Key words buprenorphine-naloxone - dependence treatment - buprenorphine - naloxone - opioids
- routine care - safety
Introduction
Opioid dependence is a major health and social issue [1 ]
[2 ] and is associated with an excess rate of somatic and psychiatric complications including
HIV, hepatitis, depression, suicidality and antisocial behaviour [1 ]
[3 ]
[4 ]. Approximately 200 000 persons in Germany have a risky use of illicit substances,
excluding cannabis use [5 ]. Although the number of drug-related deaths continues to decrease still 1 237 persons
died in 2010 because of drug use, most of them because of heroin overdose (42.8%),
12.5% of the deaths were related to methadone/levo-methadone alone or in combination
with other drugs and 0.5% were related to buprenorphine alone or in combination with
other drugs [5 ].
One of the reasons for the lowest number of drug-related deaths in the past 10 years
[5 ] is opioid maintenance treatment which is an established and well-studied approach
in opioid dependence and recommended by current treatment guidelines worldwide [6 ]
[7 ]
[8 ]
[9 ]. The main goals of opioid drug dependence treatment are risk and harm reduction,
social reintegration, and interruption of the vicious circle of drug use and procurement
crime. Furthermore the therapy aims to establish best possible conditions for the
treatment of concomitant diseases [10 ]. Although abstinence is no longer the only primary goal, the long-term target of
opioid drug dependence treatment is to support the patients to stop using drugs entirely
[10 ].
In 2010 more than 77 000 of approximately 200 000 opioid-dependent patients in Germany
were registered as currently in maintenance treatment with d/l-methadone (58%), levo-methadone
(23%), buprenorphine (19%) and other substitution drugs including diamorphine (0.3%)
[7 ]
[11 ]. Both treatments with full opioid agonists (e. g., methadone) and partial agonist/antagonist
(buprenorphine) have been found to be effective in reducing substance use and improving
somatic, psychiatric as well as social functioning [2 ]
[12 ]
[13 ]
[14 ]. However the increasing level of diversion [8 ]
[15 ]
[16 ] and the risk of fatal outcomes in opioid maintenance treatment have raised concerns
about safety issues in the treatment of opioid dependence.
The combination of the partial mu-agonist/kappa-antagonist buprenorphine with the
full mu-antagonist naloxone in a ratio of 4:1 was developed to improve treatment outcomes
and to reduce the risk of diversion [17 ]
[18 ]. When the combination is administered sublingually as prescribed, naloxone is inactive
because of its low sublingual bioavailability [19 ] and only the effects of buprenorphine are experienced [16 ]
[20 ] blocking most of the mu-receptors [12 ]. But when the medication is administered parenterally (intravenous or nasal) the
effects of naloxone are experienced for the first 15–90 min [21 ]. Both buprenorphine and naloxone have a very high bioavailability but naloxone binds
more rapidly to the opioid mu-receptors than buprenorphine causing precipitated withdrawal
if the user has full agonists in the body [16 ]
[18 ]. Thus the combination of buprenorphine with naloxone is expected to reduce the risk
of intravenous or nasal misuse [19 ]. The combination minimizes the risk of opioid overdose and diversion by making it
unattractive for selling [17 ]
[21 ] because of the unpleasant experience directly after parenteral abuse [18 ]
[21 ]. In addition the potential pleasurable effects of buprenorphine are diminished due
to the smaller and delayed agonist effects after the subsiding antagonistic effect
of naloxone [21 ].
While a number of randomized clinical trials [2 ]
[12 ]
[17 ]
[22 ] demonstrated the overall efficacy of buprenorphine-naloxone in the treatment of
opioid dependence, to date no non-interventional observational studies on the effectiveness
and safety of the novel buprenorphine-naloxone combination reflecting “real world”
conditions with a profound and comprehensive assessment both for physicians and patients
have been published. Such studies are essential to verify clinical trial results and
to receive reliable safety data from routine care treatment. The study was designed
to collect comprehensive safety and effectiveness data on a large patient sample in
office-based routine opioid drug dependence treatment with buprenorphine-naloxone
over a 12-month period (2008–2010).
Methods
Study goals
The primary objectives of the non-interventional study was to describe the retention
rate of patients pre-treated with buprenorphine, methadone, levo-methadone or another
maintenance drug after 12 months of treatment with buprenorphine-naloxone under real-life
conditions and to collect comprehensive safety data during switch to and treatment
with buprenorphine-naloxone.
The secondary objectives were to describe the switch to the new medication in terms
of dosing, mode of prescription and subjective effects. Data on effectiveness, acceptance
and tolerance of opioid dependence treatment with buprenorphine-naloxone should be
examined regarding met and unmet needs.
Study design
The study was a nationwide, prospective 12-month observational, non-interventional,
post-authorization safety study (PASS) with patients currently in drug dependence
treatment with another medication such as d/l-methadone, levo-methadone or buprenorphine
for whom a switch to buprenorphine-naloxone was indicated and planned ([Fig. 1 ]). A comprehensive paper-based clinical research form was used for data capture.
The study was part of the Risk Management Plan (RMP) for the newly marketed product
buprenorphine-naloxone (Suboxone® ) and therefore a requirement of the European Medicine Agency (EMA). The study is
registered with the National Institute of Health (NIH) at ClinicalTrials.gov (NCT00723749).
Fig. 1 Design of the non-interventional study with buprenorphine-naloxone.
Study population
From N=69 physicians working in addiction medicine and qualified pursuant to German
Controlled Substances Regulation (Betäubungsmittelverordnung, BtMVV) § 5 (2) (1) (6)
and with authorization granted by the Association of Statutory Health Insurance Physicians
(Kassenärztliche Vereinigung, KV) N=384 opioid-dependent patients were enrolled (total
population). All patients over 15 years of age who had consented to opioid drug dependence
treatment within the scope of medical, social and psychotherapeutic measures, for
whom the switch to buprenorphine-naloxone was indicated and planned and who had signed
the informed consent form could be included. The participating physicians were not
subject to directives in terms of the use of buprenorphine-naloxone and prescribed
the medication in the form of a conventional, commercially available product. Therapeutic
indications and contraindications for opioid dependence treatment according to the
Summary of Product Characterization (SmPC) for buprenorphine-naloxone and national
treatment guidelines had to be observed when selecting patients for participation
in the non-interventional study.
Of this total population n=47 datasets were excluded from the final analysis. Reasons
were treatment not started (only baseline documentation available, n=18), missing
final documentation (month 12 or drop-out, n=21) and incomplete documentation (no
documentation of induction phase and follow-up documentation, n=8).
