Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the “Bernese method”

Abstract

Background:
Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use.

Cases:
We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms.

Discussion:
Overlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction.

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Substance Abuse and Rehabilitation 2016:7 99–105
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CASE SERIES
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/SAR.S109919
Use of microdoses for induction of
buprenorphine treatment with overlapping full
opioid agonist use: the Bernese method
Robert Hämmig1
Antje Kemter2
Johannes Strasser2
Ulrich von Bardeleben1
Barbara Gugger1
Marc Walter2
Kenneth M Dürsteler2
Marc Vogel2
1Division of Addiction, University
Psychiatric Services Bern, Bern,
Switzerland; 2Division of Substance
Use and Addictive Disorders,
University of Basel Psychiatric
Hospital, Basel, Switzerland
Background: Buprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment
of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate
withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore,
current guidelines and drug labels recommend leaving a sufficient time period since the last full
agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full
agonist therapies before administering buprenorphine. However, even with these precautions,
for many patients the induction of buprenorphine is a difficult experience, due to withdrawal
symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use.
Cases: We present two cases of successful initiation of buprenorphine treatment with the
Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began
buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, with-
drawal, and trauma reactivation symptoms during conventional induction. The second patient
was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone
during induction. Both patients tolerated the induction procedure well and reported only mild
withdrawal symptoms.
Discussion: Overlapping induction of buprenorphine maintenance treatment with full µ-opioid
receptor agonist use is feasible and may be associated with better tolerability and acceptability
in some patients compared to the conventional method of induction.
Keywords: subutex, suboxone, heroin, opiate, substitution
Introduction
Buprenorphine is a partial µ-opioid agonist and κ-opioid antagonist used for main-
tenance treatment of opioid dependence (OMT). It is as effective as methadone in
suppressing opioid use and is slightly less effective in retaining patients in treatment.1
Buprenorphine has potential advantages over methadone, including a lower risk of over-
dose due to the partial agonism and the associated “low ceiling effect” for respiratory
depression, fewer pharmaceutical interactions, and absence of corrected QT interval
(QTc)-prolongation.2–4 However, because buprenorphine replaces other opioids at the
µ-receptor due to its high affinity, the partial agonism at the µ-opioid receptor may
precipitate severe withdrawal in persons regularly using opioids.5 Therefore, guidelines
on buprenorphine induction in OMT and drug labels recommend consideration of the
nature of opioid dependence (ie, long- or short-acting opioid), its degree, and the time
since last opioid use:4,6,7 physicians should leave sufficient time between last use of opioid
agonist and buprenorphine. This time depends on the opioid used and ranges between
Correspondence: Marc Vogel
Division of Substance Use and Addictive
Disorders, University of Basel Psychiatric
Hospital, Wilhelm Klein-Strasse 27, 4012
Basel, Switzerland
Tel +41 61 325 5111
Fax +41 61 325 5583
Email Marc.Vogel@upkbs.ch
Journal name: Substance Abuse and Rehabilitation
Article Designation: CASE SERIES
Year: 2016
Volume: 7
Running head verso: Hämmig et al
Running head recto: Overlapping induction of buprenorphine with full opioid agonist use
DOI: http://dx.doi.org/10.2147/SAR.S109919
This article was published in the following Dove Press journal:
Substance Abuse and Rehabilitation
20 July 2016
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Hämmig et al
4 (heroin) and 36–48 hours (methadone). Moreover, waiting
for observable opioid withdrawal symptoms before starting
buprenorphine is recommended. A switch of the substitute
from methadone to buprenorphine requires prior tapering of
methadone to a daily dose of 30–40 mg.8
Clinical experience shows that despite these precautions,
the induction of buprenorphine can precipitate severe opioid
withdrawal. In addition to the discomfort, this may lead to
treatment dropout or relapse with full opioid agonists. Pre-
cipitated withdrawal and the complicated induction process
may result in differences between buprenorphine and metha-
done with regard to treatment retention in the first 2 weeks.9
Between 40% and 60% of buprenorphine-maintained
persons concomitantly use full µ-receptor agonists.10–12
According to patients’ accounts and experimental studies, this
use is not associated with opioid withdrawal but attenuated
subjective opioid effects such as euphoria.13 The attenuation
persists for some days after termination of buprenorphine
use. The likely explanation is the higher opioid receptor
binding capacity of buprenorphine. Other opioid agonists
and their active metabolites can replace only a small fraction
of buprenorphine at the receptor. Moreover, because of its
low dissociation constant, buprenorphine separates slowly
from the receptor once it is bound.14 The slow association/
dissociation kinetics allow for 72-hour dosing intervals in
buprenorphine treatment.4,15 Because of the high µ-opioid
receptor affinity, buprenorphine can replace a full µ-agonist
at the receptor while at the same time providing less µ-opioid
effects.16
Resnick et al17 showed that repetitive administration of
the µ-antagonist naloxone quickly leads to a maximum of
withdrawal symptoms that decline afterward despite contin-
ued naloxone application. This phenomenon was used in the
1980s in the development of rapid withdrawal procedures.18
Furthermore, it was shown that a very small dose of 0.2
mg buprenorphine intravenous (iv) did not produce opioid
withdrawal in methadone-maintained individuals.19
From this, we developed the following hypotheses: 1)
Repetitive administration of very small buprenorphine doses
with sufficient dosing intervals (eg, 12 hours) should not
precipitate opioid withdrawal. 2) Because of the long receptor
binding time, buprenorphine will accumulate at the receptor.
3) Over time, an increasing amount of a full µ-agonist will be
replaced by buprenorphine at the opioid receptor.
Hence, overlapping induction of buprenorphine with
ongoing use of street heroin or maintenance on high doses of a
full µ-agonist should be possible without precipitating severe
opioid withdrawal. We present two cases in which we tested
this procedure, termed the Bernese method. In both patients,
we used sublingual buprenorphine, as the buprenorphine/
naloxone combination is not available in Switzerland. We
first introduced this method in 2010, and described the initial
treatment of the first case in German.20 The second case has
never been published before. We have successfully applied
the Bernese method in a number of patients since. Clinical
treatment was conducted in agreement with the patients,
and both patients consented to the publication of their data
in anonymized form.
Case 1
The patient grew up in an unremarkable middle-class fam-
ily. At the age of 12, she was sexually abused and developed
post-traumatic stress disorder. At the age of 15, she began
using various substances (psilocybin, 3,4-methylenedioxy-
methamphetamine, cocaine, cannabis, and, sporadically,
heroin). At the age of 18, she experienced a major depressive
episode with a suicide attempt. She then started suffering
from bulimia, which remitted at age 23.
Preceding a job-related stay in Central America, she used
heroin for several weeks. During the stay, she was unable
to obtain heroin and began using crack-cocaine, quickly
developing a severe dependence. Back in Switzerland, she
successfully managed to stop crack-cocaine, but reinitiated
heroin use. After several months, she opted for buprenorphine
treatment but experienced the induction-associated symptoms
as very stressful.
She stabilized during treatment, tapered buprenorphine
and abstained from opioids for several months before initiating
sporadic use of heroin again. At the age of 30, when she entered
our outpatient treatment, she sniffed 3 g of street heroin daily.
Conventional induction
The patient was ordered to return in the morning. She had
then abstained from heroin for more than 8 hours and showed
distinct symptoms of withdrawal (rhinorrhea, mydriasis, and
stomach cramps).
Buprenorphine was started at 0.4 mg sublingually, and
the same dose was administered four times with an interval
of 30 minutes. Starting with the first and increasing with
each further administration, she felt worse and suffered from
diarrhea. She experienced trauma-related flashbacks and
showed severe anxiety and dissociative thinking. Her state
did not improve with two further doses of 8 mg buprenor-
phine. We then administered 50 mg of promazine po, which
brought some relief, and after 8 hours of surveillance she
had improved sufficiently to return home.

