Download Buprenorphine dosing every 1, 2, or 3 days in opioid

Psychopharmacology (1999) 146:111–118
© Springer-Verlag 1999
O R I G I N A L I N V E S T I G AT I O N
Warren K. Bickel · Leslie Amass · John P. Crean
Gary J. Badger
Buprenorphine dosing every 1, 2, or 3 days
in opioid-dependent patients
Received: 3 February 1998 / Final version: 26 April 1999
Abstract Rationale: Administration of double the maintenance dose of buprenorphine has been shown to permit
every-other-day dosing. Whether longer periods between
dosing can be achieved is unknown. Objectives: To examine whether triple the maintenance dose can be administered every 72 h without opioid withdrawal or intoxication. Methods: Sixteen opioid-dependent outpatients each received three conditions (1) the maintenance
dose of buprenorphine every 24 h, (2) double the maintenance dose every 48 h, and (3) triple the maintenance
dose every 72 h under double-blind placebo-controlled
conditions. Each conditions was imposed in a random
sequence for 21–22 days. Self report and observer measures were taken at 24-h intervals. Results: No significant differences were observed on measures of opioid
agonist and withdrawal effects between the dosing conditions. However, averaging effects across conditions
may obscure important within-condition effects. When
conditions were analyzed by individual days within a
condition, several significant effects were observed. For
example, 24 h after administration of triple the maintenance dose, significant effects were observed in eight
opioid agonist measures. Also, 72 h after administration
of triple the maintenance dose, significant effects were
observed on four measures of withdrawal. Neither adverse medical reactions nor excessive opioid intoxication
W.K. Bickel · L. Amass · J.P. Crean
Department of Psychiatry, University of Vermont, 38 Fletcher Place,
Burlington, VT 05401, USA
G.J. Badger
Department of Medical Biostatistics, University of Vermont,
38 Fletcher Place, Burlington, VT 05401, USA
W.K. Bickel (✉)
Human Behavioral Pharmacology Laboratory,
Department of Psychiatry, University of Vermont,
38 Fletcher Place-Ira Allen School, Burlington, VT 05401, USA
Fax: +1-802-656-9628
Current address: L. Amass
Vine Street Center, University of Colorado School of Medicine,
Department of Psychiatry, 1741 Vine St Center,
Denver, CO 80206, USA
were observed. Conclusions: These results suggest that
buprenorphine may be administered safely every 72 h by
tripling the maintenance dose, with only minimal withdrawal complaints. Importantly, this 72-h dosing may
permit patients to attend clinic thrice weekly without the
use of take-home doses.
Key words Buprenorphine · Heroin dependence ·
Opioid dependence · Human · Opioid withdrawal ·
Treatment
Introduction
Buprenorphine is a low efficacy, partial mu-opioid agonist under investigation as a medication for the treatment
of opioid dependence (see Bickel and Amass 1995, for
review). Buprenorphine’s utility as a medication stems
from its unique profile of effects. This profile includes a
ceiling on agonist activity that decreases toxicity and the
possibility of overdose (Lange et al. 1990), and may limit its abuse liability (Walsh et al. 1995). Buprenorphine
also exhibits opioid antagonist activity in that it blocks
the effects of exogenously administered opioids in a
dose-related manner (Bickel et al. 1988a; Rosen et al.
1994) and can precipitate withdrawal (Aceto 1984;
Jacobs and Bickel 1999). Moreover, buprenorphine’s
slow dissociation from µ-opioid receptors (Rance and
Dickens 1978) results in a long duration of action
(Jasinski et al. 1978). Clinical trials suggest buprenorphine has efficacy comparable to methadone (Bickel et
al. 1988b; Kosten et al. 1993; Ling et al. 1996; Schottenfeld et al. 1997).
Buprenorphine’s ceiling on agonist activity, along
with its long duration of action, has led to the examination of alternate-day dosing schedules, where the medication is administered every other day (Fudala et al.
1990; Johnson et al. 1995; Amass et al. 1994, 1998).
