.,
Fremont, CA, USA) for benzodiazepines, cannabinoids,
cocaine and adulterations. Further, the extent of self-
reported use of heroin, cocaine, alcohol, cannabis and
benzodiazepines per period was assessed by calculating
the average number of days of reported consumption
during the cross-over period. Patients received a weekly
monetary compensation of 15 for providing urine
samples, and were assured thatthe results of their urinaly-
ses had no adverse consequences. Safety during the study
was monitored by recording all adverse events (AEs) as
well as by periodic evaluation of vital signs and physical
Statistical methods
This was a non-inferiority trial, assuming that the
extent of heroin use based on urinalyses would not differ
between maintenance treatment with SROM or metha-
done. Non-inferiority was concluded if the two-sided
95% confidence intervals (CI) were below a 10% non-
inferiority margin in the per protocol (PP) population. In
order to secure the highest possible quality of data, strin-
gent criteria were set for the PP population, and included
only those patients who completed each of the two cross-
over treatment periods (11 weeks) within a specified
time-frame of 70 days and 84 days, who had urinaly-
ses for 9 of 11 weeks per cross-over period and no dis-
continuation of study medication for more than 5
consecutive days. For each cross-over period, the mean
[least-square (LS) mean] and 95% CI of individual pro-
portions of heroin-positive urine samples were calcu-
lated. Considering the cross-over design, the primary
analysis was performed by analysis of variance (ANOVA)
with fixed factors for treatment, period, sequence and
subject nested within sequence. However, in this analy-
sis, including the sequence effect allows only a limited
assessment of the carry-over effect. Therefore, the extent
of an unequal carry-over effect for each treatment was
tested by adding the proportion of heroin-positive urine
samples of both periods for each patient and comparing
those by a two-sample t-test (Welch t-test). To confirm
the robustness of non-inferiority, analyses were also per-
formed on the results from the intent-to-treat (ITT)
population [27,30]. Dose effects were analysed (LS
mean) by considering quartiles of average daily doses
of treatment and the corresponding proportions of
heroin-positive urine samples.
The sample size was calculated based on testing for
non-inferiority within a cross-over design. Sixty-four PP
patients per sequence (a total of 128 PP patients) were
required to conclude, with a power of 80% and a one-
sided significance level of 2.5%, that SROM is non-
inferior to methadone (pre-specified non-inferiority
margin of 10%) determined by the proportion of heroin-
positive urine samples per patient. Assuming that up to
40% of patients would not be eligible for the PP popula-
tion, the necessary sample size to achieve the power of
80% was calculated to be 215 patients (SAS®, version
9.1.3; SAS Institute, Cary, NC, USA).
The incidence, severity and relationship to study drug
of adverse events (AEs) was reported for each treatment.
P-values were calculated from a logistic regression
model (with treatment as fixed factor) using generalized
estimating equations (GEE).
Two hundred and seventy-six patients were enrolled; 141
(51.1%) were randomized to the treatment sequence
morphine/methadone (group 1) and 135 (48.9%) to the
treatment sequence methadone/morphine (group 2)
Maintenance treatment for opioid dependence with slow-release oral morphine 619
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
(ITT population). The 22-week cross-over phase was
completed by 110 patients (78.0%) in group 1 and 101
patients (74.8%) in group 2 (P=0.5312, χ2test) (Fig. 1).
Retention in treatment was high under both treatments
between periods and sequences: SROM 88.7% (group 1,
period 1; 95% CI =82.2%, 93.4%; n=125/141) and
82.1% (group 2, period 2; 95% CI =84.2%, 88.4%;
n=101/123); methadone 91.1% (group 2, period 1;
95% CI =85.0%, 95.3%; n=123/135) and 88.0%
(group 1, period 2; 95% CI =81.0%, 93.4%; n=110/
125). Differences per period were similar (period 1: χ2
test, P=0.4989, period 2: χ2test, P=0.1933). In the
ITT population women had a lower retention in treat-
ment than men (P=0.0350); there was no association
between psychiatric comorbidities and retention in
treatment (P=0.0644).
Owing to the narrow criteria for assessing the PP
population, a substantial number of patients had to be
excluded from the statistical analyses [group 1: n=57
(40.4%); group 2: n=62 (45.9%)], due mainly to failing
to comply with the 11-week duration of each cross-over
period and/or failing to deliver the required number of
samples for urinalyses (there were no statistically signifi-
cant differences between periods and treatments with
regard to exclusion of patients from the analyses). There
were no differences in baseline characteristics between
the PP and ITT populations (Table 1) or between patients
in groups 1 and group 2.
Treatment duration in the cross-over phase was
76.8 ±1.2 days per period for the PP population without
any significant differences between sequences or periods.
The mean SROM dose was 791 ±233 mg/day, that of
methadone 103 ±30 mg/day. Methadone doses were
converted to SROM at a mean ratio of 1:7.7 ±1.3 and
SROM doses to methadone at a mean ratio of 7.5 ±2.4:1.
Treatment switch was not associated with signs of
overdose or opioid withdrawal in any patient. Only
a few (approximately 10%) patients required dose
adaptations during cross-over, primarily when treat-
ment was switched from methadone to SROM. Patients
self-administered medication on average 2.14–2.33
times per week (without any significant differences
Figure 1 Randomization of patients and treatment completion per period
620 Thilo Beck et al.
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
regarding sequences or periods). Adherence to random
urine sampling criteria was very high in each sequence
and period of treatment (Table 2). Fewer than 1% of
urine samples were not collected, not shipped or refused
to be given by the patient; 1.1% of samples were rated
as manipulated.
In the PP population, the proportion of heroin-
positive urine samples under SROM was 0.2020 (95%
CI =0.1811, 0.2229) versus 0.1508 (95% CI =0.1299,
0.1716) under methadone. Although the difference
between treatments was statistically significant (0.0513;
95% CI =0.0217, 0.0808; P=0.0008), it was within
the pre-specified non-inferiority margin of 10%. Thus,
non-inferiority of SROM was confirmed. However, the
period effect (P=0.0389) and sequence effect (P=
0.0201) reached statistical significance. This was due
to a somewhat higher (0.24 ±0.27) but statistically
significant proportion of heroin-positive urine samples
from patients in group 1 and period 1 versus patients
in group 2 and period 1 (10.15 ±0.24; P=0.0352); no
significant differences were found in period 2 (group 1:
0.15 ±0.23, group 2: 0.17 ±0.25; P=0.6734). Despite
these differences in period 1, the test for a possible
unequal carry-over effect was not significant (P=
0.3397) (Table 2). A tendency for a treatment centre
effect was observed (effect of centre: P=0.0800;
interaction term of centre and treatment: P=0.0743).