The final analysis population of n=337 eligible datasets contains all patients with
written informed consent, as approved by the ethics committee of the Ludwig-Maximilian
University in Munich, as well as complete study documentation for at least baseline
(day 0), start of treatment with buprenorphine-naloxone (day 1) and the final documentation
either as end-of-observation (month 12) or drop-out documentation. For n=3 patients
day 1 documentation was missing and documentation of day 2 of treatment with buprenorphine-naloxone
was used instead.
Assessments
Physicians questionnaire (third-party assessment)
The treating physicians informed eligible patients about the purpose of the study,
the data collection procedure and the data privacy protection. Only after agreeing
to all aspects and signing the informed consent form the baseline assessment, which
was conducted before switching the patient to buprenorphine-naloxone, could be commenced.
The physician’s questionnaire for evaluation of the patients was a paper-based assessment
tool specially developed for the non-interventional study with 45 pages including
12 sections with several standardized instruments to document the following patient
parameters: socio-demographics, substance use history, treatment history, co-morbidities,
co-medication, concomitant drug use, urine drug screening, main reason for switch
to buprenorphine-naloxone, treatment with buprenorphine-naloxone, premature discontinuation
before end of observation, effectiveness measures with modified Clinical Global Impression
(mCGI), Objective Opiate Withdrawal Scale (OOWS), and safety. It was the physician’s
decision which treatment data were transferred from the patient’s medical chart to
the questionnaire.
The CGI [23 ] is a standard measure for global assessments of illness consisting of 3 different
global measures. In the study a modification of the Clinical Global Impression Severity
scale (CGI-S) and a modification of the Clinical Global Impression Improvement scale
(CGI-I) was used. The OOWS [24 ] is a standardized scale for measuring the physically observable signs of opiate
withdrawal for rating by the physician.
All adverse events (non-serious and serious including adverse drug reactions and pregnancies)
were listed as they were spontaneously reported and documented at each visit by the
treating physician.
Patients questionnaires (self assessment)
During the 12-month observational period all patients were asked to complete 4 standardized
questionnaires in accordance with the schedule of observation points ([Fig. 2 ]): 1) Short Form 36 – Health Survey (SF-36) [25 ], a 36-item self-assessment questionnaire to survey the current health status with
2 modified indication specific questions in reference to drug dependence; 2) Subjective
Opiate Withdrawal Scale (SOWS) [24 ], the subjective counterpart of the OOWS is a standardized scale for measuring the
intensity of symptoms of opiate withdrawal from the perspective of the patient; 3)
revised psychiatric Symptom Check-List (SCL-90R) [26 ]
[27 ], a standardized self-assessment tool to measure subjective impairment due to somatic
and psychiatric symptoms; 4) visual analogue scale for craving (VAS Craving), an instrument
specially invented for the non-interventional study by the first author containing
twelve 100-mm visual analogue scales for the substances alcohol, cannabis, amphetamines,
hallucinogens, cocaine, barbiturates, benzodiazepines, opiates, d/l-methadone/levo-methadone,
buprenorphine, codeine/DHC and other. Patients were asked to visualize their current
craving for each of the listed substances.
Fig. 2 Flow chart parameters, methods and time points of observation.
Assessment schedule
To ensure eligible and valid data collection for comprehensive evaluation of induction
and course of drug dependence treatment with buprenorphine-naloxone compared to baseline
data before switch to the new medication, physician’s and patient’s questionnaires
were scheduled for specific time points of observation ([Fig. 2 ]).
Statistics and analysis
Except for socio-demographics, retention rate, regular end of treatment and safety
all comparisons were made between baseline (day 0) and final assessment as regular
end of observation (month 12) or premature discontinuation documentation (dropout)
for the total sample as well as for the analysis groups. Analyses concerning treatment
with buprenorphine-naloxone used day 1/start of treatment as baseline measures.
Single and multinomial logistic regression and chi-square tests were used for descriptive
correlations between the defined analysis groups, start and end of observation. For
numerical parameters, sample statistics, mean and standard deviation, minimum and
maximum were calculated. For categorical data, absolute and relative frequencies were
calculated. Data generated repeatedly in the course of time were evaluated per observation
point. The differences between baseline and final assessment are shown for specific
numerical data as absolute and relative difference.
Retention rates were estimated using Kaplan-Meier method and are presented as survival
curves and 12-month survival estimates.
The options “not tested” and “no test” were set to missing values. For the option
“no change” the status from the previous visit was carried forward.
Statistical significance was defined as p-values<0.05. Statistical analysis was done
with STATA/SE 9 [28 ].
Measures and specifications
Retention rate:
percentage of patients still in drug dependence treatment with buprenorphine-naloxone
at the end of the observation period or who completed treatment after achieving a
successful therapeutic outcome (regular end of treatment/abstinence).
Safety:
percentage of all documented non-serious and serious adverse events including adverse
drug reactions, which were coded using MedDRA version 11.1 [29 ].
Effectiveness:
improvement of scores from the standardized instruments mCGI for general health, SCL-90R
for mental health, OOWS and SOWS for withdrawal; regular end of treatment (patient
abstinent) documented by the treating physician in the final assessment as premature
discontinuation documentation was defined as positive treatment outcome and patients
were counted as completers.
Quality of life (QoL):
improvement of scores from the standardized instrument SF-36 comparing baseline with
the final assessment.
Acceptance and tolerance:
reduction of concomitant drug use measured by urine drug screening, craving for illicit
substances measured by the standardized instrument VAS craving and number of fresh
needle marks.
Analysis groups (post-hoc generation)
Completers:
patients still in drug dependence treatment with buprenorphine-naloxone at the end
of observation (month 12) including patients with dropout reason regular end of treatment
(patient abstinent from all illegal drugs including opiate-substitution).
Non-completers:
patients with documented premature discontinuation of treatment with buprenorphine-naloxone
for any reason other than regular end of treatment (patient abstinent).
Pre-treated:
patients with documented current maintenance pharmacotherapy at baseline.
Untreated:
patients without any documented previous maintenance pharmacotherapy at baseline [patients
with no current maintenance treatment at study entry, but with a history of previous
substitution treatment(s) are excluded from analysis between pre-treated and untreated
patients].
Buprenorphine:
patients in treatment with the mono compound buprenorphine at baseline.
(Levo-)methadone:
patients in treatment with d/l-methadone or levo-methadone at baseline.·
The term analysis groups refers to the above defined groups of completer/non-completer,
pre-treated/untreated and buprenorphine/(levo-)methadone.
Results
Data from N=337 eligible patients was examined.