These less than daily dosing procedures, if clinically efficacious, may result in at least three benefits. First, less
than daily attendance may remove the barrier to treat-
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ment imposed by a long commute to the treatment facility. Second, because these alternative dosing approaches
do not entail the use of take-home medication, they may
prevent illegal medication diversion. Third, by reducing
the number of clinic visits for each patient, these dosing
procedures may permit more patients to be served by
treatment facilities.
Alternative dosing schedules were initially examined
in a study where the standard daily buprenorphine maintenance dose was administered every 48 h (Fudala et al.
1990). Specifically, two groups of opioid-dependent inpatients received 8 mg buprenorphine sublingual (SL):
one group received that dose every day, while the other
group received that dose every other day with placebo
administered on the intervening days. Although group
differences were not observed on measures of self-reported drug and withdrawal effects, increased reports of
urges for opioids and dysphoria followed administration
of placebo within the alternative-day group. These findings were systematically replicated in a larger, placebocontrolled, outpatient study that compared the effects of
administering 8 mg buprenorphine SL every day with the
effects of administering that same buprenorphine dose
every other day in two groups of patients (Johnson et al.
1995). Again, no significant group differences were observed. However, the group receiving buprenorphine every other day exhibited worse outcomes on measures of
retention, medication compliance, illicit opioid use, and
self-reported withdrawal relative to the daily dosing
group. These two studies suggest that providing the
maintenance dose every 2 days results in withdrawal
during the second day.
A better profile of results was produced by alternateday dosing procedures that administered twice the daily
dose every other day (Amass et al. 1994, 1998). For
example, in a double-blind, placebo-controlled, crossover trial, opioid-dependent outpatients were exposed
to 8 mg/70 kg of buprenorphine SL every day and
16 mg/70 kg SL every other day (Amass et al. 1994).
Significant differences were not found between alternate-day and daily dosing in terms of opioid intoxication, opioid withdrawal, the ability to discriminate placebo from active doses, or treatment retention. Subject-rated opioid agonist ratings, however, distinguished the two
treatments, with alternate-day treatment producing lower
agonist ratings. A systematic replication of this study
demonstrated that administering double the maintenance
dose every 48 h produced results comparable to daily
dosing when examined under open-label conditions. Importantly, that study also demonstrated that patients preferred double the maintenance dose when given a choice
between double the maintenance dose every other day or
every day dosing with the maintenance dose (Amass et
al. 1998). Collectively, these studies suggest that double
the maintenance dose does not increase withdrawal
symptomatology.
The results obtained with alternate-day dosing, where
double the maintenance dose was administered every
other day, raise the possibility that even less frequent
dosing may be possible and effective with buprenorphine. To investigate this possibility, the current study
used a double-blind, placebo-controlled, crossover design to examine (1) whether tripling the buprenorphine
maintenance dose would permit dosing once every 72 h
and (2) replicate our prior findings of doubling the maintenance dose every 48 h. These two conditions were
compared to a condition where the maintenance dose
was administered every 24 h. Central to this study is to
determine whether sufficient withdrawal or agonist effects would be observed that would preclude clinical application. To observe these effects required that results
not be confounded by illicit opioids, thus evidence of
continued illicit opioid use was grounds for discontinuation from the study.
Materials and methods
Subjects
Sixteen opioid-dependent outpatients (13 male, three female) completed the study. Individuals had to be ≥18 years old, in good
health, meet DSM-III-R criteria for opioid dependence and FDA
qualification criteria for methadone treatment (i.e., a history of
opioid dependence and either significant current opioid use, e.g.,
opioid-positive urine samples, or signs of opioid withdrawal, e.g.,
gooseflesh, sweating, lacrimation, excessive yawning, etc.) for inclusion. Health status was determined by history, physical exam,
and laboratory evaluation (including electrocardiogram, complete
blood cell count, clinical chemistry profiles, and urinalyses). Evidence of active psychosis, manic-depressive illness, organic psychiatric disorders or serious medical illness (e.g., cardiovascular
disease) were exclusion criteria. Co-dependence for cocaine, ethanol or sedative-hypnotics did not exclude individuals from participation. The study was approved by the appropriate Institutional
Review Board for human research. Subjects provided written informed consent after receiving a full explanation of the procedures. Five additional subjects were enrolled but failed to complete the study: Three subjects withdrew from the study for personal reasons, one subject was discharged for repeated opioid use
during the double the maintenance dose every 48 h condition, and
one subject was discharged for violating urinalysis testing procedures in the maintenance dose every 24 h condition.