The treatment differences of SROM versus methadone
between centres were 0.0489 to 0.1709. No interaction
between number of days with take-home medication
and proportion of heroin-positive urine samples was
found (SROM: P=0.0657; methadone: P=0.8519). No
notable difference between the proportion of heroin-
positive urine samples regarding the number of patients
recruited at the centres was observed. There was no
association between the proportion of heroin-positive
urine samples and treatment in period 1 with respect to
dose ratios after treatment switch from methadone to
Non-inferiority of SROM was also confirmed in the
ITT population. The proportion of heroin-positive urine
samples in patients receiving SROM was 0.2564 (95%
CI =0.2330, 0.2799) versus 0.2584 (95% CI =0.2344,
0.2823) for methadone, a treatment difference of
0.0019 (95% CI =−0.0355, 0.0316; P=0.9104). The
effect of the periods was significant (P=0.0293), but
effects for sequence (P=0.1610) and carry-over
(P=0.5152) were not (Table 2).
A significant (P=0.0003) dose effect was observed
with both treatments: the proportion of heroin-positive
urine samples decreased with increasing doses (Fig. 2).
Quartiles of average SROM doses correlated inversely
Table 1 Baseline characteristics of patients.
ITT population PP population
n=276 n =157
Male 225 (81.5%) 132 (84.1%)
Female 51 (18.5%) 25 (15.9%)
Agea38.1 ±7.6 (38.00) 38.9 ±7.4 (39.00)
Body mass index (calculated)a25.2 ±4.38 (24.5) 24.77 ±4.16 (24.3)
Civil status: single 206 (74.6%) 122 (77.7%)
Employment status: full-time job 70% 36 (13.0%) 12 (7.6%)
Years of prior maintenance treatmenta3.85 ±4.43 (2.00) 3.58 ±4.40 (2.00)
Pretreatment: last dose of methadone (mg/day)a98.03 ±39.95 (90.00) 92.03 ±30.78 (90.00)
Addiction history
EuropASI—alcohola0.12 ±0.17 (0.03) 0.12 ±0.18 (0.02)
EuropASI—drugs (modified)a0.31 ±0.14 (0.31) 0.31 ±0.15 (0.31)
Age at first heroin consumptiona20.26 ±5.11 (19.00) 20.53 ±5.08 (19.00)
Patients with ongoing somatic comorbidity 218 (79.0%) 132 (84.1%)
Number of ongoing somatic comorbidities per patient 2.88 ±1.97 2.84 ±1.75
HIV—positive 10 (3.6%) 7 (4.5%)
Syphilis—positive 1 (0.4%) 1 (0.6%)
Hepatitis B virus—positive 140 (57.4%) 71 (51.1%)
Hepatitis C virus—positive 158 (57.7%) 105 (67.3%)
Patients with ongoing psychiatric comorbidity 191 (69.2%) 90 (57.3%)
Number of ongoing psychiatric comorbidities per patient 2.19 ±1.20 1.82 ±0.98
Number of comedications per patient 3.80 ±3.52 3.98 ±3.46
EuropASI =European Addiction Severity Index; PP =per protocol; ITT =intention-to-treat. aMean ±standard deviation (median).
Maintenance treatment for opioid dependence with slow-release oral morphine 621
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
with the number of urine samples testing positive for
6-MAM (Pearson’s correlation coefficient: 0.1941;
P=0.0149) and 6-A-cod (Pearson’s correlation coeffi-
cient: 0.1709; P=0.0323). Similar effects were con-
firmed for methadone: an inverse correlation was found
between quartiles of average daily methadone doses with
urine samples tested positive for 6-MAM (Pearson’s cor-
relation coefficient 0.2225; P=0.0051) and 6-A-cod
(Pearson’s correlation coefficient: 0.1868; P=0.0192).
The magnitude of dose effect was 0.49 for SROM and
0.71 for methadone (Cohen’s d, comparing the first and
the fourth dose quartiles of the PP population).
In the PP population 12 (8%) patients received pre-
scribed benzodiazepines, but 75 (47.7%) patients used
non-prescribed benzodiazepines in both cross-over
periods, according to urinalyses. No differences between
period and sequences of treatment were found for the
number of patients and the extent of co-consumed
benzodiazepines (proportion of benzodiazepine-positive
urine samples: SROM 0.32 ±0.41; methadone 0.35 ±
0.42; P=0.0642). No significant differences between
treatments were observed in the self-reported use (pro-
portion of days with use per period) of heroin, cocaine or
benzodiazepines. In addition, the proportions of urine
samples that were positive for cannabis, cocaine or
benzodiazepines were not significantly different between
treatments. Self-reported cocaine and benzodiazepines
use correlated strongly with urinalysis results. However,
self-reported use of heroin was lower than the proportion
of positive urine samples (Table 3).
Overall, safety profiles of SROM and methadone by
ICH criteria were similar (Table 4), with no statistical dif-
ferences between treatments in incidence of AEs, their
severity or causality. One patient died under methadone
treatment due to intentional multiple drug overdose. The
detailed safety outcomes, considering preferred terms as
stated by investigators from this study, will be submitted
for separate publication.
Table 2 Collection of urine samples and results of urinalysis.
ITT population (n =276) PP population (n =157)
Number of visits 5265 3454
% weeks with two randomly taken urine samples 73.2 93.9
Total number of assessable urine samples for heroin 4707 (100.0%) 3451 (100.0%)
Number of missing/not analysed urine samples for
558 (11.9%) 3 (0.1%)
Number of urine samples set positive for heroina257 (5.5%) 62 (1.8%)
Number of urine samples testing heroin-positive 837 (17.8%) 553 (16.0%)
Number of urine samples testing heroin-negative 3613 (76.8%) 2836 (82.2%)
Use of heroin
Proportion of heroin-positive urine samples
per patient under morphine
0.2564 (95% CI =0.2330, 0.2799) 0.2020 (95% CI =0.1811, 0.2229)
Proportion of heroin-positive urine samples
per patient under methadone
0.2584 (95% CI =0.2344, 0.2823) 0.1508 (95% CI =0.1299, 0.1716)
Difference between morphine and methadone 0.0019 (95% CI =−0.0355, 0.0316)
0.0513 (95% CI =0.0217, 0.0808)
Sequence P=0.1610 P=0.0201
Period P=0.0293 P=0.0389
Carry-over effect P=0.5152 P=0.3397
aCriteria for setting a sample positive for opioids (heroin): urine sample not collected, urine sample refused bypatient, urine sample manipulated. PP =per
protocol; ITT =intention-to-treat; CI =confidence interval.
