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

  • University of Basel Psychiatric Clinics
  • Dr. Robert Ltd
  • University Psychiatric Clinics (UPK) Basel

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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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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
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
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
This article was published in the following Dove Press journal:
Substance Abuse and Rehabilitation
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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
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.
Substance Abuse and Rehabilitation 2016:7 submit your manuscript |
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
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
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
Substance Abuse and Rehabilitation 2016:7 submit your manuscript |
Overlapping induction of buprenorphine with full opioid agonist use
Table 2 Opioid doses, withdrawal symptoms, cravings, and mental state in case 2
Withdrawal symptoms
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
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
11 4.8 800 80 180 3 Mild feelings of coldness,
moderate yawning
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
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:
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.
The authors report no conflicts of interest in this work.
1. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance
versus placebo or methadone maintenance for opioid dependence.
Cochrane Database Syst Rev. 2014;2:CD002207.
2. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence
and clinical relevance of corrected QT interval prolongation during
methadone and buprenorphine treatment: a mortality assessment study.
Addiction. 2009;104:993–999.
3. Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortal-
ity among clients of a state-wide opioid pharmacotherapy program
over 20 years: risk factors and lives saved. Drug Alcohol Depend.
4. Swiss Society of Addiction Medicine (SSAM). Clinical Recommenda-
tions for Substitution-assisted Treatment in Opioid Dependence 2012
[Medizinische Empfehlungen für substitutionsgestützte Behandlungen
(SGB) bei Opioidabhängigkeit 2012]. Mediscope AG, Zurich: Swiss
Society of Addiction Medicine; 2013. Available from: http://www.ssam.
ch/SSAM/sites/default/files/Empfehlungen SGB_2012_FINAL_05 03
2013.pdf. Accessed March 30, 2015.
5. Jasinski DR, Preston KL. Laboratory studies of buprenorphine in opioid
abusers. In: Cowan A, Lewis J, editors. Buprenorphine: Combatting
Drug Abuse with a Unique Opioid. New York, NY: Wiley-Liss, Inc.;
Figure 1 Daily buprenorphine dose (mg), full agonist dose (in MEQDD), and SOWS scores of case 2.
Abbreviations: MEQDD, methadone equivalent daily dose; SOWS, short opioid withdrawal scale.
30 25
Buprenorphine dose
Full opioid agonist dose
10 15
Time (days)
20 25 30
Buprenorphine dose (mg)
Full opioid agonist dose (mg MEQDD)
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6. FDA US Food and Drug Administration. Buprenorphine – Drug Label.
Silver Spring, MD: Food and Drug Administration; 2010. Available
Accessed November 21, 2015.
7. Center for Substance Abuse Treatment. Clinical Guidelines for the Use
of Buprenorphine in the Treatment of Opioid Addiction. Rockville, MD:
Substance Abuse and Mental Health Services Administration; 2004.
Available from:
lines.pdf. Accessed November 30, 2015.
8. Levin FR, Fischman MW, Connerney I, Foltin RW. A protocol to switch
high-dose, methadone-maintained subjects to buprenorphine. Am J
Addict. 1997;6:105–116.
9. Mattick RP, Ali R, White JM, O’Brien S, Wolk S, Danz C. Buprenor-
phine versus methadone maintenance therapy: a randomized
double-blind trial with 405 opioid-dependent patients. Addiction.
10. Pani PP, Maremmani I, Pirastu R, Tagliamonte A, Gessa GL. Buprenor-
phine: a controlled clinical trial in the treatment of opioid dependence.
Drug Alcohol Depend. 2000;60:39–50.
11. Petitjean S, Stohler R, Déglon JJ, et al. Double-blind randomized trial
of buprenorphine and methadone in opiate dependence. Drug Alcohol
Depend. 2001;62:97–104.
12. Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR.
Buprenorphine vs methadone maintenance treatment for concurrent
opioid dependence and cocaine abuse. Arch Gen Psychiatry. 1997;54:
13. Comer SD, Walker EA, Collins ED. Buprenorphine/naloxone reduces
the reinforcing and subjective effects of heroin in heroin-dependent
volunteers. Psychopharmacology (Berl). 2005;181:664–675.