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Overlapping induction of buprenorphine with full opioid agonist use
Bernese method
After 2 weeks, the patient stopped taking buprenorphine and
reinitiated sniffed heroin use. A week later, she presented
herself again with the wish for buprenorphine treatment,
but was afraid of being unable to tolerate the induction pro-
cess and the related symptoms. We suggested overlapping
buprenorphine induction with the Bernese method (ie, start
with a low dose of 0.2 mg buprenorphine overlapping with
heroin use, small daily dose increases, and abrupt cessation
of heroin use at sufficient dose). Furthermore, we offered her
the support of a physician (via text message) to flexibly adapt
dosing. Buprenorphine dosing and use of street heroin were
noted (Table 1). The patient tolerated this induction process
much better than the conventional induction.
She was stable with 12 mg/d buprenorphine. Throughout
further treatment she stopped buprenorphine several times,
used heroin, and afterward reinitiated buprenorphine treat-
ment with the Bernese method. However, after these short
disruptions, she increased buprenorphine dosing more rap-
idly. She then developed a major depressive episode and was
started on 20 mg/d escitalopram and psychotherapy. With this
treatment, she stabilized further and abstained from heroin
for 2.5 years.
Because of the desire for complete abstinence, she then
wanted to stop buprenorphine and initiate naltrexone treatment
to reduce opioid craving. However, she was worried about the
first week after cessation of buprenorphine, where naltrexone
should not be administered according to the drug label.
Overlapping induction of a full antagonist
We assumed that naltrexone could be initiated analogous
to the overlapping induction of buprenorphine. Prelimi-
nary data suggest that very low naltrexone doses during
µ-agonist treatment may not be associated with reduced
analgesic efficacy.21 However, naltrexone tablets available
in Switzerland contain a rather large dose of 50 mg drug.
After tapering of buprenorphine to 2 mg/d, the patient
started with small amounts of naltrexone scratched off from
a tablet and increased the dose daily. She did not develop any
withdrawal symptoms or craving, stopped buprenorphine,
and increased naltrexone to 25 mg/d. After several months,
she stopped naltrexone and has since been abstinent for an
ongoing period of 3 years and 3 months.
Case 2
After using heroin for several years and unsuccessful
treatment attempts with methadone, the patient entered
heroin-assisted treatment (HAT) at the age of 49. In addition
to heroin dependence, he fulfilled International Classification
of Diseases-10 criteria for cocaine and tobacco dependence.
He suffered from mild chronic obstructive pulmonary disease,
chronic hepatitis C-infection, and recurrent thrombosis due to
groin injection. Furthermore, the patient had a long history
of substance-related crime and imprisonment. Throughout
6 years in HAT, he completely stopped using street heroin,
reduced cocaine use to once per month, and entered a job
rehabilitation program. At this point, he received 200 mg
diacetylmorphine (DAM; ie, pharmaceutical heroin) iv twice
daily, and 40 mg of methadone to avoid nighttime withdrawal
symptoms. Because he wanted to stop iv injections, iv DAM
was switched to oral tablets at the equivalent dose of 400 mg
twice daily. After another 2 months without using nonpre-
scribed opioids, the patient desired a less rigid therapeutic
setting (HAT entails twice daily medication dispensing 365
days per year). We suggested switching to buprenorphine.
Because of fears that the guideline-recommended reduction
of the full agonist dose prior to switching might lead to a
destabilization, we suggested induction with the Bernese
method.
Overlapping induction of buprenorphine
with maintenance on full µ-agonists
At first administration of buprenorphine, the patient had been
on a stable oral maintenance dose of 40 mg methadone and
800 mg DAM per day for 2 months. It is important to note
that we did not grant take-home dosages for DAM tablets,
but substituted these with methadone. The patient received
methadone instead of DAM when he could not attend on-site
dispensing. He completed the short opioid withdrawal scale
(SOWS) daily. The SOWS is a ten-item questionnaire rating
withdrawal symptoms on a scale of 0–3, yielding a maximum
score of 30.22 Another question on opiate craving answered
likewise was added. Furthermore, every third day the patient
Table 1 Buprenorphine dosing and use of street heroin in case 1
Day Buprenorphine (sl) Street heroin (sniffed)
1 0.2 mg 2.5 g
2 0.2 mg 2 g
30.8+2 mg 0.5 g
42+2.5 mg 1.5 g
52.5+2.5 mg 0.5 g
62.5+4 mg 0
74+4 mg 0
84+4 mg 0
98+4 mg 0
Abbreviation: sl, sublingual.