Patient population
Socio-demographics
[Table 1 ] summarizes patient characteristics at baseline for the total sample and all analysis
groups. Most of the patients were male and in their mid-thirties, ranging from 18–62
years, and German nationality. Completers were older, married or living with a partner,
working in a full-time job and living in their own flat. Higher rates of the more
unfavourable characteristics such as unemployment, being divorced or single and being
homeless are found in the group of non-completers.
Table 1 Patient’s characteristics at baseline.
Total Sample
Completers
Non-Completers
p
Pre-Treated
Un-Treated
p
Buprenorphine
(Levo-) Methadone
337*
195
142
244
49
162
75
p
*Eligible datasets
Age in years [mean (SD)] N=336
35.1 (8.8)
36 (9.0)
33.9 (8.4)
0.029
35.7 (8.8)
32.6 (8.6)
0.025
36.8 (8.8)
33.5 (7.8)
0.006
Male [n (%)] N=337
258 (76.6)
154 (79.0)
104 (73.2)
0.220
192 (78.7)
36 (73.5)
0.422
119 (73.5)
66 (88.0)
0.012
German nationality [n (%)] N=336
281 (83.6)
162 (83.1)
119 (84.4)
0.747
196 (80.3)
43 (87.8)
0.221
134 (82.7)
56 (74.7)
0.148
BMI [mean (SD)] N=332
23.8 (3.9)
24 (3.9)
23.5 (3.9)
0.214
23.9 (3.9)
23.2 (3.9)
0.226
23.9 (4.1)
24 (3.5)
0.911
Marital status [n (%)] N=334
– Single
201 (60.2)
108 (56.3)
93 (65.5)
0.088
145 (60.2)
29 (59.2)
0.898
91 (57.2)
47 (62.7)
0.430
– Married/living together
102 (30.6)
69 (35.9)
33 (23.2)
0.013
73 (30.3)
16 (32.7)
0.744
49 (30.8)
24 (32.0)
0.855
– Divorced
30 (9.0)
14 (7.3)
16 (11.3)
0.209
23 (9.5)
4 (8.2)
0.762
19 (11.9)
4 (5.3)
0.113
Children [n (%)] N=331
120 (36.3)
70 (37.0)
50 (35.2)
0.732
90 (37.8)
13 (26.5)
0.134
68 (42.5)
22 (31.0)
0.098
Occupation [n (%)] N=337
– Full-time job
77 (22.8)
51 (26.1)
26 (18.3)
0.090
60 (24.6)
8 (16.3)
0.211
49 (30.3)
11 (14.7)
0.010
– Part-time job
48 (14.2)
24 (12.3)
24 (16.9)
0.233
40 (16.4)
3 (6.1)
0.064
28 (17.3)
11 (14.7)
0.613
– Unemployed
179 (53.1)
100 (51.3)
79 (55.6)
0.429
122 (50.0)
29 (59.2)
0.240
69 (42.6)
48 (64.0)
0.002
Residential status [n (%)] N=337
– Own flat
246 (73.0)
150 (76.9)
96 (67.6)
0.057
185 (75.8)
32 (65.3)
0.125
137 (84.6)
45 (60.0)
<0.001
– With family/friends
63 (18.7)
35 (17.9)
28 (19.7)
0.681
42 (17.2)
14 (28.6)
0.065
15 (9.3)
23 (30.7)
<0.001
– Homeless
5 (1.5)
0 (0.0)
5 (3.5)
0.008
3 (1.2)
1 (2.0)
0.655
1 (0.6)
2 (2.7)
0.189
Years of dependence [mean (SD)] N=311
13.8 (8.7)
14.6 (8.5)
12.8 (8.8)
0.077
14.9 (8.9)
8.5 (6.4)
<0.001
15.9 (9.3)
12.7 (6.8)
0.009
In maintenance treatment with [n (%)] N=244
– Buprenorphine
162 (66.4)
93 (66.4)
69 (66.4)
0.989
162 (66.4)
0 (0.0)
162 (100.0)
0 (0.0)
– D/l methadone
51 (20.9)
29 (20.7)
22 (21.2)
0.933
51 (20.9)
0 (0.0)
0 (0.0)
51 (68.0)
– Levo-methadone
24 (9.8)
18 (12.9)
6 (5.8)
0.066
24 (9.8)
0 (0.0)
0 (0.0)
24 (32.0)
Without prior maintenance treatment [n (%)] N=337
49 (14.5)
29 (14.9)
20 (14.1)
0.958
0 (0.0)
49 (100.0)
0 (0.0)
0 (0.0)
≥1 prior detoxification attempt [n (%)] N=254
209 (82.3)
119 (79.9)
90 (85.7)
0.229
158 (84.5)
15 (55.6)
<0.001
105 (83.3)
48 (87.3)
0.500
≥1 prior withdrawal attempt [n (%)] N=229
142 (62.0)
83 (60.6)
59 (64.1)
0.588
108 (65.1)
8 (30.8)
0.001
72 (65.5)
34 (65.4)
0.993
≥1 prior self detoxification attempt [n (%)] N=197
151 (76.7)
85 (77.3)
66 (75.9)
0.816
105 (75.5)
17 (65.4)
0.279
63 (70.0)
38 (86.4)
0.039
Hepatitis C infection [n (%)] N=335
121 (36.1)
62 (31.8)
59 (42.1)
0.009
96 (43.2)
9 (27.3)
0.082
63 (43.2)
30 (43.5)
0.964
HIV infection [n (%)] N=272
4 (1.2)
2 (1.0)
2 (1.4)
0.637
4 (1.9)
0 (0.0)
0.454
3 (2.2)
0 (0.0)
0.228
Psychiatric comorbidity [n (%)] N=337
193 (57.3)
106 (54.4)
87 (61.3)
0.195
144 (59.0)
27 (55.1)
0.612
93 (57.4)
47 (62.7)
0.444
Number of psychiatric comorbidities [mean (SD)]
2 (1.5)
1.9 (1.6)
2.1 (1.5)
0.538
2.1 (1.6)
1.4 (0.7)
0.027
1.8 (1.4)
2.7 (1.9)
0.005
Addiction history
As shown in [Table 1 ] N=244 patients were in maintenance treatment with buprenorphine (66.4%), d/l-methadone
(20.9%), levo-methadone (9.8%) or another maintenance drug (2.9%) at baseline. For
n=49 patients the treatment with buprenorphine-naloxone was their first opioid drug
dependence treatment and n=44 patients were previously but not at baseline in maintenance
treatment. Most of the participating patients had a long opioid addiction history
from almost 14 years on average, ranging from 4 months to 50 years. Patients switched
from the mono-compound buprenorphine and pre-treated patients had a significantly
longer drug addiction history [patients with no current maintenance treatment at study
entry, but with a history of previous substitution treatment(s) are excluded from
analysis between pre-treated and untreated patients].