Figure 2 Dose–response: correlation of
the proportion of heroin-positive urine
samples and quartiles of mean daily doses
(data presented as least-square means and
corresponding 95% confidence interval (CI),
per protocol (PP) population, n=157)
622 Thilo Beck et al.
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
This is the first confirmatory clinical trial comparing
SROM and methadone as adequate OMT in a ‘real-
world’ situation. The non-inferiority of SROM to metha-
done regarding illicit heroin use and concomitant
drug consumption was shown in this robustly designed
trial using an established comparator and outcomes
relevant to maintenance out-patient treatment under
daily practice conditions [4,31]. The proportion of
heroin-positive urine samples per patient was selected
as the efficacy-related end-point because the use of
heroin was expected to be more relevant in a cross-over
study than an outcome of retention in treatment.
Regarding urinalyses, two aspects were considered:
(i) urine samples were collected and selected for analy-
sis according to a two-way randomization procedure
depending on relevant regulations for take-home
medication; and (ii) urine samples were analysed by
LCMS, a more sensitive method than immunoassay
[32,33]. The effect on retention rate was estimated to be
relatively modest in clinically stable patients with 26
weeks of ongoing methadone maintenance treatment.
Other efficacy results will be submitted for subsequent
Stringent criteria were set for the PP population to
enhance the quality of individual data for statistical
analyses. Equal duration of treatment periods and equal
numbers of urine samples taken during cross-over were
selected as the main criteria for a patient’s inclusion in
the PP population. The statistical analysis was based on a
pre-defined non-inferiority margin of 10%, a strict
margin for clinical trials in patients with multiple mor-
bidities [34–38]. Although a 5% difference in the propor-
tion of heroin-positive urine samples in favour of
methadone was found, the 95% CI were within the
10% non-inferiority margin.
The impact of the observed sequence regarding the
proportion of heroin-positive urine samples in period 1
and group 1 in the PP population cannot be explained on
clinical grounds, especially as there were no differences
between groups at baseline, or centre or treatment inter-
actions. A carry-over effect can definitively be excluded,
and no differences between treatments were found
when analysing the proportion of heroin-positive urine
samples from the ITT population, confirming the robust-
ness of the results.
Furthermore, retention in treatment was high and
without any differences between periods or sequences of
treatment. In addition, a dose effect was shown for SROM
as well as for methadone in terms of decreasing propor-
tions of heroin-positive urine samples with increasing
doses. This is in full agreement with a parallel group
methadone dose–response study [39]. This study also
confirms that SROM has the same general safety profile
as methadone.
Table 3 Individual proportion of positive urine samples and self-reported use of heroin, cocaine and benzodiazepines per treatment
[per protocol (PP) population; n=157].
Proportion of positive urine samples Proportion of self-report Pearson
coefficient P-valueMethadone Morphine Methadone Morphine
Heroin 0.15 ±0.23 0.20 ±0.26 0.08 ±0.15 0.08 ±0.15 0.4465 <0.0001
Cocaine 0.13 ±0.27 0.15 ±0.27 0.03 ±0.10 0.03 ±0.08 0.7716 <0.0001
Benzodiazepines 0.39 ±0.43 0.36 ±0.42 0.10 ±0.21 0.11 ±0.23 0.5745 <0.0001
Table 4 Summary of safety data [intention-to-treat (ITT) population].
(n =262)
(n =260) P-value
Patients with at least one AE [n(%)] 212 (81%) 205 (79%) 0.6172
Number of AEs 879 830
Patients with at least one related AE [n(%)] 154 (59%) 147 (57%) 0.5979
Number of related AEs 534 467
Patients with at least one serious AE [n(%)] 8 (3%) 11 (4%) 0.1175
Number of serious AEs 13 21
Patients with at least one related serious AE [n(%)] 1 (0%) 2 (1%) 0.3191
Number of related serious AEs 1 5
Patients who died [n(%)] 0 (0%) 1 (0%) NA
AE =adverse event; NA =not applicable.
Maintenance treatment for opioid dependence with slow-release oral morphine 623
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
Although a possible limitation, the cross-over design with
no wash-out period was considered appropriate. A
double-blind, double-dummy design was deemed inap-
propriate for two reasons. Retention rates in studies com-
paring methadone and buprenorphine with flexible
dosing are identical, independent of open or double-blind
methods [25]. The intrinsic pharmacological differences
of morphine and methadone mean that patients are
experienced in perceiving specific drug effects, either from
prior illicit consumption or from previous maintenance
treatment, so that blinding of study medications would
not have a meaningful impact on the overall results of a
study of OMT [40–42]. Included patients were assumed
to be stable (average maintenance for more than 3 years
and 90 mg dose of methadone/day at baseline), further
justifying the cross-over design [26,43]. An actual wash-
out period with no treatment would have been inappro-
priate for this study, as any interruption of OMT would
have led to withdrawal symptoms. The chosen design also
allowed repeated measurements in individual patients
under different treatments.
Although not assessed specifically in this study,
misuse of opioid substitution medicines is of general
concern [44]. According to a recent review of published
literature on methadone and buprenorphine, motives for,
as well as the extent of, misuse depend largely upon the
individual’s symptom control and treatment status [45].
However, the incidence of misuse varies significantly on a
regional geographic basis, and is influenced by prescrib-
ing regulations and treating-physicians’ specific prefer-
ences for a particular medicine. Regarding misuse of
SROM, no clear definite conclusions can be drawn from
data published to date, despite licensing for OST in some
European countries. In a recent survey, levels of misuse
ranged from 5 to 51% across 10 European countries [46];
the greatest misuse was observed in Austria (49%) and
Denmark (51%), where the main medications are SROM
and methadone, respectively. However, no single risk
factor for misuse was identified in the survey and one or
several factors may have contributed, including, but not
limited to, drug formulation, utilization of psychosocial
support, duration of treatment, levels of dosing supervi-
sion and patient satisfaction with treatment. Safety
concerns related to the misuse of SROM have also
been discussed by Beer et al. [47], who postulated that
morphine preparations were abused more frequently
than other OST preparations, but did not provide data
contextualizing the incidence of abuse or the number of
subjects at risk.
