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Drug and Alcohol Dependence 58 (2000) 143 – 152
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Efficacy of daily and alternate-day dosing regimens with the
combination buprenorphine–naloxone tablet
Leslie Amass a,*, Jonathan B. Kamien b, Susan K. Mikulich a
a
Department of Psychiatry, Uni6ersity of Colorado School of Medicine, Vine Street Center, 1741 Vine Street, Den6er, CO 80206, USA
b
BioPsych Consulting, 360 Birch Street, Den6er, CO 80220, USA
Received 25 February 1999; received in revised form 1 July 1999; accepted 1 July 1999
Abstract
This study evaluated the efficacy of a combination tablet formulation of buprenorphine containing 8 mg of buprenorphine and
2 mg of naloxone for every other day treatment and whether increasing the daily maintenance dose was essential for maintaining
an efficacious alternate-day treatment. Twenty-six opioid-dependent outpatients completing a 16-day baseline entered a doubleblind, placebo-controlled, triple crossover trial. Twenty-one days of daily combination tablet administration were compared to
two different 21-day periods of alternate-day buprenorphine administration where subjects received either 8 or 16 mg of the
combination tablet every other day with placebo on the interposed day. Fifty-four percent (14/26) of subjects completed the study,
but only two subjects dropped out during the 16-mg alternate-day condition. Rates of medication compliance, illicit opioid use
and subject- and observer-rated measures of opioid effects did not distinguish daily from alternate-day treatments in subjects
completing the study. However, pupillary diameter was significantly increased during 8-mg alternate-day compared to the 8-mg
daily or 16-mg alternate-day treatment. These data replicate earlier findings describing the acceptability of alternate-day
buprenorphine treatment using multiples of the daily maintenance dose and extend these findings by establishing the clinical
efficacy of daily and alternate-day dosing regimens with the combination buprenorphine– naloxone tablet. This study also suggests
slightly improved outcomes during alternate-day treatment using multiples of the daily dose. © 2000 Elsevier Science Ireland Ltd.
All rights reserved.
Keywords: Alternate-day dosing; Buprenorphine; Buprenorphine– naloxone; Heroin treatment; Human; Methadone treatment
1. Introduction
Buprenorphine is a high affinity, partial m-opioid
agonist pending FDA approval as a pharmacotherapy
for opioid dependence (see Bickel and Amass, 1995).
Buprenorphine’s utility as a pharmacotherapy results
from a unique profile of effects related to its partial
agonist character and slow dissociation from m-opioid
receptors. Buprenorphine’s ceiling on agonist activity
decreases the danger of overdose, may limit its abuse
liability (Walsh et al., 1994, 1995) and confers low
toxicity even at high intravenous doses (Lange et al.,
1990; Huestis et al., 1999), increasing the dose range
over which it may be safely administered. Buprenor* Corresponding author. Tel.: +1-303-315-0029; fax: + 1-303-3883218.
E-mail address: [email protected] (L. Amass)
phine can also produce sufficient tolerance to block the
effects of exogenously administered opioids (Bickel et
al., 1988a; Rosen et al., 1994; Walsh et al., 1995),
suggesting that it may help reduce illicit opioid use.
Finally, buprenorphine’s slow dissociation from m-opioid receptors (Rance and Dickens, 1978) not only results in a long duration of action but also diminishes
withdrawal signs and symptoms upon its discontinuation (Jasinski et al., 1978; Seow et al., 1986; Fudala et
al., 1990; Amass et al., 1994b; Bickel et al., 1995, 1997;
Cheskin et al., 1994), making it particularly useful for
opioid detoxification.
Controlled clinical evaluations confirm buprenorphine’s utility for opioid dependence treatment. Studies
comparing the relative efficacy of a sublingual
buprenorphine solution to oral methadone have reported comparable retention and abstinence rates for
up to 25 weeks of maintenance and detoxification treat-
0376-8716/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 6 - 8 7 1 6 ( 9 9 ) 0 0 0 7 4 - 5
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L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
ment (Bickel et al., 1988b; Johnson et al., 1992; Strain
et al., 1994). Additionally, buprenorphine is a safe,
effective candidate for long term maintenance (Ling et
al., 1996), compares favorably to other full-agonist
alternatives such as levomethadyl acetate hydrochloride
(LAAM; Chutuape et al., 1999), and produces significant and substantial improvements over time in psychosocial functioning (Strain et al., 1996).