14. Rothman R, Ni Q, Xu H. Buprenorphine: a review of the binding
literature. In: Cowan A, Lewis J, editors. Buprenorphine: Combatting
Drug Abuse with a Unique Opioid. New York, NY: Wiley-Liss, Inc.;
15. Bickel WK, Amass L, Crean JP, Badger GJ. Buprenorphine dosing every
1, 2, or 3 days in opioid-dependent patients. Psychopharmacology (Berl).
16. Walsh SL, June HL, Schuh KJ, Preston KL, Bigelow GE, Stitzer ML.
Effects of buprenorphine and methadone in methadone-maintained
subjects. Psychopharmacology (Berl). 1995;119:268–276.
17. Resnick RB, Kestenbaum RS, Washton A, Poole D. Naloxone-precip-
itated withdrawal: a method for rapid induction onto naltrexone. Clin
Pharmacol Ther. 1977;21:409–413.
18. Loimer N, Schmid RW, Presslich O, Lenz K. Continuous naloxone
administration suppresses opiate withdrawal symptoms in human opiate
addicts during detoxification treatment. J Psychiatr Res. 1989;23:81–86.
19. Mendelson J, Jones RT, Welm S, Brown J, Batki SL. Buprenorphine
and naloxone interactions in methadone maintenance patients. Biol
Psychiatry. 1997;41:1095–1101.
20. Hämmig R. Einleitung einer Substitutionsbehandlung mit Buprenor phin
unter vorübergehender Überlappung mit Heroinkonsum: ein neuer
Ansatz (“Berner Methode”). [Induction of a buprenorphine substitu-
tion treatment with temporary overlap of heroin use: a new approach
(“Bernese Method”)] Suchttherapie. 2010;11:129–132. German.
21. Meissner W, Leyendecker P, Mueller-Lissner S, et al. A randomised
controlled trial with prolonged-release oral oxycodone and naloxone to
prevent and reverse opioid-induced constipation. Eur J Pain. 2009;13:
22. Gossop M. The development of a Short Opiate Withdrawal Scale
(SOWS). Addict Behav. 1990;15:487–490.
23. Vogel M, Dürsteler-MacFarland KM, Walter M, et al. Prolonged use
of benzodiazepines is associated with childhood trauma in opioid-
maintained patients. Drug Alcohol Depend. 2011;119:93–98.
24. Lingford-Hughes A, Welch S, Peters L, Nutt D. BAP updated guidelines:
evidence-based guidelines for the pharmacological management of
substance abuse, harmful use, addiction and comorbidity: recommenda-
tions from BAP. J Psychopharmacol. 2012;26:899–952.
25. Nordt C, Vogel M, Dürsteler KM, Stohler R, Herdener M. A compre-
hensive model of treatment participation in chronic disease allowed
prediction of opioid substitution treatment participation in Zurich,
1992–2012. J Clin Epidemiol. 2015;68:1346–1354.
26. Hess M, Boesch L, Leisinger R, Stohler R. Transdermal buprenorphine
to switch patients from higher dose methadone to buprenorphine without
severe withdrawal symptoms. Am J Addict. 2011;20:480–481.
... A case report in Switzerland in 2016 explored the use and effectiveness of the Bernese method [14]. The Bernese method is the repetitively administering small buprenorphine doses at intervals of around 12 h [14]. ...
... A case report in Switzerland in 2016 explored the use and effectiveness of the Bernese method [14]. The Bernese method is the repetitively administering small buprenorphine doses at intervals of around 12 h [14]. This allows sufficient buprenorphine to gather at the mu receptor and, with a large enough accumulation, will be able to replace the full agonist at the receptor site [14]. ...
... The Bernese method is the repetitively administering small buprenorphine doses at intervals of around 12 h [14]. This allows sufficient buprenorphine to gather at the mu receptor and, with a large enough accumulation, will be able to replace the full agonist at the receptor site [14]. This process makes for the "overlapping induction of buprenorphine with ongoing use of street heroin or in patients on high doses of full mu agonist maintenance therapy" [14]. ...