This study supports previous publications suggesting
the potential of SROM as a valuable option to adapt OMT
more effectively to the needs of patients.
Clinical trial registration
Registration number and name of trial registry—
EudraCT no.: 2008-002185-60, Swissmedic no.:
2007DR3124, NIH Study code: NCT01079117.
Declaration of interests
None. All authors are independent of any significant
financial or other relationship to the sponsor, except for
appropriate compensation for the conduct of this study
and related expenditure.
The authors are indebted to the participating patients.
The authors would like to thank Toni Berthel,
Winterthur, Karin Bonorden-Kleij, Hamburg, Robert
Haemmig, Bern, Doris Hoepner, Berlin, Wilfried Koehler,
Frankfurt, Karin Lebentrau, Munich, Karl Mann,
Mannheim, Rudolf Stohler, Zurich and Rainer Ullmann,
Hamburg, for conducting the study and including their
patients. Thanks to Roswitha Skendaj and André Scholer,
University Hospital Basel, for their analytical work,
Andreas Kolt, Monitoring Services, Munich, Germany
and Salome Kiefer, CTM ClinicalTrial Monitoring, Liestal,
Switzerland for monitoring the study conduct and Nicole
Hornemann, IZKS Mainz, Germany for statistical pro-
gramming. The clinical trial was designed and financed
by Mundipharma Medical Company, Basel, and con-
ducted by qualified investigators under the sponsorship of
Mundipharma Medical Company. The authors received
writing/editorial support in the preparation of this
manuscript from Daniel Salamon, of Publicis Life Brands
Resolute, funded by Mundipharma Gesellschaft m.b.H.
Sabine Gaa and Ulrich Ganzinger, of Mundipharma
Gesellschaft m.b.H., assisted in the administrative coordi-
nation required for the preparation of this manuscript.
1. World Health Organization/United Nations Office on Drugs
and Crime/Joint United Nations Programme on HIV/AIDS
paper. 2004. Available at:
(accessed 7 February 2012) (archived at http://www on 24 December 2013).
2. Amato L., Minozzi S., Davoli M., Vecchi S. Psychosocial com-
bined with agonist maintenance treatments versus agonist
maintenance treatments alone for treatment of opioid
dependence. Cochrane Database Syst Rev 2011; 10:
3. Kreek M. J. Neurobiological basis for use of opioid agonist
maintenance in the treatment of heroin addiction. In: Waal
H., Haga E., editors. Maintenance Treatment of Heroin Addic-
tion. Oslo: Cappelen Akademisk Forlag; 2003, pp. 10–39.
624 Thilo Beck et al.
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
4. Amato L., Davoli M., Perucci C. A., Ferri M., Faggiano F.,
Mattick R. P. An overview of systematic reviews of the
effectiveness of opiate maintenance therapies: available evi-
dence to inform clinical practice and research. J Subst Abuse
Treat 2005; 28: 321–9.
5. Dyer K. R., White J. M. Patterns of symptom complaints in
methadone maintenance patients. Addiction 1997; 92:
6. Brown R., Kraus C., Flemming M., Reddy S. Methadone:
applied pharmacology and use as adjunctive treatment in
chronic pain. Postgrad Med J 2004; 80: 654–9.
7. Woody G. E. New horizons: sustained release morphine as
agonist treatment. Addiction 2005; 100: 1758–9.
8. Haasen C., van den Brink W. Innovations in agonist main-
tenance treatment of opioid-dependent patients. Curr Opin
Psychiatry 2006; 19: 631–6.
9. White J. M., Lopatko O. V. Opioid maintenance: a compara-
tive review of pharmacological strategies. Expert Opin
Pharmacother 2007; 8: 1–11.
10. Trescot A. M., Datta S., Lee M., Hansen H. Opioid pharma-
cology. Pain Physician 2008; 11: 133–53.
11. Borg L., Kravets I., Kreek M. J. The pharmacology of
long-acting as contrasted with short-acting opioids. In:
Ries R. K., Fiellin D. A., Miller S. C., Saitz R., editors. Princi-
ples of Addiction Medicine, 4th edn. Philadelphia: Lipincott
Williams & Wilkins; 2009, pp. 117–31.
12. Dole V. P., Nyswander M. A medical treatment for
diacetylmorphine (heroin) addiction. A clinical trial with
methadone hydrochloride. JAMA 1965; 193: 646–50.
13. Broomhead A., West R., Eglinton L., Jones M., Bubner R.,
Sienko D. et al. Comparative single-dose pharmacokinetics
of sustained-release and modified-release morphine sulfate
capsules under fed and fasting conditions. Clin Drug Invest
1997; 13: 162–70.
14. Hagen N. A., Thirlwell M., Eisenhoffer J., Quigley P.,
Harsanyi Z., Darke A. Efficacy, safety, and steady-state
pharmacokinetics of once-a-day controlled-release mor-
phine (MS Contin XL) in cancer pain. J Pain Symptom
Manage 2005; 29: 80–90.
15. Fischer G., Presslich O., Diamant K., Schneider C., Pezawas
L., Kasper S. Oral morphine-sulphate in the treatment
of opiate dependent patients. Alcoholism 1996; 32: 35–
16. Mitchell T. B., White J. M., Somogyi A. A., Bochner F. Slow-
release morphine versus methadone: a crossover compari-
son of patient outcomes and acceptability as maintenance
pharmacotherapies for opioid dependence. Addiction 2004;
99: 940–5.
17. Kraigher D., Jagsch R., Gombas W., Ortner R., Eder H.,
Primorac A. et al. Use of slow-release oral morphine for the
treatment of opioid dependence. Eur Addict Res 2005; 11:
18. 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: 1101–9.
19. Hermann P., Wagner W., Lindenbauer B. Safety and efficacy
of oral prolonged release morphine for the maintenance
therapy for opioid dependence—results of a pilot study in
outpatients. Suchtmed Forsch Praxis 2005; 7: 215–20.
20. Vasilev G. N., Alexieva D. Z., Pavlova R. Z. Safety and efficacy
of oral slow release morphine for maintenance treatment
in heroin addicts: a 6-month open non comparative study.
Eur Addict Res 2006; 12: 53–60.
21. Kastelic A., Dubajic G., Strbad E. Slow-release oral
morphine for maintenance treatment of opioid addicts
intolerant to methadone or with inadequate withdrawal
suppression. Addiction 2008; 103: 1837–46.