An important feature of buprenorphine is that, unlike methadone and like LAAM, it can be used safely
on an alternate-day or thrice-weekly basis without the
use of take-home medication. However, like methadone
and unlike LAAM, buprenorphine can also be administered safely on a daily basis. Although alternate-day
dosing regimens have been examined in several placebocontrolled studies with buprenorphine solution formulations, the most effective doses to use when
administering buprenorphine on a less than daily basis
have not yet been resolved (Fudala et al., 1990; Amass
et al., 1994a, 1998; Johnson et al., 1995; Bickel et al.,
1999). Some studies have given an 8-mg dose of
buprenorphine every 48 h (Fudala et al., 1990; Johnson
et al., 1995) while others have increased the dose to 16
mg when dosing every other day (Amass et al., 1994a,
1998; Bickel et al., 1999). Subjects receiving 8 mg of
buprenorphine every other day have reported increased
withdrawal scores relative to subjects receiving 8 mg
every day (Fudala et al., 1990) and their treatment
outcomes have tended to be slightly worse, even though
these latter effects were not statistically significant
(Johnson et al., 1995). Using multiples of the daily dose
when administering buprenorphine every other day has
resulted in minimal reports of withdrawal relative to
daily dosing, an improved therapeutic profile (Amass et
al., 1994a, 1998) and is preferred by subjects to daily
dosing even when evaluated under open-label conditions (Amass et al., 1998). Multiplying the daily dose
when dosing less than daily is feasible because the
ceiling on buprenorphine’s agonist activity renders high
dose therapy safe and does not interfere with patient
management (Amass et al., 1993; Walsh et al., 1994,
1995). Moreover, since plasma concentrations of
buprenorphine and its metabolites increase proportionately as a function of dose following single dose administration (Walsh et al., 1994), multiplying the daily dose
can also maintain buprenorphine blood levels that are
comparable to those seen with daily dosing using a
lower dose. Thus, while increasing the daily dose of
buprenorphine appears to improve the clinical response
to alternate-day dosing, finding optimal doses for alternate-day dosing awaits more research.
Treatment with buprenorphine in the USA will employ a sublingual combination tablet containing
buprenorphine and naloxone in a 4:1 ratio (Chiang and
Hawks, 1994; Chiang et al., 1996a,b). Combination
tablet dosages will be 8 mg of buprenorphine and 2 mg
of naloxone, and 2 mg of buprenorphine and 0.5 mg of
naloxone, respectively. The combination tablet was developed to help mitigate potential diversion and abuse
of buprenorphine once it becomes available for widespread clinical use and is expected to be particularly
useful sublingually because of the different parenteral
to sublingual potencies of buprenorphine and naloxone.
While buprenorphine has an approximately 2:1 parenteral to sublingual potency ratio (McQuay et al.,
1986), studies with opioid-dependent subjects indicate a
parenteral to sublingual potency ratio up to 20:1 for
naloxone (Preston et al., 1990). A sublingual naloxone
dose up to five times greater than the intravenous dose
that reverses toxic opioid overdose can be administered
safely to opioid abusers without precipitating withdrawal (Preston et al., 1990). Thus, this combination
tablet may permit buprenorphine’s agonist effects to be
expressed when administered sublingually, in essence,
permitting the combination tablet to behave like
buprenorphine alone, while precipitating withdrawal if
administered
parenterally
by
opioid-dependent
individuals.
Less than daily dosing strategies have not been evaluated using the buprenorphine –naloxone combination
tablet and no studies have been published in which the
two different alternate-day dosing strategies noted
above have been directly compared to each other and
to daily dosing. The purpose of the present study was
to establish the clinical efficacy of alternate-day
buprenorphine treatment using the combination
buprenorphine –naloxone tablet and determine whether
using multiples of the daily dose during alternate-day
dosing was essential for providing an efficacious alternate-day treatment. Daily dosing with the combination
tablet was compared to alternate-day combination
tablet dosing during which either the daily dose or a
multiple of the daily dose was dispensed every other
day.
2. Methods
2.1. Subjects
Forty-seven opioid-dependent subjects (33 male, 14
female) participated in an 11-week outpatient study.
Subjects were recruited through newspaper and poster
advertisements and referred from local treatment programs. To be included in the study, subjects had to be
at least 18 years old, in good health, and meet DSM-IV
criteria for opioid dependence and FDA criteria for
methadone treatment [i.e. a history of opioid dependence and either significant current opioid use (i.e.
opioid-positive urines) or signs of opioid withdrawal
(i.e. gooseflesh, sweating, lacrimation, excessive yawning, etc.)]. Eligibility was determined via a comprehen-
L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
sive intake interview conducted in a 2 – 3-h session prior
to admission.