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Purpose of Review Opioid use disorder (OUD) is a chronic disorder in which a person loses control over the use of opioids, develops a compulsive behavior, and defends the use despite knowing the negative consequences. There are numerous treatments for OUD, including buprenorphine. Since it is displacing a full agonist opioid, precipitated withdrawal can occur with standard inductions involving buprenorphine. Recent Findings Case reports have noted success with a low-dose initiation of buprenorphine, which is different from typical protocols, relatively limited by adverse effects when patients were recently administered full agonists. A cohort investigation studied the use of a transdermal patch as part of the protocol, which was fairly well tolerated. Summary While ongoing research is being conducted on this topic, recent case studies and smaller cohort studies have demonstrated the feasibility of a trial to treat OUD with low-dose initiation of buprenorphine.
... Newer buprenorphine dosing strategies, such as micro-induction and macro-induction, have emerged to curtail these risks. 23,24 This is an evolving area of MAR; newer low-threshold initiation strategies 25 (see "Low-threshold MOUD prescribing models, " in the text that follows) and evidence that supports micro-induction 26 might eliminate the practice of requiring active withdrawal for treatment. ...
Considering offering medical intervention for OUD to reduce mortality? It's essential to understand the clinical benefits, limitations, and regulation of available agents.
... Buprenorphine has a partial intrinsic activity but has a high affinity at the mu-opioid receptors. 6,7 Hence, if administered concomitantly with a full agonist, it potentially can displace the full agonist and cause a sudden, precipitated withdrawal. Traditional buprenorphine induction protocol requires full abstinence from opioid agonists for a period of 24 to 72 hours before initiation. ...
Background: Opioid overdose deaths in the U.S. continue to increase, largely due to the prevalence of fentanyl, a very powerful opioid, in the illicit drug supply. Buprenorphine treatment is effective for treating opioid use disorder, but it can be challenging for clinicians to introduce buprenorphine treatment to people who use fentanyl due to risks of precipitated withdrawal. Induction could be facilitated through a buprenorphine microdosing approach called "the Bernese method." Objective: In this commentary, we describe how federal laws inadvertently limit optimal use of the Bernese method and how federal laws could be reformed to facilitate use of the Bernese method. Results: The Bernese method requires patients to continue using the opioid of misuse (e.g., fentanyl) for seven to ten days while receiving very low doses of buprenorphine. Under federal law, the typical office-based buprenorphine prescriber can neither prescribe nor administer fentanyl short-term for buprenorphine induction purposes, essentially forcing patients to continue to temporarily obtain fentanyl via the illicit market. Conclusion: The federal government has already indicated its support for increasing buprenorphine access. We argue that the government should permit short-term dispensing of fentanyl to office-based patients undergoing buprenorphine induction.
Background: Buprenorphine microdosing ("low-dosing") allows for initiation of buprenorphine without requiring patients to endure withdrawal. Case studies suggest its favorable utility as an alternative to conventional buprenorphine induction. However, published regimens vary in duration, dosage forms used, and timing of full opioid agonist discontinuation. Methods: This cross-sectional survey study sought to determine how buprenorphine low-dosing is approached by medical institutions across the United States. The primary end point was characterization of inpatient buprenorphine low-dosing regimens. Situations and types of patients in which low-dosing is used and obstacles to institutional protocol development were also collected. An online survey was disseminated through professional pharmacy organizations and personal contacts. Responses were collected over 4 weeks. Results: Twenty-three unique protocols were collected from 25 institutions. Most protocols used buccal (8 protocols) or transdermal (8 protocols) buprenorphine as first doses before transitioning to sublingual buprenorphine. The most common starting doses were buprenorphine 20 μg/h transdermal, 150 μg buccal, and 0.5 mg sublingual. Patients unable to tolerate conventional buprenorphine induction or those who potentially used fentanyl nonmedically were most likely to be prescribed low-dosing. The most common obstacle to developing an internal low-dosing protocol was lack of existing consensus guidelines. Conclusions: Similar to published regimens, internal protocols are variable. Buccal first doses may be used more commonly in practice based on survey results, while transdermal first doses are more commonly reported in publications. More research is needed to determine whether differences in starting formulations impact safety and efficacy of buprenorphine low-dosing in the inpatient setting.