Almost all patients used opioids in their life (94.6%) with no difference within the
analysis groups. Non-completers revealed significantly higher rates in the use of
benzodiazepines (72.7% vs. 56.5% completer, p=0.003), cocaine (85.5% vs. 64.9%, p≤0.001),
amphetamines (67.2% vs. 36.8%, p≤0.001), hallucinogens (42.5% vs. 25.8%, p=0.002),
codeine (36.1% vs. 18.8%, p=0.001), barbiturates (29.0% vs. 11.2%, p≤0.001). Pre-treated
patients revealed significantly higher rates in the use of cocaine (75.4% vs. 59.6%
untreated, p=0.039), benzodiazepines (64.2% vs. 47.9%, p=0.035) and codeine (27.4%
vs. 10.9%, p=0.018). Significantly higher rates of life-time cannabis use were found
in the group of patients switched from buprenorphine [91.9% vs. 79.7% (levo-)methadone,
p=0.008].
The average daily dosage for pre-treated d/l-methadone patients was 41.8±37.2 mg (2–160 mg),
levo-methadone patients 26.5±17.1 mg (4–60 mg) and buprenorphine patients 7.7±4.3 mg
(1–24 mg) at baseline.
Retention rate and drop-out
Retention rate
Of the total eligible patients n=181 were still in treatment at the end of observation
after 12 months of treatment with buprenorphine-naloxone and n=14 patients terminated
their treatment during the observation period because they were rated as abstinent
by their treating physician. The 12-month retention rate, analyzed with Kaplan-Meier
estimator, was 57.1% for the total analysis population ([Fig. 3 ]). There were no differences between pre-treated and untreated patients ([Fig. 3 ]). A slightly higher retention rate was found in (levo-)methadone patients ([Fig. 4 ]).
Fig. 3 12-month retention of the total analysis population (N=337), pre-treated (n=244)
and untreated (n=49) patients.
Fig. 4 12-month retention of buprenorphine (n=162) and (levo-)methadone (n=75) patients.
Reasons for dropout
N=142 patient terminated treatment before end of observation. The most frequently
documented reasons for drop out were “lost to follow up” (16.7%), “concomitant drug
use/relapse” (12.2%), “side effects” (12.2%) and “non-compliance/disciplinary reasons”
(10.9%). Significantly more untreated patients (16.7% vs. 4.6% pre-treated, p=0.033)
were rated as abstinent by the treating physician.
No deaths occurred during the entire observational period. Only n=1 hospitalization
and n=3 pregnancies led to premature termination of treatment with buprenorphine-naloxone.
Safety
Safety reporting for non-interventional studies is done according to regulations for
routine care practice in Germany. The research forms of this study contained special
sheets for documentation of all adverse events and the physician’s folder provided
reporting forms for serious adverse events but it was the physician’s decision if
an incident during the observation period required documentation and reporting, respectively.
Therefore only non-serious and serious adverse events documented and reported by the
treating physician could be included in the analysis. In this paper the adverse events
reported were evaluated for the analysis population only.
Serious adverse events (SAE)
For n=4 (1.2%) of the patients from the analysis population (N=337) there were n=4
serious adverse events reported during the complete observational period including
30 days post-study time. The events, listed as system organ class and the term reported
by the treating physician (in brackets) were n=1 psychiatric disorder (hospitalization
because of suspected adjustment disorder), n=1 social circumstances (concomitant drug
use), n=1 surgical and medical procedure (stay in hospital) and n=1 nervous system
disorder (epilepsy). One event was reported with certain correlation to the study
drug (concomitant drug use), one with likely correlation (hospitalization because
of suspected adjustment disorder), one with unlikely correlation (epilepsy) and one
with unknown relation to the study drug (stay in hospital).
No differences within the analysis groups were found in reference to the occurrence
of SAEs. No deaths were reported during the study.
Non-serious adverse events (NSAE)
For n=59 (17.5%) patients n=141 non-serious adverse events were reported. NSAEs with
a threshold of over 5.0% were psychiatric disorders (17.7%), social circumstances
(15.6%, most of them concomitant drug use/non-compliance), gastrointestinal disorders
(12.8%), infections and infestations (12.8%), nervous system disorders (9.9%) and
musculoskeletal and connective tissue disorders (9.2%). 5 of the NSAEs were reported
as certainly correlated to the study drug, n=27 likely related, n=32 possibly related,
n=67 unlikely related and n=10 were reported as unknown concerning relation to the
study drug. Significantly more non-completers (23.2% vs. 13.3% completers, p=0.018)
and pre-treated patients (20.5% vs. 8.2% untreated, p=0.042) were reported with non-serious
adverse events. No difference was found between buprenorphine and (levo-) methadone
patients concerning number of NSAEs.
Treatment with buprenorphine-naloxone
Reason for switch to buprenorphine-naloxone
The main reasons for switching to buprenorphine-naloxone were long-term maintenance
treatment with or without abstinence as final goal (28.8%), prior maintenance treatment
not successful (21.4%), planned detoxification treatment (17.8%) and prevention of
buprenorphine misuse (17.5%). For 11.9% the physicians reported “patient’s wish for
take home” as reason for the switch to buprenorphine-naloxone.
Dosing of buprenorphine-naloxone
The mean induction dose of buprenorphine-naloxone was 9.2±5.1 mg per day with a maximum
of 32.0 mg. This dose slightly increased to 9.6 mg on day 2 and 3 of the treatment
with buprenorphine-naloxone and decreased continuously in the course of treatment
to 7.7 mg per day. Non-completers received generally higher doses, but those non-completers
who were still in treatment at month 6 (n=37) received virtually the same dose as
completers ([Fig. 5 ]). Patients switched from d/l-methadone or levo-methadone received higher doses of
buprenorphine-naloxone than patients switched from the mono-compound buprenorphine
([Fig. 6 ]). Doses of previous buprenorphine patients did not change during the course of treatment
with buprenorphine-naloxone. Interestingly pre-treated and untreated patients’ dose
of buprenorphine-naloxone did not differ ([Fig. 7 ]).
Fig. 5 Mean dose buprenorphine-naloxone (mg/day) for all eligible patients (N=323), completers
(n=181) and non-completers (n=142).
Fig. 6 Mean dose buprenorphine-naloxone (mg/day) for buprenorphine patients (n=159) and
(levo-)methadone patients (n=73).
Fig. 7 Mean dose buprenorphine-naloxone (mg/day) for pre-treated (n=239) and untreated (n=45)
patients.