The interview included online administration of computerized versions of the psychoactive substance abuse
disorder sections of the DSM-IV Criteria Checklist
(modified from Hudziak et al., 1993) and the fifth
edition of the Addiction Severity Index (McLellan et
al., 1985). Additional questionnaires were also completed to provide information about demographics and
drug history. Health status was determined by medical
history, physical exam and laboratory evaluation (including complete blood count, clinical chemistry profiles and urinalyses). Exclusion criteria included evidence
of active psychosis, manic-depressive illness, organic
psychiatric disorders or serious medical (e.g. liver or
cardiovascular disease) illness. Co-dependence on other
drugs (e.g. cocaine, ethanol or sedative-hypnotics) did
not exclude individuals from participation.
The study was approved by the Colorado Multiple
Institution Review Board for human research. Subjects
provided written, informed consent after receiving a full
explanation of the procedures prior to their inclusion in
the study. Participants were required to pay a fee
averaging $60/month to help support clinic services; no
subjects were discharged due to non-payment of fees.
Subjects’ mean age was 42.4 years (range 22–64).
Subjects reported using opioids regularly for an average
of 16.5 years (range 1 – 45) and spending $386.49 (range
$105 –1750) per week on opioids. Thirty-eight subjects
reported primarily intravenous, seven reported primarily intranasal and two reported primarily intramuscular
opioid use. Forty subjects reported having received
methadone treatment previously. Eleven subjects transferred from a methadone maintenance program directly
into this study. Weekly pregnancy tests (urine hCG,
Abbott Laboratories) for the 14 female subjects were
negative throughout the study.
2.2. Buprenorphine induction and stabilization
A 2-day, rapid induction procedure was used in
accordance with published guidelines for transitioning
patients onto buprenorphine (Bickel and Amass, 1995).
On the first day of participation, the first 29 subjects
enrolled in the study received two combination tablets
that each contained 2 mg of buprenorphine and 0.5 mg
naloxone, comprising a total dose of 4 mg of buprenorphine and 1 mg of naloxone. On the second day of
participation, these subjects received one tablet containing 8 mg of buprenorphine and 2 mg of naloxone.
Following complaints of withdrawal symptoms by
seven (24%) of the 29 subjects on the second day of
participation, the induction procedure was changed so
that the next 18 subjects were induced with buprenorphine alone rather than the combination tablet. On the
first day of participation, these latter 18 subjects re-
145
ceived two tablets that each contained 2 mg of
buprenorphine, comprising a total dose of 4 mg
buprenorphine. On the second day of participation,
these 18 subjects received one tablet containing 8 mg of
buprenorphine. Only two (11%) of the 18 subjects
inducted with buprenorphine alone complained of withdrawal symptoms on the second day of treatment.
Following buprenorphine induction, subjects received
one placebo tablet and one combination tablet containing 8 mg of buprenorphine and 2 mg of naloxone each
day for the next 14 days (days 3–16) to establish a
treatment baseline. The purpose of this baseline was (1)
to stabilize subjects on a 24-h dosing schedule of the
buprenorphine –naloxone tablet and (2) to allow a period during which early treatment dropouts could be
identified and culled from the final target study sample
of at least 24 participants as determined by a prior
power analysis. On day 2, subjects were told ‘‘This is
your maintenance dose’’ by the dispensing nurse. On all
subsequent days, subjects were not instructed regarding
what doses they were receiving.
2.3. Medication administration
Placebo, buprenorphine-alone and buprenorphine
combination tablets were manufactured by Reckitt and
Colman Products (Hull, UK) and supplied through the
National Institute on Drug Abuse and Research Triangle Institute. Active tablets were flavored, white, flat
and oval-shaped with a beveled edge; placebo tablets
were matched in flavor, color, shape and size. Dosing
conditions were double-blind and doses were masked
for taste with a 1-ml sublingual flavor solution of Bitrex
granules (6 mg/ml; Macfarlan-Smith Ltd., Edinburgh,
UK) and peppermint spirits (Amass et al., 1994a, 1998).
Subjects swished the flavor solution in their mouth for
1 min and discarded it into a cup before receiving
medication each day. The dispensing nurse gave the
day’s tablet(s) to the subject in a plastic cup and
instructed the subject to hold the tablet(s) under the
tongue until dissolved.