22. Bond A. J., Reed K. D., Beavan P., Strang J. After the
randomized injectable opiate treatment trial: post-trial
investigation of slow-release oral morphine as an alterna-
tive opiate maintenance medication. Drug Alcohol Rev 2012;
31: 492–8.
23. Giacomuzzi S., Kemmler G., Ertl M., Riemer Y. Opioid addicts
at admission vs. slow-release oral morphine, methadone,
and sublingual buprenorphine maintenance treatment par-
ticipants. Subst Use Misuse 2006; 41: 223–44.
24. Jegu J., Gallini A., Soler P. Slow-release oral morphine for
opioid maintenance treatment: a systematic review. Br J
Clin Pharmacol 2011; 71: 832–43.
25. Mattick R. P., Kimber J., Breen C., Davoli M. Buprenorphine
maintenance versus placebo or methadone maintenance
for opioid dependence. Cochrane Database Syst Rev 2008; (2):
CD002207. doi: 10.1002/14651858.CD002207.pub3
26. Senn S. Cross-over trial in drug development: theory and
practice. J Stat Plan Inference 2001; 96: 29–40.
27. D’Agostino R. B. Sr, Massaro J. M., Sullivan L. M. Non-
inferiority trials: design concepts and issues—the encoun-
ters of academic consultants in statistics. Stat Med 2003;
22: 169–86.
28. Matsumoto M., Nishimura T. Mersenne twister: a 623-
dimensionally equidistributed uniform pseudo-random
number generator. ACM Trans Model Comput Simul 1998; 8:
29. Sturm S., Hammann F., Drew J., Maurer H. H., Scholer A.
An automated screening method for drugs and toxic
compounds in human serum and urine using liquid
chromatography–tandem mass spectrometry. J Chromatogr
B Analyt Technol Biomed Life Sci 2010; 878: 2726–32.
30. Scott I. A. Non-inferiority trials: determining whether alter-
native treatments are good enough. Med J Aust 2009; 190:
31. Donovan D. M., Bigelow G. E., Brigham G. S., Carroll K. M.,
Cohen A. J., Gardin J. G. et al. Primary outcome indices in
illicit drug dependence treatment research: systematic
approach to selection and measurement of drug use
end-points in clinical trials. Addiction 2012; 107: 694–
32. Reisfield G. M., Goldberger B. A., Bertholf R. L. ‘False-
positive’ and ‘false-negative’ test results in clinical urine
drug testing. Bioanalysis 2009; 1: 937–52.
33. Stefanidou M., Athanaselis S., Spiliopoulou C., Dona A.,
Maravelias C. Biomarkers of opiate use. Int J Clin Pract
2010; 64: 1712–8.
34. Jones B., Jarvis P., Lewis J. A., Ebbutt A. F. Trials to assess
equivalence: the importance of rigorous methods. BMJ
1996; 313: 36–9.
35. Lange S., Freitag G. Choice of delta: requirements and
reality—results of a systematic review. Biomed J 2005; 47:
36. European Medicines Agency (EMEA). Guideline on the choice
of the non-inferiority margin. Doc.Ref.: EMEA/CPMP/EWP/
2158/99, 27 July 2005, pp. 1–11. (Accessed 14 February
2012) (archived at
6M6j4VSRJ on 24 December 2013).
37. Hung H. M., Wang S. J., O’Neill R. A regulatory perspective
on choice of margin and statistical inference issue in
non-inferiority trials. Biomed J 2005; 47: 28–36.
Maintenance treatment for opioid dependence with slow-release oral morphine 625
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
38. Food and Drug Administration (FDA). Guidance for indus-
try non-inferiority clinical trials. March 2010. Washington,
DC: US Department of Health and Human Services.
39. Strain E. C., Stitzer M. L., Liebson I., Bigelow G. E.
Dose–response effects of methadone in the treatment of
opioid dependence. Ann Intern Med 1993; 119: 23–7.
40. Bammer G., Dobler-Mikola A., Fleming P. M., Strang J.,
Uchtenhagen A. The heroin prescribing debate: integrating
science and politics. Science 1999; 284: 1277–8.
41. Gossop M. Randomised and controlled, but irrelevant?
In: Waal H., Haga E., editors. Maintenance Treatment of
Heroin Addiction—Evidence at the Crossroads. Oslo: Cappelen
Akademisk Forlag; 2003, pp. 91–105.
42. Freemantle N., Blonde L., Bolinder B., Gerber R. A., Hobbs
F. D., Martinez L. et al. Real-world trials to answer real-
world questions. Pharmacoeconomics 2005; 23: 747–54.
43. Kane J. M. Issues in clinical trial designs. In: Davis K. L.,
Charney D., Coyle J. T., Nemeroff C. H., editors. Neurophar-
macology: The Fifth Generation of Progress. Brentwood, TN:
American College of Neuropsychopharmacology; 2002,
pp. 537–46.
44. European Monitoring Centre for Drugs and Drug Addiction
(EMCDDA).Reviewing current practice in dr ug-substitution
treatment in the European Union. Insights Series, number
3. Lisbon: EMCDDA; 2000.
45. Casati A., Sedefov R., Pfeiffer-Gerchel T. Misuse of medicines
in the European Union: a systematic review of the litera-
ture. Eur Addict Res 2012; 18: 228–45.
46. Dale-Perera A., Goulão J., Stöver H. Quality of care provided
to patients receiving opioid maintenance treatment in
Europe: results from the EQUATOR analysis. Heroin Addict
Relat Clin Probl 2012; 14: 23–38.
47. Beer B., Rabl W., Libiseller K., Giacomuzzi S., Riemer Y.,
Pavlic M. Impact of slow-release oral morphine on drug
abusing habits in Austria. Neuropsychiatr 2010; 24: 108–
626 Thilo Beck et al.
© 2013 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Addiction,109, 617–626
... The study assigned patients to either opium tincture (OT; 10 mg/ml) or methadone syrup (5 mg/ml), both manufactured by (Tehran, Iran) using a patient-centred flexible dosing strategy, described in the published protocol [8]. In summary, the initial maximum induction dose for participants who entered the treatment were 50 and 200 mg for methadone and OT, respectively, consistent with a 4:1 morphine equivalent potency ratio of methadone versus OT [12,13] (please see the Discussion for further details). Higher doses were allowed as per judgement of the clinician only for patients who were already in methadone treatment in other centres. ...