Patients rated as abstinent during the observation period (n=14) were not included
in the analyses shown above. Their mean induction dose of buprenorphine-naloxone was
8.5±6.3 mg which decreased rapidly to 7.0±4.7 mg at day 7, 4.6±2.6 mg at week 4 and
2.0±1.6 mg at their final assessment.
Mode of prescription
At the induction day most of the patients (87.1%) received buprenorphine-naloxone
on a daily basis at the practice of the treating physician and 8.4% as take-home prescription.
All of the take-home prescriptions were documented for pre-treated patients and significantly
more for buprenorphine patients (14.4% vs. 5.3% (levo-)methadone, p=0.043). Take-home
prescription increased during treatment with buprenorphine-naloxone and was documented
for 25.1% of the patients at the final assessment. Significantly more completers (30.1%
vs. 18.3% non-completers, p=0.014) received take-home at the time of their final assessment.
Quality of life
SF-36
As shown in [Table 2 ] the scores of the standardized patient questionnaire SF-36 were relatively low at
baseline but increased during treatment with buprenorphine-naloxone significantly
for all scales. There was no difference between completers and non-completers at baseline
except for pain. At the final assessment completers had significantly higher scores
in all scales and non-completers revealed no substantial improvement from baseline
to final assessment.
Table 2 SF-36 at baseline and final assessment for all eligible patients (N=337).
SF-36
Baseline (BL) vs. Final assessment (FA)
Mean (SD)
Physical functioning
Physical role functioning
Pain
General Health
Energy/Fatigue
Social functioning
Emotional role functioning
Emotional well being
Drug dependence
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
Significance level baseline vs. final assessment: *<0.05; **<0.01; ***<0.001
# n=22 final SF-36 assessments from untreated patients available
Total
79.1 (23.9)
90.1*** (16.5)
28.8 (21.2)
41.7*** (16.7)
55.7 (26.0)
72.8*** (18.0)
48.5 (20.9)
54.4*** (20.8)
43.5 (19.8)
55.9*** (19.3)
58.3 (29.1)
78.1*** (22.5)
51.8 (44.2)
83.7*** (32.2)
49.4 (20.9)
62.6*** (17.9)
53.9 (24.5)
73.8*** (20.1)
Completer
78.9 (24.1)
91.4*** (13.9)
30 (21.2)
43.3*** (15.2)
59.3 (24.3)
74.7*** (15.9)
49 (21.1)
55.8*** (20.9)
43.4 (20.6)
57.6*** (19.0)
59.8 (28.5)
79.6*** (20.7)
55.1 (43.9)
87.0*** (29.2)
49.5 (21.5)
64.4*** (16.9)
55.1 (24.7)
75.4*** (18.3)
Non-completer
79.3 (23.8)
82.8 (26.0)
27 (21.0)
33.1 (21.8)
50.5 (27.5)
62.3 (24.5)
47.7 (20.6)
46.7 (19.1)
43.7 (18.8)
46.2 (18.7)
56.1 (30.0)
69.8 (30.0)
47.2 (44.4)
65.6 (41.5)
49.1 (20.1)
52.7 (20.6)
52.3 (24.4)
65.1 (26.6)
Diff. C vs. NC
p=0.895
p=0.009
p=0.202
p=0.002
p=0.003
p<0.001
p=0.585
p=0.031
p=0.904
p=0.003
p=0.265
p=0.031
p=0.120
p<0.001
p=0.861
p=0.001
p=0.305
p=0.010
Pre-treated
81.2 (22.5)
89.1*** (17.6)
31.8 (20.6)
41.2*** (16.9)
59.9 (24.1)
72.2*** (19.0)
50.8 (21.2)
54.0* (21.4)
46.3 (19.8)
55.5*** (19.2)
61.7 (28.5)
77.0*** (23.5)
56.4 (44.2)
82.2*** (33.4)
52.5 (20.6)
61.8*** (18.4)
56.7 (24.3)
72.4*** (20.8)
Untreated#
73.8 (27.9)
93.8* (11.2)
22.8 (20.7)
42.9** (17.9)
43.7 (27.6)
74.7*** (14.2)
42.4 (17.5)
61.8** (18.6)
33.5 (16.4)
63.0*** (18.4)
44.4 (29.3)
83.0*** (17.5)
46.5 (46.1)
95.2** (21.8)
38.9 (18.6)
70.9*** (15.5)
46 (24.9)
82.0*** (17.0)
Diff. PT vs. UT
p=0.052
p=0.232
p=0.008
p=0.676
p<0.001
p=0.557
p=0.014
p=0.109
p<0.001
p=0.088
p<0.001
p=0.258
p=0.183
p=0.086
p<0.001
p=0.028
p=0.007
p=0.041
Buprenorphine
84.8 (19.8)
90.4 (17.1)
35.3 (18.8)
41 (17.3)
62.6 (58.9)
72.8* (19.1)
54.6 (21.8)
55 (23.0)
50.8 (18.8)
55.1 (20.1)
67.3 (28.3)
77.5* (25.2)
64.4 (41.7)
83.2** (33.8)
57 (19.4)
61.7 (19.4)
60.7 (23.6)
73.7** (21.3)
(Levo-) methadone
73.2 (19.8)
88.9*** (13.5)
23.5 (22.2)
42.7*** (14.9)
55.1 (23.6)
74.1*** (14.7)
43.3 (17.5)
52.7*** (18.1)
37.4 (18.7)
57.3*** (16.2)
50 (25.0)
77.8*** (16.6)
38.2 (45.1)
82.3*** (31.3)
43 (20.0)
62.9*** (14.6)
48.9 (23.4)
71.0*** (17.6)
Diff. B vs. LM
p<0.001
p=0.602
p<0.001
p=0.560
p=0.029
p=0.678
p<0.001
p=0.531
p<0.001
p=0.503
p<0.001
p=0.934
p<0.001
p=0.882
p<0.001
p=0.684
p<0.001
p=0.442
Pre-treated patients had higher scores at baseline but at the final assessment untreated
patients achieved higher scores in all scales of the SF-36 and significantly for the
scales emotional well-being and drug dependence compared to pre-treated patients.
At baseline buprenorphine patients achieved significantly higher rates compared to
(levo-)methadone patients but no difference was found at the final assessment. While
(levo-)methadone patients improved significantly in all scales, buprenorphine patients
showed only for pain, social functioning, emotional role functioning and drug dependence
significant improvement from baseline to final assessment.