2.4. Study design
Beginning on day 17, subjects received in randomized
order each of three, 21-day dosing conditions: 8 mg/24
h, 8 mg/48 h and 16 mg/48 h. Subjects were instructed
before the study that they would receive medication in
each of three ways, but would not be told when dosing
conditions changed. For ‘24-h dosing’, subjects were
told they would receive their daily dose each day. For
‘48-h ‘‘single’’ dosing’, subjects were told they would
receive their daily dose (i.e. a single dose) every other
day with inactive placebo (blank) doses on the other
days. For ‘48-h ‘‘double’’ dosing’, subjects were told
they would receive twice their daily dose (i.e. a double
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L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
dose) every other day with placebo (blank) doses on the
other days. Every subject was scheduled to experience
each of the three dosing schedules according to one of
six possible sequences. Subjects were randomly assigned
to one of these dosing schedule sequences, and the
order in which the dosing schedules were received was
balanced across subjects.
the study. Additionally, subjects could also participate
in weekly group counseling sessions. Therapy sessions
focussed primarily on helping subjects make lifestyle
changes in the areas of their drug use, employment,
family interactions, and social/recreational activities.
Subjects also received AIDS education.
2.7. Subject- and obser6er-rated measures
2.5. General procedures
Subjects were compensated for their study participation according to a contingent compensation schedule
designed to reinforce opioid abstinence and clinic attendance. Subjects received $2 for each opioid-negative
sample provided and $2 each day they attended the
clinic (defined as taking their scheduled dose of medication and completing any questionnaires). Further, if
subjects provided three opioid-negative urine samples
and attended all 7 days during any given treatment
week, they received a bonus of $5. Thus, subjects could
be compensated up to $25 per week and could earn a
maximum of $275 for completing the 11-week study.
Subjects who did not complete the study for any
reason were offered detoxification with buprenorphine,
transfer into the methadone or LAAM maintenance
programs within our service, or referral to another local
treatment facility. Buprenorphine detoxification was accomplished by decreasing the subject’s buprenorphine
dose by 2 mg a week until a zero dose was reached.
Subjects were withdrawn from the study and offered
alternative treatment if they failed to take their medication on three consecutive days and/or failed to provide
urine samples on five consecutive occasions.
Urine samples were collected thrice weekly (Mondays, Wednesdays and Fridays) before medication administration under observation and analyzed for the
presence of opioids using the enzyme multiplied immunoassay technique (Behring Corporation, San Jose,
CA). Samples were also analyzed for the presence of
cocaine metabolites, amphetamines, benzodiazepines,
barbiturates and cannabinoids on one randomly chosen
day per week. Cutoff calibration concentrations of 300
ng/ml were used for tests of opioid and cocaine
metabolites, 200 ng/ml for benzodiazepines and barbiturates, 50 ng/ml for cannabinoids and 1000 ng/ml for
amphetamines. Missed urine samples were considered
drug-positive for the purposes of data analysis. Breath
alcohol samples were collected on urine testing days as
part of routine clinical procedure and subjects were not
permitted to attend the clinic intoxicated.
2.6. Counseling
Subjects received individual, manualized behavioral
counseling sessions (L. Amass, unpublished) with a
trained therapist every other week for the duration of
Subject- and observer-rated measurements were collected every day prior to medication administration
using a Macintosh Powerbook 520 computer (Apple
Computer, Inc., Cupertino, CA) running custom-designed data acquisition software (BioPsych Consulting,
Denver, CO). Subjects completed an adjective rating
scale (Bickel et al., 1988a,b), six visual analog scales
(VAS), the Addiction Research Center Inventory
(ARCI) short form (Martin et al., 1971; Jasinski, 1977)
and a dose identification questionnaire (Amass et al.,
1994a, 1998). Subjects were instructed to respond to
these questions according to their experience over the
past 24 h. The adjective rating scale was comprised of
16 signs and symptoms of opioid withdrawal and 16
typical opioid agonist effects. Subjects rated themselves
on a scale ranging from 0 (none) to 9 (severe) (maximum cumulative score=144). The items in the opioid
withdrawal scale were muscle cramps, depressed or sad,
painful joints, excessive yawning, hot or cold flashes,
trouble getting to sleep, sick to stomach, irritable,
runny nose, poor appetite, weak knees, excessive sneezing, tense and jittery, watery eyes, abdominal cramps
and fitful sleep. The items in the opioid agonist effects
scale were drug effect, loaded or high, rush, flushing,
excessive sweating, nodding, dry mouth, turning of
stomach, itchy skin, relaxed, coasting or spaced out,
talkative, pleasant sickness, drive, nervousness and
drunken. The VAS items were: ‘‘How HIGH have you
been?’’, ‘‘Have you felt any DRUG EFFECT at all?’’,
‘‘Have you felt any GOOD drug effects?’’, ‘‘Have you
felt any BAD drug effects?’’, ‘‘Have you felt any
WITHDRAWAL SICKNESS?’’ and ‘‘How much did
you LIKE the drug effect?’’. Subjects positioned a
cursor on the computer screen and clicked along a
100-unit line, anchored at each end by ‘Not at all’ and
‘Extremely’. The ARCI short form consisted of 49
true/false items and contained five major subscales:
MBG, PCAG, LSD, and BG and A, an index in
opioid-abusing subjects of euphoria, sedation, dysphoria and stimulation, respectively. For the dose identification questionnaire, subjects responded to the
question, ‘‘What do you think you received for your
medication yesterday?’’ by choosing ‘‘Placebo (no
dose)’’, ‘‘Single dose of buprenorphine’’ or ‘‘Double
dose of buprenorphine’’.