... The non-inferiority margin for this analysis was set at 10%. Although this was planned post hoc, previous studies have used a similar procedure with a non-inferiority margin of 10-15% [13,22]. Drug use results must be interpreted with caution, as they were collected from participants only while they remained active in treatment. ...
... This was mitigated later in the follow-up period by instructing patients to avoid taking a.m. and p.m. doses together. Also, when compared to previous studies of OAT and the prevalence of side effects for methadone [13], a higher number of AEs were expected in this study. However, AEs with OT have remained largely unreported in previous studies [30]. ...
Aim: To test if opium tincture (OT) was non-inferior to methadone in retaining participants in opioid agonist treatment (OAT). Design: A phase III, multicentre, parallel group, non-inferiority, double-blind randomized controlled trial with an allocation ratio of 1:1. Participants were provided treatment and followed for a period of 85 days. Setting: Four OAT clinics in Iran. Participants: 204 participants with opioid use disorder [Mean age (standard deviation): 37.4 (9.3); Female 11.3%] recruited between July 2017 and January 2018. Interventions: Participants were assigned to either OT (102) or methadone (102) using a patient-centred flexible dosing strategy. Measurements: Treatment retention over 85 days was the primary outcome. Self-reported opioid use outside treatment and occurrence of adverse events (AEs) were the secondary outcomes. Findings: Remaining in treatment at the end of the follow-up were 68.6% in the methadone arm and 59.8% in the OT arm. The relative retention rate of methadone to OT was 1.15 (0.97, 1.36) in both intention-to-treat and per-protocol analyses; non-inferiority was not supported statistically as the upper bound of the confidence interval exceeded our pre-specified non-inferiority margin (1.25). Opioid use outside treatment was reported by 30.3% of OT (N=152) and 49.4% of methadone (N=168) patients, a difference in proportions of -19%: 90% confidence interval (-28%, -10%). The total count of AEs in the OT arm (22 among 9 individuals) was significantly higher (p = .04) than that in the methadone arm (3 among 2 individuals). Nausea was the most common side-effect. Conclusion: While this study could not conclude the non-inferiority of opium tincture (OT) to methadone for retaining patients in opioid agonist treatment, OT retained 60% of participants to end of follow up (85 days) and was superior to methadone in reducing self-reported opioid use outside treatment.
... SROM is an effective substitute for methadone or buprenorphine for those who fail rst line treatment with methadone and / or buprenorphine or for those with dose limiting issues including QT prolongation (10). Observed doses of once daily SROM provide effective management of opiate withdrawal and manage opiate cravings (11). Emerging evidence for the use of slow-release morphine as an adjunct to typical forms of OAT is growing (11,12). ...
... Observed doses of once daily SROM provide effective management of opiate withdrawal and manage opiate cravings (11). Emerging evidence for the use of slow-release morphine as an adjunct to typical forms of OAT is growing (11,12). ...
Full-text available
Background : Methadone titration in an outpatient setting typically involves initiation with subtherapeutic doses with slow titration to mitigate the risks of respiratory depression and overdose. In pregnancy, subtherapeutic doses of methadone and slow titrations are associated with poorer outcomes in terms of retreatment retention and ongoing illicit opioid use. We aim to describe rapid titration of OAT in an inpatient setting for pregnant injection opioid users with high opioid tolerance secondary to a fentanyl-based illicit drug supply. Methods : Retrospective case series of patients admitted to a tertiary center with a primary indication of opiate withdrawal and treatment for severe opioid use disorder in pregnancy. Results : Twelve women received rapid methadone titrations with or without slow-release oral morphine for opioid use disorder during a total of fifteen hospital admissions. All women included in the study were active fentanyl users (12/12). Methadone dosing was increased rapidly with no adverse events with a median dose at day 7 of 65mg (IQR 60-70mg) and median discharge dose of 85mg (IQR 70-92.5mg). Slow-release oral morphine was used in half of the titration admissions (8/15) with a median dose of 340mg (IQR 187.5-425mg) at discharge. The median length of admission was 12 days (IQR 9.5-15). Conclusions : A rapid titration of methadone was completed in an inpatient setting with or without slow-release oral morphine, without adverse events showing feasibility of this protocol for a pregnant population in an inpatient setting. Patients achieved therapeutic doses of methadone (and/or SROM) faster than outpatient counterparts with no adverse events.
... Cependant des antalgiques opioïdes forts ont pu être prescrits comme traitement substitutif aux opiacés (TSO) du fait de leurs propriétés agonistes opioïdes bien que cette indication thérapeutique ne figure pas dans leur Autorisation de Mise sur le Marché (AMM) [1,2] . ...
... En effets outre leur incontestable bénéfice thérapeutique ces deux classes ont en commun la capacité à procurer un plaisir intense (opiate high, flash, apaisement, euphorie, sensation d'extase) responsable de risques de trouble de l'usage et de « fuitage » (pharmaceutical leakage) depuis la sphère médicale 1 [3][4][5] étant bien entendu que le rapport bénéfice-risque leur est très favorable, que ce soit pour les antalgiques avec une meilleure prise en compte de la douleur dans des pathologies 1 Enquête DRAMES (Décès en Relation avec l'Abus de Médicaments Et de Substances) dont les résultats sont publiés par l'Agence nationale de sécurité du médicament et des produits de santé (ANSM) . https://www .ansm ...
Full-text available
Objective: Our aim was to evaluate community consumption of strong prescription opioid treatments in France in 2015 and 2017.Methods: A nation-wide French health care insurance claims database was analyzed for opioids average annual cost, annual prevalence of dispensations and users by mean of two repeated retrospective cross sectional study in 2015 and 2017.Results: In 2015–2017 prevalence of users per 100 000 beneficiaries per year rose from 878 to 932 (+6%) for strong opioid analgesics and lowered from 160 to 150 (-6%) for opiate substitution treatments. Prevalence of users of oxycodone, fentanyl, morphine, hydromorphone, buprenorphine, and methadone shifted by +17%, -5%, +4%, -8%, -13%, and +10%, respectively (+20% for methadone capsules). Oxycodone moved from third place to first place in terms of number of dispensation. Highest prevalence were in the western half of France, age over 60 and female for strong analgesic opioids and the north-east quarter and the south-west quarter of France, age 30 to 49 and male for opiate substitution treatments. The factor most strongly associated with prevalencewas age in strong analgesic opioids and gender in opiate substitution treatments.Conclusions: In 2 years the use of analgesics progresses, especially for oxycodone, while that of the substitution drugs decreases. Despite its greater danger, methadone tends to replace buprenorphine and capsule form tends to replace the syrup. Regulatory changes or enhanced controls may have played a role. The age of strong analgesic opioids consumers highlights the issue of severe pain in the elderly.