Effectiveness of the treatment with buprenorphine-naloxone
Mental health
As shown in [Table 3 ] the mean scores of the SCL-90-R at baseline are higher in all scales for non-completers,
untreated and (levo-)methadone patients. All patients achieved a significant improvement
of psychiatric distress at their final assessment irrespective of analysis group.
Table 3 Changes in psychiatric status: SCL-90-R.
Psychiatric Status: SCL90-R individual scales
Baseline vs. Final assessment
Mean sum score (SD)
Somatization
Obsessive-Compulsive
Interpersonal Sensitivity
Depression
Anxiety
Hostility
Phobic Anxiety
Paranoid Ideation
Psychoticism
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
Significance level baseline vs. final assessment shown at the FA-value: * <0.05; **
<0.01; *** <0.001
Evaluable assessments at baseline: Total 321; completer 185; non-completer 136; pre-treated
233; untreated 45; buprenorphine 161; (levo-)methadone 66
Evaluable assessments at final assessment: Total 192; completer 162; non-completer
30, pre-treated 150, untreated 21, buprenorphine 100, (levo-) methadone 46
BL: Baseline
FA: Final assessment
Total
8.7 (8.6)
3.6*** (6.2)
8.2 (7.3)
3.2*** (5.8)
6.1 (6.2)
2.5*** (4.7)
11.8 (10.5)
4.8*** (7.9)
7.2 (7.3)
2.7*** (5.5)
4.8 (4.5)
2.0*** (3.4)
3 (4.4)
1.3*** (3.2)
4 (4.2)
1.5*** (3.0)
4.2 (5.7)
1.6*** (4.1)
Completer
7.9 (8.8)
3.1*** (5.6)
7.5 (7.3)
2.7*** (5.5)
5.8 (6.4)
2.2*** (4.6)
10.9 (10.7)
4.1*** (7.2)
6.5 (7.2)
2.0*** (4.5)
4.4 (4.2)
1.7*** (3.1)
2.7 (4.4)
1.0*** (2.9)
3.8 (4.4)
1.4*** (3.0)
3.7 (5.7)
1.4*** (3.9)
Non-completer
9.7 (8.3)
6.3 (8.2)
9.2 (7.2)
5.7 (6.9)
6.5 (6.0)
4.2* (5.2)
13 (10.1)
8.7 (10.0)
8.2 (7.3)
6.5 (8.1)
5.3 (4.9)
3.6 (5.0)
3.5 (4.3)
2.8 (4.6)
4.2 (4.0)
2.2 (3.1)
4.8 (5.7)
2.9 (4.8)
p=0.076
p=0.008
p=0.039
p=0.010
p=0.345
p=0.026
p=0.085
p=0.003
p=0.040
p<0.001
p=0.094
p=0.005
p=0.135
p=0.006
p=0.440
p=0.191
p=0.078
p=0.059
Pre-treated
7.8 (8.0)
3.9*** (6.8)
7.5 (6.9)
3.6*** (6.4)
5.9 (6.0)
2.9*** (5.1)
11 (10.0)
5.5*** (8.6)
6.6 (7.1)
3.2*** (6.1)
4.4 (4.3)
2.3*** (3.8)
2.8 (4.1)
1.5*** (3.6)
3.8 (3.9)
1.8*** (3.3)
4.1 (5.4)
2.0*** (4.5)
Untreated
9.8 (10.4)
1.6** (2.2)
9.7 (8.4)
1.2** (1.8)
6.6 (6.7)
1.3** (1.8)
14.3 (12.1)
2.3** (2.9)
8.5 (7.3)
1.0*** (1.1)
5.7 (4.9)
1.0** (1.7)
3.9 (5.2)
0.8 (1.7)
4.4 (4.7)
0.5** (0.9)
4.4 (6.7)
0.5* (1.4)
p=0.137
p=0.127
p=0.060
p=0.090
p=0.501
p=0.163
p=0.053
p=0.091
p=106
p=0.101
p=0.085
p=0.118
p=0.127
p=0.363
p=0.312
p=0.074
p=0.681
p=0.127
Buprenorphine
6.6 (6.9)
3.6* (6.0)
6.2 (5.9)
3.2** (6.3)
4.9 (5.3)
2.4*** (5.0)
9.4 (9.3)
5.0*** (8.3)
5.1 (5.6)
2.7* (5.3)
3.5 (3.5)
2.0** (3.4)
2.1 (3.4)
1 (2.8)
3.2 (3.6)
1.6*** (3.2)
3.2 (4.0)
1.4** (3.2)
(Levo-)methadone
9.8 (9.5)
3.5*** (7.0)
10.1 (7.9)
4.0*** (6.3)
7.7 (6.9)
3.3*** (4.8)
14.7 10.7)
5.8*** (8.4)
9.5 (8.4)
3.3*** (6.3)
6.2 (5.0)
2.3*** (3.5)
4.2 (4.8)
2.2*** (4.0)
4.8 (44.4)
2.1*** (3.3)
5.8 (7.2)
2.9*** (5.8)
p=0.006
p=0.937
p<0.001
p=0.507
p=0.001
p=0.355
p<0.001
p=0.598
p<0.001
p=0.547
p<0.001
p=0.573
p<0.001
p=0.047
p=0.005
p=0.320
p<0.001
p=0.035
Modified Clinical Global Impression – Severity scale (mCGI-S)
[Fig. 8 ] shows the modified CGI measuring the general health of the patient from the perspective
of the physician. The categories were transformed to numeric scores (0=very good to
5=extremely bad). There was no difference between completers and non-completers but
untreated and (levo-) methadone patients received significantly higher scores at baseline.
According to the physicians the general health of all patients improved significantly
during treatment with buprenorphine-naloxone except for non-completers. Their general
health slightly worsened and the score was significantly higher (p<0.001) at the final
assessment compared to completers.
Fig. 8 Modified CGI score at baseline and final assessment for all eligible patients (N=337).
Withdrawal
SOWS:
The total score of the subjective opiate withdrawal scale at baseline was 17.2±13.5
and decreased to 5.1±8.4 at final assessment. Non-completers achieved a significantly
higher score at baseline (19.0±13.6 vs. 15.9±13.4 completers, p=0.043) and final assessment
(11.7±11.7 vs. 3.9±7.0, p<0.001). Untreated patients (20.8±14.7 vs. 14.9±12.5 pre-treated,
p=0.005) and (levo-)methadone patients (20.3±13.2 vs. 11.8±10.5 buprenorphine, p<0.001)
achieved a significantly higher score at baseline but did not differ from their comparison
group at final assessment. All groups, except non-completer, achieved a significant
reduction of subjective opiate withdrawal during the treatment with buprenorphine-naloxone.