Introduction: Limited research examines buprenorphine-naloxone interest among adolescents and young adults (AYA). This longitudinal study examined factors associated with initial buprenorphine-naloxone interest and with the time to a positive change in buprenorphine-naloxone interest or enrollment, in addition to identifying reasons for buprenorphine-naloxone disinterest. Methods: The study derived data from a cohort of street-involved AYA in Vancouver, Canada, between December 2014 and June 2018. The analysis was restricted to AYA who reported weekly or daily illicit opioid use in the last six months but had not initiated buprenorphine-naloxone. The study examined factors associated with initial buprenorphine-naloxone interest using multivariable logistic regression, while multivariable Cox regression identified factors associated with the time to a positive change in buprenorphine-naloxone interest or actual enrollment over follow-up among AYA initially disinterested in buprenorphine-naloxone. Results: Of 281 participants who reported weekly illicit opioid use but were not on buprenorphine-naloxone, 52 (18.5 %) AYA reported initial buprenorphine-naloxone interest, while 68 (24.2 %) AYA who were initially disinterested in buprenorphine-naloxone reported interest or enrollment over follow-up. In multivariable logistic regression, initial interest was positively associated with older age (Adjusted Odds Ratio [AOR] = 1.09, 95 % Confidence Interval [CI]: 1.03-1.15), but negatively associated with self-reported Indigenous identity (AOR = 0.22, 95 % CI: 0.07-0.68). In multivariable Cox regression, recent detoxification program access (Adjusted Hazard Ratio [AHR] = 0.85, 95 % CI: 0.73-0.98) was positively associated with the time to a positive change in buprenorphine-naloxone interest or enrollment. Common reasons for buprenorphine-naloxone disinterest included not wanting opioid agonist treatments (OAT) (initial n = 67, follow-up n = 105); not wanting to experience precipitated withdrawal (initial n = 42, follow-up n = 54), being satisfied with or preferring other OAT (initial n = 33, follow-up n = 52), not knowing what buprenorphine-naloxone is (initial n = 27, follow-up n = 9), previous negative treatment experiences (initial n = 19, follow-up n = 20), and wanting to continue opioid use (initial n = 13, follow-up n = 9), among others. Conclusions: We documented persistent disinterest in buprenorphine-naloxone among AYA, though participants' reasons for disinterest provide insight into the potential benefits of expanding micro-dosing induction; ensuring treatment is culturally safe; and communicating changes in buprenorphine-naloxone programming to AYA. Nevertheless, a need remains to improve the continuum of harm reduction and treatment supports for AYA.
Objectives: Buprenorphine treatment significantly reduces morbidity and mortality for people with opioid use disorder. Fear of precipitated withdrawal remains a barrier to starting buprenorphine for patients who use synthetic opioids, particularly fentanyl. We aim to evaluate the development and implementation of a buprenorphine low dose overlap initiation (LDOI) protocol in an urban public health community pharmacy. Methods: We performed a retrospective chart review of patients with nonprescribed fentanyl use (N = 27) to examine clinical outcomes of a buprenorphine LDOI schedule, named the Howard Street Method, dispensed from a community pharmacy in San Francisco from January to December 2020. Results: Twenty-seven patients were prescribed the Howard Street Method. Twenty-six patients picked up the prescription and 14 completed the protocol. Of those who completed the protocol, 11 (79%) reported no symptoms of withdrawal and 3 (21%) reported mild symptoms. Four patients (29%) reported cessation of full opioid agonist use and 10 (71%) reported reduction in their use by the end of the protocol. At 30 days, 12 patients (86%) were retained in care and 10 (71%) continued buprenorphine. At 180 days, 6 patients (43%) were retained in care and 2 (14%) were still receiving buprenorphine treatment. Conclusions: We found that a LDOI blister-pack protocol based at a community pharmacy was a viable intervention for starting buprenorphine treatment and a promising alternative method for buprenorphine initiation in an underresourced, safety-net population of people using fentanyl.