... 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). Concerning this last point, our data provided some nuances regarding the impact of SROM on craving. ...
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.
... This could be a marker of early substance usage disorder (31), which should be a warning sign for prescribers. However, these high dosages are similar to those reported in clinical trials assessing the use of MS as an alternative OMT (77)(78)(79)(80)(81)(82)(83). Improving the training of physicians in the identification of OUD and proper prescription rules would promote early detection of these patients and safer use of opioids. ...
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Background National health monitoring agencies have reported the alternative use of morphine sulfate painkiller for maintenance treatment of opioid use disorder (OUD), associated with a potential increase in overdose risk.Objectives This study sought to assess the prevalence of regular and occasional legally prescribed morphine use in patients treated for OUD and compare their characteristics to those of patients receiving conventional opioid maintenance treatment (OMT), buprenorphine or methadone. Then, we assessed the factors associated with opioid overdose risk.Methods Data were extracted from the French national healthcare system database, covering the entire population in 2015. Diagnosis associated with hospital discharge and long-term disease codes were extracted to select the population and identify outcomes and covariates. OUD non-chronic pain patients were divided into regular (≤35 days between dispensing and ≥3 months of continuous treatment duration) morphine users, and occasional users. Their sociodemographic and health characteristics were compared to OMT controls. A multivariate logistic regression model was performed to determine factors associated with opioid overdose.ResultsIn patients treated for OUD, 2,237 (2.2%) morphine users (1,288 regular and 949 occasional), 64,578 (63.7%) buprenorphine and 34,638 (34.1%) methadone controls were included. The prevalence of regular morphine use among patients treated for OUD regularly receiving an opioid was 1.3%. Compared to users who receive morphine regularly, occasional users had an increased risk of overdose [OR = 2.2 (1.5–3.3)], while the risk was reduced in the buprenorphine group [OR = 0.5 (0.4–0.7)] and not significantly different for methadone [OR = 1.0 (0.7–1.4)]. Other overdose risk factors were low-income, comorbidity, i.e., psychiatric conditions, alcohol use disorder or complications related to intravenous drug use, and coprescription with benzodiazepines or pregabalin. These factors were more frequent in morphine groups.Conclusions Patients that were prescribed oral morphine represented a small minority of the treated for OUD. The poorer health condition affected by numerous comorbidities and higher risk of opioid overdose in patients treated with oral morphine compared with OMT controls points toward the need to better supervise the practices of these patients, to strengthen multidisciplinary care and risk reduction measures.
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Introduction Several pharmacotherapeutic interventions are available for maintenance treatment for opioid-related disorders. However, previous meta-analyses have been limited to pairwise comparisons of these interventions, and their efficacy relative to all others remains unclear. Our objective was to unify findings from different healthcare practices and generate evidence to strengthen clinical treatment protocols for the most widely prescribed medications for opioid-use disorders. Methods We searched Medline, EMBASE, PsycINFO, CENTRAL, and for all relevant randomized controlled trials (RCT) from database inception to February 12, 2022. Primary outcome was treatment retention, and secondary outcome was opioid use measured by urinalysis. We calculated risk ratios (RR) and 95% credible interval (CrI) using Bayesian network meta-analysis (NMA) for available evidence. We assessed the credibility of the NMA using the Confidence in Network Meta-Analysis tool. Results Seventy-nine RCTs met the inclusion criteria. Due to heterogeneity in measuring opioid use and reporting format between studies, we conducted NMA only for treatment retention. Methadone was the highest ranked intervention (Surface Under the Cumulative Ranking [SUCRA] = 0.901) in the network with control being the lowest (SUCRA = 0.000). Methadone was superior to buprenorphine for treatment retention (RR = 1.22; 95% CrI = 1.06–1.40) and buprenorphine superior to naltrexone (RR = 1.39; 95% CrI = 1.10–1.80). However, due to a limited number of high-quality trials, confidence in the network estimates of other treatment pairs involving naltrexone and slow-release oral morphine (SROM) remains low. Conclusion All treatments had higher retention than the non-pharmacotherapeutic control group. However, additional high-quality RCTs are needed to estimate more accurately the extent of efficacy of naltrexone and SROM relative to other medications. For pharmacotherapies with established efficacy profiles, assessment of their long-term comparative effectiveness may be warranted. Trial Registration This systematic review has been registered with PROSPERO ( ) (identifier CRD42021256212 ).
Background The Ottawa Inner City Health's Managed Opioid Program is the first, to our knowledge, to pair injectable opioid agonist hydromorphone treatment with assisted housing for people experiencing homelessness with severe opioid use disorder (OUD) and injection drug use. We aimed to describe this program and evaluate retention, health, and social wellbeing outcomes. Methods We retrospectively assessed the first cohort of clients enrolled in the Managed Opioid Program between August 2017–2018. The primary outcome was retention at 12 months. Secondary outcomes included injectable and oral opioid dose titration, non-prescribed opioid use, overdoses, connection with behavioural health services, and social well-being. Descriptive statistics were used to summarize baseline demographics and secondary outcomes. Actuarial survival analysis was used to assess retention among participants. Results The study sample included 26 participants: median age was 36 years, 14 were female, 22 were White, eight had alcohol use disorders, 25 had stimulant use disorders, and all had a history of concurrent psychiatric illness. Retention at 12 months was 77% (95% CI 62–95). Throughout the first-year participants’ opioid treatment doses increased. The median daily dose of injectable hydromorphone was 36 mg [17–54 mg] and 156 mg [108–188 mg] at enrollment and one year respectively. The median daily dose of oral opioid treatment was 120-milligram morphine equivalents [83–180 mg morphine equivalents] and 330-milligram morphine equivalents [285–428 mg morphine equivalents] at enrollment and one year respectively. Over half had no overdoses and there were no deaths among participants who remained enrolled. At one year, 45% stopped non-prescribed opioid use, 96% connected to behavioral health services, 73% reconnected with estranged families, and 31% started work or vocational programs. Conclusion Individuals with severe OUD engaged in injectable hydromorphone treatment and housing showed high retention in care and substantive improvements in patient-centered health and social well-being outcomes.