Nursing staff blind to the treatment conditions completed an observer rating inventory on which they rated
L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
147
the subjects on a scale of 0 (not at all) to 9 (severe) on
seven signs of opioid withdrawal (tearing eyes, runny
nose, perspiration, gooseflesh, yawning, restlessness,
tremor; maximum cumulative score=63) and five signs
of opioid effects (skin itching, vomiting, sedation, nodding, soap-boxing and rapping; maximum cumulative
score =45). This observer-rating scale, based on Addiction Research Center agonist and withdrawal scales
(Himmelsbach, 1939; Jasinski et al., 1978), has been
used previously in similar studies of alternate-day dosing (Amass et al., 1994a, 1998; Bickel et al., 1999).
within each treatment condition. These latter analyses
were done to elucidate any potential differences between active drug and placebo days during alternateday dosing (or between odd and even days during daily
dosing).
Analyses were conducted using SAS (SAS Institute
Inc., 1996) statistical software. All tests were two-tailed
and statistical significance was specified at a= 0.05.
2.8. Pupil measurements
3.1. Buprenorphine induction
Pupil diameter was determined daily before medication administration. Photographs were taken of one of
the subject’s eyes with a Polaroid close-up camera at
2 × magnification at 1 foot-candle of ambient illumination (Amass et al., 1994a; Bickel et al., 1999).
Seven (24%) of the 29 subjects inducted with combination products complained of withdrawal symptoms
sufficient to warrant notation by medical staff on the
second day of participation. The symptoms consisted of
prototypic signs of opioid withdrawal including sweating, runny nose, chills and vomiting. By comparison,
only two (11%) of the 18 subjects inducted with
buprenorphine alone products complained of withdrawal symptoms on the second day of treatment.
Of the 29 subjects inducted with combination tablets,
six subjects (21%) had transferred into the study from
methadone-maintenance programs. The average methadone dose at the time of transfer onto buprenorphine
was 50 mg (range 35–60). Of the seven subjects who
had reactions following combination tablet induction,
four (57%) were methadone-maintenance transfers receiving an average methadone maintenance dose of 48
mg (range 35–60) at the time of buprenorphine
induction.
Of the 18 subjects inducted with buprenorphine alone
tablets, three subjects (17%) had transferred into the
study from methadone-maintenance programs. The average methadone dose at the time of transfer onto
buprenorphine was 39 mg (range 30–44). The two
subjects who had reactions following induction with
buprenorphine alone products were both illicit users of
heroin and did not transfer into the study from a
methadone-maintenance program.
2.9. Data analysis
The study sample was classified into three groups for
the purposes of data analyses: ‘dropouts’ (n = 21) were
defined as those subjects who left treatment sometime
during the 16-day baseline period; ‘non-completers’
(n= 12) were defined as those subjects who completed
the baseline period but left the study at some point
during exposure to the three 21-day treatment conditions; and ‘completers’ (n =14) were defined as those
subjects who completed the entire study.
Analyses of variance (ANOVAs) were used to compare dropouts, non-completers and completers on selected intake measures (e.g. ASI composite scores,
number of DSM-IV Substance Dependence or Abuse
diagnoses, age and years of regular opioid use) to
determine if any of these characteristics distinguished
these groups from one another. Similarly, repeated
measures ANOVAs were used to compare non-completers and completers on average baseline measures of
subject- and observer-rated effects to determine if baseline responding could predict early treatment termination. Wilcoxon rank sum tests, appropriate for
comparing two groups with non-normally distributed
data, compared differences in the mean number of
drug-positive urines obtained during baseline for the
non-completer and completer groups.