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The British Association for Psychopharmacology guidelines for the treatment of substance abuse, harmful use, addiction and comorbidity with psychiatric disorders primarily focus on their pharmacological management. They are based explicitly on the available evidence and presented as recommendations to aid clinical decision making for practitioners alongside a detailed review of the evidence. A consensus meeting, involving experts in the treatment of these disorders, reviewed key areas and considered the strength of the evidence and clinical implications. The guidelines were drawn up after feedback from participants. The guidelines primarily cover the pharmacological management of withdrawal, short- and long-term substitution, maintenance of abstinence and prevention of complications, where appropriate, for substance abuse or harmful use or addiction as well management in pregnancy, comorbidity with psychiatric disorders and in younger and older people.
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.
Chronic diseases are often associated with cycling in and out of treatment. We used data of a large opioid substitution treatment case register to (1) identify associated factors and (2) integrate retention and readmission into a model of overall participation over subsequent treatment episodes of various groups. Data of all 9,407 patients undergoing 26,545 methadone or buprenorphine substitution treatment episodes between 1992 and 2012 in the canton of Zurich, Switzerland, were analyzed. We used extended survival analysis to estimate the duration of, and time between, treatment episodes, with the number of episodes, gender, nationality, administration route, age at onset of first regular heroin use, and provider type as independent variables. A similar analysis was applied to estimate overall participation (the probability of being in treatment at a given day after first entry independent of current number of treatment episode) and to test for group differences. The time between treatment episodes shortened with the increasing number of episodes. Retention slightly increased after the first episode and then shortened for later treatment episodes. Effect sizes were generally rather weak (odds ratio ≤1.47). Effects were usually equal for all episodes, and if changing, weakened for later episodes. The complex process of leaving and entering treatment as well as the daily probability of being in treatment independent of treatment episode can be predicted by comprehensible statistical models applied to patient-period data sets. Copyright © 2015 Elsevier Inc. All rights reserved.
In allen internationalen Empfehlungen zur Substitutionsbehandlung mit Buprenorphin findet sich der Hinweis, dass die Behandlung mit Buprenorphin frühestens 4 Stunden nach dem letzten Heroinkonsum und beim Vorhandensein von eindeutigen Entzugserscheinungen eingeleitet werden soll. Trotz dieser Vorsichtsmaßnahmen zeigen einige Patienten signifikante Entzugserscheinungen, die durch die antagonistischen Effekte von Buprenorphin ausgelöst werden. In der wissenschaftlichen Literatur finden sich 2 wichtige Befunde. Eine beträchtliche Zahl von Patienten unter Buprenorphin-Substitution konsumiert weiterhin Heroin ohne negative Effekte und der maximale Effekt von Antagonisten nimmt unter wiederholten kleinen Dosen ab. Aus diesen Gründen sollten wiederholte kleine Dosen von Buprenorphin, die im Verlauf gesteigert werden, bei Patienten, die weiter Heroin konsumieren, keine schweren Entzugssymptome auslösen. Gleichzeitig werden die Heroineffekte abgedämpft durch die Verdrängung der Opiate von den Rezeptoren durch Buprenorphin. Der Fall einer heroinabhängigen Frau mit PTSD, die bei der „traditionellen” Einleitung unter schweren Entzugssymptomen gelitten hatte (generelles Malaise, Diarrhoe, Flashbacks, Gedanken-Dissoziation) wird vorgestellt. Nach Absetzen der Buprenorphin-Behandlung und Heroinrückfall wollte sie die Behandlung erneut aufzunehmen, hatte aber große Angst davor. Ihr wurde deshalb die „Berner Methode” vorgeschlagen: • Beginn mit der Einnahme von 0,2 mg Buprenorphin bei vorerst noch nicht gestopptem Heroinkonsum (Überlappung) • allmähliche Steigerung der täglichen Buprenorphin Dosis • bei genügender Buprenorphin-Dosis Beendigung des Heroinkonsum ohne wesentliche Entzugssymptome Tatsächlich konnte die Patientin ihren Heroinkonsum am 6. Tag unter einer Dosis von 8 mg Buprenorphin abrupt beenden. Diese Einleitung der Behandlung konnte die Patientin mit wenig Belastung umsetzen.