Evidenz-basierte Empfehlungen der Schweizerischen Gesellschaft für Suchtmedizin zur Opioid-Agonisten-Therapie
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Introduction Buprenorphine and methadone are highly effective first-line medications for opioid agonist treatment (OAT) but are not acceptable to all patients. We aimed to assess the uptake of slow-release oral morphine (SROM) as second-line OAT among medically ill, hospitalised patients with opioid use disorder who declined buprenorphine and methadone. Methods This study included consecutive hospitalised patients with untreated moderate-to-severe opioid use disorder referred to an inpatient addiction medicine consultation service, between June 2018 and September 2019, in Nova Scotia, Canada. We assessed the proportion of patients initiating first-line OAT (buprenorphine or methadone) in-hospital, and the proportion initiating SROM after declining first-line OAT. We compared rates of outpatient OAT continuation (i.e., filling outpatient OAT prescription or attending first outpatient OAT clinic visit) by medication type, and compared OAT selection between patients with and without chronic pain, using χ² tests. Results Thirty-four patients were offered OAT initiation in-hospital; six patients (18%) also had chronic pain. Twenty-one patients (62%) initiated first-line OAT with buprenorphine or methadone. Of the 13 patients who declined first-line OAT, seven (54%) initiated second-line OAT with SROM in-hospital. Rates of outpatient OAT continuation after hospital discharge were high (>80%) and did not differ between medications (P = 0.4). Patients with co-existing chronic pain were more likely to choose SROM over buprenorphine or methadone (P = 0.005). Discussion and Conclusions The ability to offer SROM (in addition to buprenorphine or methadone) increased rates of OAT initiation among hospitalised patients. Increasing access to SROM would help narrow the opioid use disorder treatment gap of unmet need.
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.
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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.
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Patients receiving treatment for opioid dependence are prone to relapse into illicit drug use, risking significant harms to themselves and to society. The European Quality Audit of Opioid Treatment (EQUATOR) analysis assessed aspects of opioid maintenance treatment (OMT) delivery and the quality of care offered to patients undergoing OMT across 10 European countries. Findings suggest quality of care may be improved by: ensuring patients and physicians discuss the range of available treatment options, achieving the appropriate balance between control and patient flexibility, reducing the likelihood of misuse and diversion, and providing appropriate psychosocial care in conjunction with pharmacotherapy.
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.], Alcohol and Drug Council of Australia (ADCA) [], Australian Drug Foundation (ADF -VIC) [], Centre for Education and Information on Drugs and Alcohol (CEIDA) [], 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.
Background: The safety and efficacy of oral slow release morphine was evaluated in patients with known opioid dependency. Method: 40 outpatients were enrolled in an open, non comparative trial. Slow release morphine was administered orally once daily. During the first week the daily dose was titrated depending on signs and symptoms of opioid withdrawal. Thereafter the dose was kept constant. During the 4 weeks observation period signs and symptoms of opioid withdrawal (Wang scale), craving for substances and the duration of sleep were evaluated in regular intervals. In addition well-being was assessed by using different psychometric scales (B-L, SCL-90-R, BDI). Results: Daily oral administration of slow release morphine significantly (p < 0.001) reduced signs and symptoms of opioid withdrawal already during the first week. Thereafter withdrawal symptoms were controlled on a very low level at nearly constant daily dose levels. During the first week of morphine administration craving for heroin and cocaine was significantly (p < 0.001) reduced. The treatment with morphine resulted in significantly improved well-being based on the reduction of subjective somatic and psychic complaints. Oral slow release morphine was well tolerated. Conclusions: This study supports evidence that oral slow release morphine may be a suitable option for the maintenance therapy of opioid addicts on an outpatient basis.
A group of 22 patients, previously addicted to diacetylmorphine (heroin), have been stabilized with oral methadone hydrochloride. This medication appears to have two useful effects: (1) relief of narcotic hunger, and (2) induction of sufficient tolerance to block the euphoric effect of an average illegal dose of diacetylmorphine. With this medication, and a comprehensive program of rehabilitation, patients have shown marked improvement; they have returned to school, obtained jobs, and have become reconciled with their families. Medical and psychometric tests have disclosed no signs of toxicity, apart from constipation. This treatment requires careful medical supervision and many social services. In our opinion, both the medication and the supporting program are essential.
Objective: To compare the dose effectiveness of low to moderate doses of methadone in a sample of a contemporary population of opioid abusers, because the optimal dosing of methadone in the treatment of opioid dependence remains an issue. Design: A randomized, double-blind, placebocontrolled study. Setting: A methadone treatment research clinic. Patients: Participants (n=247) were opioiddependent patients with a high rate of cocaine use. Intervention: All participants were initially treated with active methadone for a minimum of 5 weeks and then received 15 weeks of stable dosing at 50, 20, or 0 mg per day. Individual counseling and group therapy were included
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.
People dependent on heroin who do not respond to other treatments have been treated by a combination of heroin and methadone. In this Policy Forum, Bammer et al. argue that the debate about the merits of this treatment could be substantially informed by clinical trials that meet rigorous scientific standards. Because of the complexities of working with the dependent user population and the social and individual risks associated with this potential treatment, a series of interlocking trials with various designs and control groups are essential, and social impacts must also be monitored. Heroin will always be a second- rather than first-choice treatment, and if trials show that it has any value, the political outcome will be medicalization, not legalization.
An essential problem in planning clinical non-inferiority or equivalence studies is the specification of the ‘irrelevant difference’ (irrelevance margin; delta). This quantifies the amount of non-inferiority or difference, respectively, between a new test therapy and an established standard treatment which is to be considered as tolerable. In the past, most recommendations and guidelines for clinical non-inferiority and equivalence studies contained only general statements and formulations concerning the specification of delta. The current unsatisfactory situation was the reason for performing a systematic review of published clinical non-inferiority and equivalence studies. It was the aim to gain an overview on the irrelevance margins used in such studies, and on reasons for choosing the particular margins. For the sake of comparability, the irrelevance margins were converted into standardized differences and odds ratios. Overall, there were 332 non-inferiority or equivalence trials obtained by means of an extensive literature search. The results of the systematic review show that current requirements on the choice of delta and the reality of recent clinical non-inferiority and equivalence trials differ substantially. In about one half of the trials a difference of 0.5 standard deviations or more was regarded as ‘irrelevant’ – explicitly or implicitly. Estimates of standard-placebo differences formed the basis of the irrelevance margin in less than every tenth trial. Reasons for this very low proportion might be (1) the possibly resulting very small irrelevance margins, and (2) unsolved problems of the requirements themselves. Overall, it seems that a more global definition of ‘irrelevance’ might be warranted. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)