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Hämmig et al
completed visual analog scales related to general mental state
and feeling stressed, relaxed, and nervous.
We began with a dose of 0.2 mg buprenorphine sublin-
gually, which was well tolerated. The next day, the dose was
increased to 0.4 mg twice daily. We decided to dose twice
daily in the beginning as the effect of buprenorphine is
shorter at lower doses and switched to once-daily dosing at
2 mg/d. Buprenorphine was principally increased by 0.4 mg/
d up to a dose of 3.4 mg, then we increased the daily dose
by 20%–30%. The patient tolerated buprenorphine induction
very well but reported mild opioid withdrawal symptoms on
day 8 at 3 mg/d and day 11 at 4.8 mg/d (Table 2). At 6 mg/d
on day 14, the patient went on a 5-day vacation and was
switched to 180 mg/d methadone (as DAM tablets were not
available as take-home medication), while the buprenorphine
dose remained unchanged. During days 13–16, he reported
slightly stronger withdrawal symptoms, although they were
still mild to moderate (maximum score of 7 in the SOWS).
Days 15 and 16 were the only days during induction on which
he reported any opiate craving (moderate). Unfortunately, he
did not complete the SOWS on days 17–19 but retrospectively
reported a complete remission of withdrawal symptoms dur-
ing that time. When he returned 1 day later than planned on
day 19, he did not show signs of withdrawal. On day 22, we
increased the buprenorphine dose again. The patient did not
show any substantial withdrawal symptoms thereafter. One
day after reaching the target dose of buprenorphine 24 mg/d,
all full agonists were abruptly and completely stopped at day
29 without any symptoms of opioid withdrawal. The patient
has now been on buprenorphine treatment for an on-going
period of 7 months, abstaining from any additional substance
use. Figure 1 illustrates SOWS scores in relation to daily
doses of buprenorphine and combined full agonists. For the
latter, we calculated methadone equivalent daily doses by
using the following ratio: oral DAM:methadone 8:1.23
Discussion
The two case reports illustrate that buprenorphine main-
tenance can be induced by overlapping with street heroin
use or OMT with high-dosed full µ-agonists. Both patients
tolerated the induction well and experienced only very mild
opioid withdrawal and craving. Twice, the first patient had
experienced the conventional method of buprenorphine
induction (ie, induction after more than 4 hours since using
street heroin and in the presence of clear objective symptoms
of withdrawal) as very difficult. She reported substantially
fewer symptoms with the Bernese method.
While the duration until stable buprenorphine dosing may
be longer than with the conventional method, the Bernese
method of overlapping induction may have considerable
advantages. It may be helpful for patients fearing withdrawal
or experiencing severe symptoms during conventional induc-
tion. It may be associated with fewer and less severe opioid
withdrawal symptoms. Furthermore, it is no longer neces-
sary to wait for these before induction. In addition to the
discomfort, opioid withdrawal may lead to dropout during the
induction process. In fact, the slightly better treatment reten-
tion with methadone compared to buprenorphine seems to be
related to higher dropout rates during the first 2 weeks.9,24 In
our experience, some patients are deterred from buprenor-
phine treatment because they fear these symptoms. Moreover,
providers may be reluctant to use buprenorphine due to the
complex conventional induction method. With overlapping
induction, buprenorphine can be initiated directly, indepen-
dent of last opioid use and type of full agonist used. This is
particularly important considering the repeated cycling in
and out of treatment observed in OMT.25
The Bernese method may also be beneficial when a switch
to buprenorphine is desired for patients maintained on a full
µ-agonist such as methadone, slow-release oral morphine
sulfate, or DAM. With the conventional induction method,
tapering of the full µ-agonist, for example to 30–40 mg
methadone per day, is recommended before buprenorphine
is initiated.8 Furthermore, it is again necessary to wait for
objective signs of withdrawal.4 Both prerequisites do not
apply with the Bernese method: buprenorphine can be
increased gradually with overlapping use of the full agonist
maintenance dose. Once the target dose is reached, the full
agonists can be stopped abruptly. Hess et al26 have previously
described a method of switching from doses between 70
and 100 mg methadone, but used transdermal patches and
a quicker scheme of dose increases. In our clinical experi-
ence, this scheme can also lead to substantial withdrawal
symptoms. More research into these methods is necessary
to investigate tolerability and symptomatology.
Comparing both our cases, it is noteworthy that the dose
increase in case 2 was done slower and in smaller steps. This
cautious strategy was chosen for two reasons. First, the patient
was on high doses of full µ-agonists, likely increasing the
danger of precipitated withdrawal compared to patient 1 who
used street heroin containing an unknown, but most probably
lower, full µ-agonist dose. Second, as patient 2 had stabilized
well during treatment with full µ-agonists, we did not want
to jeopardize the improvements by inducing buprenorphine