Finally, data from the 14 completers were used to
compare the efficacy of the three 21-day treatment
conditions. Each dependent variable was reduced to an
average (e.g. self-reports, pupil diameter) or sum (e.g.
positive/missed urines, medication compliance) across
each treatment condition. Repeated measures ANOVA
were then performed with the subject effect treated as
random. Similar analyses were conducted to evaluate
day-to-day fluctuations in the dependent variables
3. Results
3.2. Treatment retention and post-study status
Forty-five percent of the subjects (21/47) dropped out
during the treatment baseline. Six of these subjects
dropped out following the first or second day, six did so
following the fourth, sixth or seventh day and the
remainder dropped out after 8–13 days. Eight of these
subjects dropped out abruptly and did not provide a
reason for leaving; two subjects left due to difficulty
adjusting to the medication; two subjects left because
their friend discontinued the study; one subject left due
to administrative problems at the clinic; and two subjects left due to inability to commute to the clinic each
148
L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
day. Four of these subjects later returned to participate
in an efficacy evaluation of buprenorphine –naloxone and methadone (Amass et al., 2000a); one transferred to methadone maintenance treatment at
another facility; and one who had been in the present
study for only a few days later returned to participate
in another laboratory study at the center (Amass et al.,
2000b).
Fifty-five percent of the subjects (26/47) initiated at
least one of the three treatment conditions. Of these 26
subjects, 54% (14/26) completed the study. Of the 12
subjects who did not complete the three treatment
conditions (i.e. non-completers), five dropped out during the 8 mg/24 h condition, five dropped out during
the 8 mg/48 h condition and two dropped out during
the 16 mg/48 h condition. The condition under which
the non-completer subjects left the study did not vary
as a function of the order to which they were exposed
to the treatment conditions.
Of the 12 non-completers, four left treatment
abruptly and did not provide a reason for leaving,
seven later returned to participate in an efficacy evaluation of buprenorphine – naloxone and methadone
(Amass et al., 2000a), and one transferred to methadone maintenance treatment at another facility.
Of the 14 completers, 12 subjects transferred directly
into another an efficacy evaluation of buprenorphine –
naloxone and methadone (Amass et al., 2000a) and two
requested detoxification with buprenorphine – naloxone.
One of these two subjects completed detoxification and
continued on naltrexone; the other subject left treatment during the detoxification without providing a
reason.
3.3. Intake differences amongst dropouts, completers
and non-completers
Subjects who dropped out of the study during the
baseline condition had significantly higher Addiction
Severity Index (ASI) Drug Problem composite scores
than those who completed the study (t = 2.53, P =0.01;
data not shown). Dropout’s ASI scores did not differ
from those obtained from non-completers. No other
significant differences were observed on intake variables
among these three groups of subjects.
3.4. Baseline differences amongst completers and
non-completers
Completers differed significantly from non-completers on several baseline measures of self-reported
drug effects as well as on the degree of illicit opioid use
during baseline. Mean baseline subject-reported opioid
withdrawal effect ratings (F =7.87, P = 0.01), opioid
agonist effect ratings (F =7.84, P = 0.01), and visual
analog scale ratings of ‘bad drug effects’ (F=6.90,
P= 0.01), ‘withdrawal sickness’ (F= 7.90, P=0.01)
and ‘drug effect’ (F= 4.57, P = 0.04) were significantly
lower in completers compared to non-completers (Fig.
1). Moreover, completers submitted significantly fewer
opioid-positive urine samples than non-completers during the baseline (z= 2.22, P = 0.03; Fig. 2).
3.5. Condition effects: treatment completer sample
3.5.1. Medication compliance
There were no differences in compliance across the
three dosing conditions. Subjects were medicated on
86%, 84% and 88% of days during the 8 mg daily, 8 mg
and 16 mg alternate-day conditions, respectively.
3.5.2. Illicit drug use
The percentages of drug-positive urine samples obtained from subjects who completed the study are
shown in Table 1. There were no significant differences
in the number of drug-positive samples obtained across
conditions.
3.5.3. Subject- and obser6er-rated measures
Subject- and observer-rated measures did not differ
across the three treatment conditions. There were also
no significant day-to-day fluctuations (i.e. odd versus
even day differences) within each treatment condition
on any of these measures.
3.5.4. Pupil diameter
Average pupil diameter differed significantly across
each 21-day treatment condition (F= 4.02, P =0.03;
Fig. 3). Mean pupil diameter was significantly larger
during the 8 mg/48 h condition (4.190.25) than it was
during the 16 mg/48 h condition (3.8 9 0.25; t= −
2.79, P= 0.01) and there was a trend toward larger
pupil diameter during the 8 mg/48 h condition as
compared to the 8 mg/24 h condition (3.9 9 0.25; t=
−1.82, P= 0.08). There were no significant day-to-day
fluctuations within each treatment condition in pupil
diameter.