OOWS:
The total score of the objective opiate withdrawal scale reported by the treating
physicians was 8.8±8.1 at baseline and decreased significantly to 2.2±4.8 (p<0.001).
From the physician’s perspective there was no difference between completers and non-completers
concerning opiate withdrawal at baseline, but at the final assessment non-completers
received a significantly higher score (3.8±6.2 vs. 1.1±3.0 completers, p<0.001). Untreated
(12.7±7.4 vs. 7.2±7.6 pre-treated, p<0.001) and (levo-) methadone (11.1±7.7 vs. 4.9±6.3
buprenorphine, p<0.001) patients showed significantly more withdrawal symptoms at
baseline. At the end of the observation physicians saw no difference between untreated
and pre-treated patients, but in buprenorphine patients they identified more objective
withdrawal symptoms [2.2±4.4 vs. 1.1±3.3 (levo-)methadone, p=0.050].
Regular end of treatment
For n=14 patients the premature discontinuation within the 12-month observation period
was the regular end of treatment with buprenorphine-naloxone because they were rated
as abstinent by their treating physician (4.2% of the total eligible patient population).
Significantly more patients without prior maintenance treatment became abstinent (8.2%
vs. 2.1% pre-treated, p=0.002). No difference was found between patients with prior
buprenorphine treatment and treatment with (levo-)methadone.
Acceptance and tolerance
Concomitant drug use
According to the results of urine drug screenings ([Table 4 ]) approximately one-third of the patients had a current use of opioids and cannabis
at baseline. Significantly higher rates of opioid use were found in non-completers
and untreated patients. Significantly more non-completers used cocaine and benzodiazepines,
significantly more untreated patients used benzodiazepines and amphetamines and significantly
more (levo-)methadone patients used cannabis. During the treatment with buprenorphine-naloxone
urine drug screenings revealed a significant reduction of drug use for all illicit
substances except barbiturates. Significantly higher rates of opioid use, cocaine,
benzodiazepines and amphetamines were found in non-completers compared to completers.
Significantly more (levo-)methadone patients were found to be active cannabis users
at the final assessment.
Table 4 Reduction of drug use during treatment with buprenorphine-naloxone: urine drug screening.
Drug use: Urine Drug Screening
Baseline vs. Final Assessment
N (%*)
Opioids
Cannabis
Cocaine
Benzodiazepines
Amphetamines
Barbiturates
Tricycl. Antidepr.
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
BL
FA
*Percentages refer to non-missing totals, which vary for every substance Significance
level baseline (BL) vs. final assessment (FA): * <0.05, ** <0.01, *** <0.001
Total
124 (37.5)
35 (12.8)
83 (32.9)
51 (29.8)
28 (8.5)
17 (6.5)
85 (25.8)
40 (15.2)
14 (5.5)
8 (4.4)
0 (0.0)
1 (1.2)
2 (2.6)
1 (1.7)
Completer
60 (31.6)
3 (1.7)
45 (31.5)
34 (27.4)
6 (3.2)
4 (2.2)
37 (19.4)
17 (9.6)
7 (4.7)
1 (0.8)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Non-completer
64 (45.4)
32 (34.4)
38 (34.9)
17 (36.2)
22 (15.6)
13 (15.5)
48 (35.5)
23 (27.1)
7 (6.6)
7 (12.5)
0 (0.0)
1 (5.6)
2 (6.9)
1 (7.7)
p
0.010
<0.001
0.570
0.264
<0.001
<0.001
0.002
<0.001
0.519
<0.001
n. a.
0.056
0.063
0.058
Pre-treated
55 (23.0)
21 (10.6)
51 (29.0)
42 (31.8)
19 (8.0)
14 (7.1)
51 (21.3)
26 (13.2)
4 (2.3)
4 (3.0)
0 (0.0)
1 (1.5)
1 (1.6)
1 (1.9)
Untreated
35 (72.9)
8 (20.5)
19 (43.2)
5 (20.0)
5 (10.4)
2 (6.3)
17 (36.2)
6 (17.7)
7 (14.9)
3 (10.7)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
p
<0.001
0.082
0.070
0.237
0.573
0.866
0.029
0.488
<00.001
0.071
n. a.
0.686
0.655
0.732
Buprenorphine
43 (26.9)
15 (11.0)
25 (22.7)
20 (24.4)
14 (8.8)
9 (6.6)
30 (18.6)
18 (13.2)
4 (3.5)
3 (3.4)
0 (0.0)
0 (0.0)
1 (3.0)
0 (0.0)
(Levo-)methadone
11 (15.3)
4 (6.9)
23 (37.7)
21 (42.9)
4 (5.5)
3 (5.3)
17 (23.6)
7 (12.3)
0 (0.0)
1 (2.3)
0 (0.0)
1 (3.2)
0 (0.0)
1 (3.9)
p
0.053
0.383
0.037
0.027
0.379
0.731
0.382
0.857
0.158
0.735
n. a.
0.271
0.362
0.313
Opiate craving (VAS)
Patients reported the highest craving at baseline and the highest decrease of craving
during treatment with buprenorphine-naloxone for opiates (32.3±33.2 vs. 7.2±17.3,
p<0.001). Non-completers (38.9±35.4 vs. 27.6±30.9 completers, p=0.003) and untreated
patients (46.4±37.9 vs. 25.7±29.7 pre-treated, p<0.001) reported a significantly higher
total score at baseline, but only non-completers reported a relatively high craving
score at the final assessment (24.7±32.5 vs. 4.2±10.5 completers, p<0.001). At the
end of the observation untreated patients did not differ from pre-treated patients
concerning craving for opiates. There was no difference found between buprenorphine
and (levo-)methadone patients at baseline and final assessment. Nevertheless the reduction
of craving for opiates was significant for all groups including non-completer.
Fresh needle marks
Physicians documented fresh needle marks for 13.5% at baseline, for slightly more
non-completers (17.3% vs. 10.8% completers, p=0.086) and significantly more untreated
patients (20.4% vs. 9.5% pre-treated, p=0.029). Most of these patients had a positive
urine drug screening for opioids (75.6%).
At the final assessment physicians reported fresh needle marks for n=10 patients,
all of them were non-completers, n=4 were pre-treated, n=2 untreated and n=4 were
switched from buprenorphine. Most of these patients had positive drug screenings for
opioids (n=7). Physicians reported no fresh needle marks for (levo-)methadone patients.
Discussion
The results of this non-interventional study underline the overall effectiveness of
opioid drug dependence treatment with the 4:1 combination buprenorphine-naloxone.