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Overlapping induction of buprenorphine with full opioid agonist use
Table 2 Opioid doses, withdrawal symptoms, cravings, and mental state in case 2
Day BUP
(mg)
DAM
(mg)
MET
(mg)
Full
agonist
MEQDD
(mg)a
SOWS
score
Withdrawal symptoms
(SOWS)
CravingbStresscOverallcRelaxedcTensecRemarks
1 0.2 800 600 160 0 0
20.4+0.4 800 40 140 1 Mild feelings of coldness 0
30.8+0.4 800 40 140 0 0 5 84 74 15
41.2+0.4 800 40 140 0 0
5 2 800 40 140 0 0
6 2.4 400 80 130 0 0 15 64 57 44
7 2.8 800 40 140 0 0
8 3 800 40 140 3 Mild feelings of coldness, mild
runny eyes, mild yawning
0
9 3.4 800 40 140 1 Mild runny eyes 0 18 85 76 6
10 4 800 40 140 2 Mild feelings of coldness, mild
yawning
0
11 4.8 800 80 180 3 Mild feelings of coldness,
moderate yawning
0
12 6 800 60 160 0 0 5 78 76 4
13 6 800 40 140 1 Mild runny eyes 0
14 6 400 90 140 3 Mild feelings of coldness, mild
yawning, mild runny eyes
0 Morning: last
medication
dispensing
before
vacation
15 6 0 180 180 7 Moderate feelings of coldness,
mild runny eyes, mild aches
and pain, moderate sleeping
problems, mild yawning
2 35 80 81 24 Vacation
16 6 0 180 180 5 Mild feelings of coldness, mild
runny eyes, mild aches and pain,
moderate sleeping problems
2 Vacation
17 6 0 180 180 Missing Missing Vacation
18 6 0 180 180 Missing Missing 20 73 79 26 Vacation
19 6 0 80 80 Missing Missing Afternoon:
rst
medication
dispensing
after vacation
20 6 0 120 120 0 0
21 6 400 80 130 0 0 15 80 73 26
22 7.2 400 40 90 0 0
23 8.8 400 80 130 0 0
24 10.8 800 40 140 0 0 5 94 94 6
25 13.2 400 40 90 0 0
26 16 800 40 140 0 0
27 20 400 60 110 0 0 7 95 92 3
28 24 800 40 140 0 0
29 24 0 0 0 1 Mild yawning 0 Cessation of
full agonists,
diarrhea in
the morning
30 24 0 0 0 0 0 8 93 84 16
31 24 0 0 0 0 0
32 24 0 0 0 0 0
33 24 0 0 0 0 0 9 85 85 15
Notes: aFull agonist (DAM + MET) MEQDD (conversion ratio DAM:methadone 8:1). b0= none, 1= mild, 2= moderate, 3= severe. cScores from visual analogue scale (0–100).
Abbreviations: BUP, sublingual buprenorphine; DAM, oral diacetylmorphine tablets; MET, oral methadone; SOWS, short opioid withdrawal scale; MEQDD, methadone
equivalent daily dose.