3.5.5. Dose identifications
There were no significant differences across conditions in the percentage of time subjects identified the
medication as a ‘Single dose’, a ‘Double dose’ or a
‘Placebo dose’ (data not shown). When data were collapsed across all three conditions, subjects identified
their dose as a ‘Single dose’ on 54% of occasions, as a
‘Double dose’ on 10% of occasions and as a ‘Placebo
dose’ on 36% of occasions. The distribution of dose
identifications within each treatment condition and
across days (i.e. odd versus even) within each condition
were similar.
L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
149
Fig. 1. Mean scores obtained during baseline are shown for subject-rated opioid withdrawal (SRWD) and opioid agonist (SRAGO) effects (top)
and the visual analog measures of ‘bad’, ‘withdrawal sickness’ and ‘drug effect’ (bottom) for the completer (shaded, n =14) and non-completer
(white, n = 12) patient samples. Maximum possible cumulative scale scores for subject-rated measures and maximum possible score for analog
measures are shown on the y-axis. Vertical bars indicate + 1 S.E.M. Asterisk denotes significant difference between completer and non-completer
patient samples.
4. Discussion
The combination buprenorphine – naloxone tablet
was as acceptable and effective when administered on
alternate days as when administered every day. There
were no reports of any significant opioid agonist or
withdrawal effects by subjects or staff during the study,
and rates of medication compliance and drug abstinence were roughly equivalent across daily and alternate-day conditions. These results compliment other
placebo-controlled studies comparing daily versus alternate-day dosing using the 8 mg buprenorphine-only
solution formulation (Fudala et al., 1990; Amass et al.,
1994a, 1998; Johnson et al., 1995) and extend these
earlier studies by establishing efficacy of alternate-day
dosing with the combination buprenorphine – naloxone
tablet. Further, increasing the daily dose of buprenorphine may not be essential for use with alternate-day
combination tablet dosing, although doing so may retain more patients in treatment when dosing every
other day since fewer subjects dropped out during the
present study’s 16-mg (double-dose) alternate-day condition. Overall, alternate-day dosing studies support the
notion that slightly better outcomes with alternate-day
dosing are likely when higher doses are used (Fudala et
al., 1990; Amass et al., 1994a, 1998; Johnson et al.,
1995). The current study’s results raise five important
points.
First, procedures for transitioning patients onto the
combination tablet should be given careful consideration. Twice as many subjects inducted with the combi-
Fig. 2. Mean percentage of opioid-positive urine samples obtained
during baseline from the completer (shaded, n = 14) and non-completer (white, n =12) patient samples are shown. Vertical bars indicate + 1 S.E.M. Asterisk denotes significant difference between
completer and non-completer patient samples.
L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
150
Table 1
Percentage of urine samples positive for drugs of abusea
Drug screened
8 mg/24 h
8 mg/48 h
16 mg/48 h
Opioids
Cocaine
Amphetamines
Cannabinoids
Benzodiazepines
Barbiturates
53
34
2
42
10
7
60
35
5
41
5
3
54
39
0
39
8
3
a
N= 14, treatment completers.
Fig. 3. Mean pupillary diameter (mm) obtained during each 21-day
exposure to the three dosing conditions from the 14 patients who
completed the study. Vertical bars indicate + 1 S.E.M. Asterisk
denotes significant difference from 8 mg/24 h and 16 mg/48 h
conditions.
nation product in this study had reactions sufficient to
cause clinical concern than did subjects inducted using
buprenorphine only. Subjects experiencing these reactions were those transferring from methadone maintenance as well as street heroin users. While we cannot
determine conclusively that the reactions observed during combination tablet induction were due solely to use
of this product, circumventing even the potential of
precipitating adverse reactions upon initiation of
buprenorphine treatment will be important. Hence, our
clinical experience recommends using buprenorphine
only during the initial dose induction period. Comfort
during buprenorphine dose induction will likely be
critical to continuation of treatment by patients new to
buprenorphine therapy.
Second, a number of subjects in this study dropped
out during the first 2 weeks of treatment or failed to
complete the entire study. One possibility is that the
fixed dose protocol led to some candidates not receiving
an optimal clinical dose of the combination tablet. This
theory is consistent with our observation of increased
self-reports of adverse effects and greater illicit opioid
use in the non-completer sample. Further, the
bioavailability of tablet preparations of buprenorphine
may be about 50–60% of the corresponding sublingual
solution dose (Mendelson et al., 1996; Schuh and Johanson, 1999) and higher doses of the combination
tablet may have reduced the number of drop outs in
this study.