In line with findings in a previous naturalistic study in routine care [30 ] the 12-month retention rate of patients induced or switched to buprenorphine-naloxone
was 55.7–62.0% depending on previous maintenance treatment. These rates are also in
line with results on retention of patients receiving standard methadone treatment
[30 ]
[31 ]
[32 ]. No deaths occurred and the very low rate of adverse events emphasizes the high
safety profile of buprenorphine-naloxone. Significant improvements in almost all evaluated
domains during the 12-month observation period, irrespective of study completion and
previous maintenance treatment, verify the effectiveness of the medication found in
previous clinical trials [2 ]
[12 ]
[17 ]
[19 ]
[22 ]. As reported by Wittchen et al. 2008 [30 ] in their naturalistic study in 2 694 patients, the same proportion of patients (4.2%)
had achieved abstinence during the observational period. Since a certain period (e. g.,
5 years) of abstinence is required to reduce the risk of future relapse [3 ] we recommend a follow-up study to verify the status of patients with documented
regular end of treatment because of abstinence.
Compared to international findings on dosing of buprenorphine-naloxone between 16–24 mg/day
[33 ], patients observed in this non-interventional study received lower doses of 10 mg/day
on average, which decreased to an average of 8 mg/day at the end of the 12-month observation,
irrespective of study completion and previous maintenance treatment. Patients switched
from d/l-methadone or l-methadone received significantly higher doses of 11 mg/day
on average decreasing until end of study to slightly but non-significantly higher
doses of approximately 9 mg/day. Dosing is a critical aspect in the treatment and
retention of opioid dependent patients – it is important to alleviate the patient’s
cravings and withdrawal symptoms. The data of this non-interventional study reveal
a significant relation between study completion status and withdrawal symptoms as
well as opioid craving scores. Non-completers started with significantly higher subjective
opiate withdrawal symptoms and craving which was still significantly higher at the
time of their premature discontinuation of treatment with buprenorphine-naloxone.
According to the physicians there was no difference concerning objective opiate withdrawal
symptoms between non-completers and completers at baseline, but at the final assessment
they reported significantly higher objective withdrawal symptoms for non-completers.
Completers achieved a significant reduction of subjective opiate withdrawal during
the treatment with buprenorphine-naloxone, however the reduction of craving for opiates
was significant for all groups including non-completers compared to baseline.
Take-home prescription is an important factor for reintegration into social and occupational
life, because it enables the patient to start or stay in employment due to more flexibility
in daily routine. 11.9% of all eligible patients wanted to switch to buprenorphine-naloxone
for take-home prescription. At start of treatment with buprenorphine-naloxone a minority
of patients received take-home prescription (8.4%) and all of these were pre-treated
patients. At the end of the observation 25.1% of all observed patients received take-home
prescription. The decision for a take-home prescription is discretionary to the treating
physician in compliance with §5 (8) BtMVV (Controlled Substances Prescription Regulation).
The patient may receive a take-home prescription for up to 7 consecutive days if the
patient is in stable maintenance treatment, without relevant concomitant drug use
and use of other substances that interact with the maintenance drug and therefore
endanger his health [34 ].
Psychiatric comorbidities are very common in this patient population [35 ]. At baseline the scores of the SCL-90-R were relatively low with higher rates in
all scales for non-completers, untreated patients and (levo-)methadone patients. Apart
from non-completers all eligible patients achieved a significant reduction of psychiatric
distress at their final assessment. However non-completers did reach lower scores
(except for the scale interpersonal sensitivity) at their final assessment. These
results are in line with the findings shown by Lieb et al. 2010 [35 ]. Opioid dependent patients with high scores in psychiatric distress should receive
specific care with integrated treatment for both opioid dependence and psychiatric
disorder.
The scores of the standardized patient questionnaire SF-36 measuring the quality of
life in terms of general health, emotional and social functioning were relatively
low at baseline but increased significantly during treatment with buprenorphine-naloxone
for all scales. At baseline no difference between completers and non-completers was
found, but at the final assessment completers had significantly higher scores and
non-completers revealed no substantial improvement during treatment. These findings
suggest that the treatment with buprenorphine-naloxone improves the patient’s perception
of his emotional and social condition and his ability to reintegrate into a functioning
social life. Since non-completers obviously did not benefit in this domain there might
be other influencing factors, such as dosing, withdrawal and psychiatric comorbidity
that need to be explored in order to support special patient groups in the treatment
with buprenorphine-naloxone at an early stage.
The results are in line with an Italian longitudinal outpatient survey, which compared
the treatment of opioid dependence with buprenorphine-naloxone and methadone [32 ]. The retention rate was similar in both groups but significant improvements of social
life, educational level and concomitant drug use were found in patients treated with
buprenorphine-naloxone.
The non-interventional study with buprenorphine-naloxone provides a unique database
with comprehensive, reliable and valid data on opioid drug dependence treatment with
buprenorphine-naloxone in routine care. However the major limitation is the strict
observational nature of the study and the lack of a control group. Confounding factors,
which may occur during a non-interventional study, cannot be controlled in contrast
to clinical trials with exact regulations and complete treatment protocol. Thus these
uncontrolled confounding factors may influence treatment outcomes. All measures used
in this paper were of descriptive quality; effects and correlations need to be interpreted
with caution. Since this observational study was part of the Risk-Management-Plan
and based on a commitment to the European Medicine Agency (EMA) after market authorization
of the product buprenorphine-naloxone, no control group was planned and necessary.
Nevertheless this database with its broad range of variables, standardized assessments
and parameters describing the course and outcome of the treatment with buprenorphine-naloxone
from the physician’s and the patient’s perspective allows detailed analyses on safety,
somatic and psychiatric health as well as subjective and objective effects in reference
to special patient groups at different time points. This is the main advantage of
this non-interventional study in routine care.
In summary, the results indicate high acceptance and tolerance of the treatment accompanied
by significant improvements in psychiatric, somatic and social functioning. According
to these data buprenorphine-naloxone has an excellent safety profile also in comparison
to methadone with a low risk especially for serious intoxications [9 ]. There are increasing safety concerns for intoxications with opioid prescription
drugs, with no corresponding European data. Data from surveillance studies like this
may help to better estimate the safety risk associated with the use of opioid maintenance
treatment.
Although only pre-treated patients were the target study population some physicians
included a small group of untreated patients and they provided encouraging results.
The treatment with buprenorphine-naloxone was highly successful for patients without
any experience in maintenance treatment with direct transfer from street heroin use
to buprenorphine-naloxone treatment.
The characteristics of non-completers need to be analysed further to identify those
at risk for negative outcome. Analyses should focus on identifying ways to retain
such patients in treatment and heighten their chances for treatment success.