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Hämmig et al
too rapidly. Taken together, our cases can be regarded as
representative of the wide spectrum of opioid-dependent
persons, from sniffers of street heroin on one hand to users
of high doses of full µ-agonists on the other.
Several questions remain open and need to be addressed
in systematic studies. The Bernese method should be directly
compared to conventional induction with randomized study
designs to determine whether it is generally associated with
better tolerability. Such studies could also investigate whether
there is an impact of the induction process on the outcome of
further OMT, in particular cycling in and out of treatment, or
whether there are subpopulations of patients for which a spe-
cific induction procedure is preferable. Other issues concern
the ideal starting dose for buprenorphine, the optimal dose
increase scheme, and whether this is influenced by blood levels
and type of full µ-agonist used. It is unclear whether there are
critical thresholds in buprenorphine dosing that may lead to
pharmacodynamic changes. Our second patient was kept on
a daily dose of 6 mg buprenorphine for 10 days, because we
did not want to increase the dose without medical supervision
during his vacation. He experienced the strongest, albeit still
mild, symptoms with buprenorphine doses of 3–6 mg.
Likewise, in pre-existing OMT, it is unknown which
buprenorphine dose allows cessation of the full µ-agonist
without producing opioid withdrawal. This dose is likely
determined by the dose of the full agonist used in OMT.
Future studies should collect data on blood levels of
buprenorphine and full agonists.
Our cases illustrate that overlapping induction of buprenor-
phine while being on full µ-agonists is feasible. We hope to
stimulate more research in this area, which will, ideally, lead to
a better tolerable, more patient-oriented induction of buprenor-
phine treatment, and diversification of opioids in OMT.
Author contributions
All authors contributed toward data analysis, drafting and
critically revising the paper and agree to be accountable for
all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
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