Third, the results of the present alternate-day dosing
evaluation differ from an earlier report with regard to
obtained differences in self-report measures across daily
and alternate-day dosing where sample sizes and study
settings were similar. Pupil diameter was the only dependent measure that distinguished the three dosing
conditions in the present study, whereas earlier work
(Amass et al. 1998) revealed small but significant differences between daily and alternate-day dosing on several
subject-rated measures of opioid effects as well as discriminations of active from inactive medication during
alternate-day dosing. Similarly, our results differ from
those reported in another placebo-controlled study in
which subjects receiving 8 mg of the solution formulation of buprenorphine every other day on a residential
research ward reported increased withdrawal scores
relative to subjects receiving 8 mg every day (Fudala et
al., 1990). However, a significant methodological difference between the present study and these earlier studies
was the absence of mandated abstinence and compliance procedures. Those procedures were eliminated in
the current study to permit comparison of the efficacy
of the dosing schedules on standard measures such as
drug use and treatment retention. Although compliance
rates were good in the present study, over 50% of urine
samples were positive for opiates across the dosing
conditions. This supplemental opioid use likely obscured any potential differences in subject ratings across
conditions that might have otherwise been observed.
Although this rate of supplemental opioid use is not
optimal, it is consistent with the pattern of drug use
reported in other controlled trials of alternate-day
buprenorphine treatment (Johnson et al., 1995), as well
as controlled comparisons of buprenorphine to methadone (Strain et al., 1994; Ling et al., 1996).
Fourth, the present study attests to the safety of
using a combination product for alternate-day dosing
when multiples of the daily maintenance dose are administered. Up to 4 mg of sublingual naloxone was
administered every other day during the 16 mg/48 h
dosing condition. No adverse reactions were observed
in response to doubling a subject’s maintenance dose in
any of the subjects studied. This latter finding is consistent with laboratory studies of sublingual naloxone in
opioid dependent subjects (Preston et al., 1990). Even
higher levels of sublingual naloxone (i.e. up to 6 mg)
are well tolerated with the combination tablet as suggested by studies with 3-day combination tablet dosing
(Amass et al., 2000b).
L. Amass et al. / Drug and Alcohol Dependence 58 (2000) 143–152
Fifth, this study’s limitations reduce the generality of
the findings to most clinical settings. For example, a
relatively small number of subjects were studied, the
duration of treatment was short, a fixed dose protocol
was used, and patients with active psychiatric comorbidity were excluded from participation. Certainly, the
fixed dose protocol may have led to some candidates
not receiving an optimal clinical dose of the combination tablet and may have affected early subject attrition. The high rate of study drop outs may have also
reduced power to detect differences across treatments,
although the crossover, counterbalanced design allowed
each subject to serve as their own control. Studies that
address these limitations are needed.
Buprenorphine’s use as both a daily and alternateday treatment has practical and therapeutic value. Alternate-day buprenorphine treatment is a clinically
viable alternative to daily dosing that does not increase
the risk of medication diversion typically associated
with take-home agonist therapy (Goldman and Thistel,
1978; Kirn, 1988). Although the combination tablet was
developed to allow take-home dosing while mitigating
diversion, the abuse liability of the combination tablet
awaits further study. There may still be occasions when
patient instability may warrant withholding take-home
medication for protective reasons. The combination
tablet can also be used on a 3-day dosing schedule (e.g.
Monday–Wednesday – Friday) and, like alternate-day
dosing (Amass et al., 1998), this thrice-weekly dosing
schedule is preferred by subjects to daily dosing (Amass
et al., 2000b). When the use of take-home medication is
not warranted, alternate-day dosing may also augment
patient outcomes during buprenorphine therapy since
reducing dosing frequency early in treatment increases
retention in opioid dependent individuals (Rhoades et
al., 1998). Finally, alternate-day (and thrice-weekly)
dosing is a feature of buprenorphine that may promote
its use in multiple settings, including primary care and
office-based practices. Such use may facilitate expanding models of opioid maintenance therapy and help
better address the ever growing problem of heroin
addiction.
Acknowledgements
We thank the staff of the Vine Street Center, especially Dr Robert Willard, Margery Johnson and Janet
Robinson, for medical services, Jason Thrun for excellent technical assistance, David Yeats and Butch
Rodgers for counseling services, and Connie Miles, for
medications preparation. Special thanks to Reckitt and
Colman, Drs Richard Hawks and Nora Chiang of the
Medications Development Division at the National Institute on Drug Abuse, and Dr George Bigelow for
their helpful comments and support of this project. This
151
project was supported by Grant DA11160 from the
National Institute on Drug Abuse. Portions of these
data were presented to the College on Problems of
Drug Dependence, Inc., in Scottsdale, AZ, in June
1998.
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