Subjects completing the protocol had a mean age of 36.9 years
(range 21–44), and mean weight of 82.8 kg (range 61–114). Subjects reported using opioids regularly for an average of 8.9 years
(range 1–23) and spending $468.8 (range $10–2000) per week on
opioids; all subjects reported using opioids intravenously. Nine
subjects received one previous treatment episode with buprenorphine, and an additional subject received four previous treatment
episodes with buprenorphine via participation in prior research
protocols. Weekly pregnancy tests conducted with the three female subjects were negative throughout the study.
General procedures
Continuation in the study and weekly monetary compensation
($50 per week) for participation were contingent on daily clinic attendance and opioid abstinence. In order to facilitate collection of
dependent measures every 24 h, subjects were required to attend
the clinic at the same time each day. Participation was discontinued immediately if a subject missed a clinic visit., and participants
were offered either a referral to another treatment facility or a detoxification treatment in our clinic. Opioid abstinence was confirmed via urinalysis. Urine samples were collected thrice weekly
(Mondays, Wednesdays and Fridays) under observation and analyzed immediately onsite for the presence of opioids using the En-
113
zyme Multiplied Immunoassay Technique (Syva Corp., San Jose,
Calif., USA). Samples also were analyzed for the presence of barbiturates, benzodiazepines, cannabinoids, and cocaine on one randomly selected scheduled urinalysis day each week. If a subject
submitted an opioid-positive urine sample, no medication was provided for that day, and data collected since the last active dose
were omitted from analyses. Subjects were permitted to continue
in the study, however, participation was discontinued upon receipt
of a second opioid-positive sample. Subjects were not permitted to
attend the clinic intoxicated, and breath alcohol samples were collected on urine testing days as part of routine clinical procedure.
Subjects were required to participate weekly in one 30-min individual counseling session (see Bickel et al. 1997 for a detailed description of standard treatment).
Medication administration
Buprenorphine hydrochloride was prepared as a stock concentration of 24 mg/ml in 35% ethanol (vol/vol) for sublingual administration. Stock solutions containing 2, 4, 8 and 16 mg/ml in 35%
ethanol (vol/vol) were prepared from serial dilutions of the
24 mg/ml stock concentration. Buprenorphine placebo consisted
of sublingual ethanol vehicle. The maximum volume (ml) necessary for the highest dose was calculated on an individual basis.
For each subject, doses were then delivered in this constant volume throughout the study. Subjects held the medication under
their tongue for a period of 5 min without speaking. Medications
were administered with a Ped-Pod Oral Dispenser (SoloPak Laboratories, Franklin Park, Ill., USA) under double-blind conditions.
All doses were masked for taste with a 1 ml sublingual flavor solution of Bitrex granules (6 mcg/ml; Macfarlan-Smith Ltd., Edinburgh, UK) and peppermint spirits. Subjects swished the flavor solution in their mouth for 1 min and discarded it into a cup prior to
receiving medication each day.
Buprenorphine induction and stabilization
The subject’s maintenance dose was determined during the
first week of participation. Subjects were initially placed on a
4 mg/70 kg dose of buprenorphine. If withdrawal signs and symptoms were evident, the dose was increased to 8 mg/70 kg. Evidence of limited opioid dependence resulted in direct placement
on 2 mg/70 kg, while evidence of substantial opioid dependence
or prior participation in other buprenorphine protocols with the
8 mg/70 kg dose resulted in direct placement on 8 mg/70 kg using
a 3-day rapid-induction procedure (Johnson et al. 1989). Six subjects received the 4 mg/70 kg maintenance dose; ten subjects received the 8 mg/70 kg maintenance dose. After the dose was adjusted, subjects participated in a safety dose run-up session where
3 times the maintenance dose was administered in three divided
doses over the course of 4.5 h to insure that subjects could tolerate
the different dosing conditions and the maximum doses to be delivered in the study. All subjects safely tolerated the buprenorphine doses administered in the dose run-up session.