This study compared the safety and efficacy of sublingual buprenorphine tablets with oral methadone in a population of opioid-dependent individuals in a double-blind, randomized, 6-week trial using a flexible dosing procedure. Fifty-eight patients seeking treatment for opioid dependence were recruited in three outpatient facilities and randomly assigned to substitution with buprenorphine or methadone. The retention rate was significantly better in the methadone maintained group (90 vs. 56%; P<0.001). Subjects completing the study in both the treatment groups had similar proportions of opioid positive urine samples (buprenorphine 62%; methadone 59%) and positive urine specimens, as well as mean heroin craving scores decreased significantly over time (P=0.035 and P<0.001). The proportion of cocaine-positive toxicology results did not differ between groups. At week six mean stabilization doses were 10.5 mg per day for the sublingual buprenorphine tablet, and 69.8 mg per day for methadone, respectively. Patient performance during maintenance was similar in both the groups. The high attrition rate in the buprenorphine group during the induction phase might reflect inadequate induction doses. Thus, buprenorphine is a viable alternative for methadone in short-term maintenance treatment for heroin dependence if treatment induction is done with adequate dosages.
The small size of previous studies of mortality in opioid dependent people has prevented an assessment of the extent to which elevated mortality risks are consistent across time, clinical and/or patient groups. The current study examines reductions in mortality related to treatment in an entire treatment population. Data from the New South Wales (NSW) Pharmaceutical Drugs of Addiction System, recording every "authority to dispense" methadone or buprenorphine as opioid replacement therapy, 1985-2006, was linked with data from the National Deaths Index, a record of all deaths in Australia. Crude mortality rates and standardized mortality ratios were calculated according to age, sex, calendar year, period in- or out-of-treatment, medication type, previous treatment exposure and cause of death. Mortality among 42,676 people entering opioid pharmacotherapy was elevated compared to age and sex peers. Drug overdose and trauma were the major contributors. Mortality was higher out of treatment, particularly during the first weeks, and it was elevated during induction onto methadone but not buprenorphine. Mortality during these risky periods changed across time and treatment episodes. Overall, mortality was similarly reduced (compared to out-of-treatment) whether patients were receiving methadone or buprenorphine. It was estimated that the program produced a 29% reduction in mortality across the entire cohort. Mortality among treatment-seeking opioid-dependent persons is dynamic across time, patient and treatment variables. The comparative reduction in mortality during buprenorphine induction may be offset by the increased risk of longer out-of-treatment time periods. Despite periods of elevated risk, this large-scale provision of pharmacotherapy is estimated to have resulted in significant reductions in mortality.
To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme. Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997-December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT. The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross-matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient-years in OMT. In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results <450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient-years. Only one death among 3850 OMT initiations occurred within the first month of treatment. Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient-years.
Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised, double-blinded study evaluated the analgesic efficacy of prolonged-release (PR) oral oxycodone when co-administered with PR oral naloxone, and its impact on opioid-induced constipation in patients with severe chronic pain. Another objective was to identify the optimal dose ratio of oxycodone and naloxone. A total of 202 patients with chronic pain (mainly non-cancer related, 2.5% of patients had cancer-related pain) under stable oral oxycodone therapy (40, 60 or 80 mg/day) were randomised to receive 10, 20, 40 mg/day naloxone or placebo. After a 4-week maintenance phase, patients received oxycodone only for 2 weeks. Pain intensity was evaluated using a numerical analogue scale and bowel function was assessed using the bowel function index. No loss of analgesic efficacy with naloxone was observed. Mean pain intensity scores on randomisation were comparable for placebo, 10mg, 20mg and 40 mg naloxone dose, and remained unchanged during treatment. Bowel function improved with increasing naloxone dose. Naloxone 20mg and 40 mg significantly improved bowel function at the end of the maintenance phase compared with placebo (p<0.05). Overall, the combination was well tolerated, with no unexpected adverse events. There was a trend towards an increased incidence of diarrhoea with higher doses of naloxone. The 2:1 oxycodone/naloxone ratio was identified as the most suitable for further development. Co-administration of PR oral naloxone and PR oral oxycodone is associated with a significant improvement in bowel function compared with PR oral oxycodone alone, with no reduction in the analgesic efficacy of oxycodone.