After dose adjustment and run-up, the maintenance dose was
administered for 13 consecutive days (days 1–13) followed by exposure to the three treatment conditions. During days 1–3, subjects
were told they were receiving their maintenance dose at dispensation. These three days during which the dosing condition was not
blinded were excluded from analyses. Subjects received their
maintenance dose for the next 10 days (days 4–13) without instruction; this 10-day maintenance period served as the treatment
baseline for all outcome measures.
every 24 h; during double the maintenance dose condition, subjects received double their maintenance dose every 48 h, with placebo on the interposed day; during triple the maintenance dose
condition, subjects received triple their maintenance dose every
72 h with placebo on the 2 interposed days. Treatment conditions
were imposed in a mixed sequence with the conditions counterbalanced across subjects.
Dependent measures
Self-reports
Subjects completed two adjective rating scales (Bickel et al.
1988a, 1988b), 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. 1994) before receiving medication at each scheduled clinic visit. Subjects were instructed to respond to these questionnaires according to their experience over the past 24 h. The adjective rating
scales were comprised of 16 signs and symptoms of opioid withdrawal and 16 typical opioid effects. Subjects rated each item on a
scale ranging from 0 (none) to 9 (severe) (max 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-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: High, Drug effect, Good, Bad, Sick and Liking.
Subjects made a mark along a 100 mm line, anchored at each end
by “not at all” and “severe”. Responses were converted to a 100point scale. 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 two measures of stimulation, respectively. On the
dose-identification questionnaire, subjects indicated whether they
thought they received placebo, their maintenance dose of buprenorphine, double their maintenance dose of buprenorphine or triple their maintenance dose of buprenorphine the previous day. The
results of the dose-identification questionnaire were then scored as
two measures; either identification of (1) less than or (2) greater
than the maintenance dose.
Observer ratings
Nursing staff completed an observer rating scale at each scheduled
clinic visit prior to dispensing medication. The nurses rated 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; max cumulative score=63)
and five signs of opioid effects (skin itching, vomiting, sedation,
nodding, soap-boxing and rapping; max cumulative score=45).
The observer-rating scale was based on Addiction Research Center agonist and withdrawal scales (Himmelsbach 1939; Jasinski et
al. 1978).
Pupil diameter
Pupil diameter was determined daily before dispensing medication
from photographs taken with a Polaroid close-up camera at ×2 magnification at 1 ft-c of ambient illumination (Jasinski and Martin 1967).
Study design
Beginning on day 14, the experimental conditions were imposed.
Subjects received three conditions in a mixed order with each condition imposed for a duration of 21–22 days: During the maintenance dose condition, subjects received their maintenance dose
Statistical methods
The first research question important to this study is whether there
are any overall differences in withdrawal or agonist effects across
114
three dosing conditions. This will indicate whether reports of
withdrawal or opioid agonist effects differentiate the three dosing
conditions when the results are averaged across the days that constitute the dosing schedules. The next research question was to determine whether any days within the various treatment conditions
were different than the maintenance dose conditions. For example,
are withdrawal scores obtained 72 h after the administration of triple the maintenance dose significantly different than the scores
obtained 24 h after a maintenance dose. Answering this second
type of research question requires the following five comparisons.
Specifically, comparing withdrawal and agonist effects obtained
24 h after administration of the maintenance dose condition to
those same measures obtained (1) 24 h following double the maintenance dose, (2) 48 h following the double dose, (3) 24 h following the triple dose, (4) 48 h following the triple dose, (5) 72 h following the triple dose. For the sake of completeness, we report the
results of all pairwise comparisons among the treatment days (see
Table 1). Our description of results will be limited to the above
five comparisons.
Comparisons between maintenance dosing every 24 h, double
the maintenance dose every 48 h, and triple the maintenance dose
every 72 h were performed using repeated measures analysis of
variance (ANOVA) to examine for overall condition effects. The
double the maintenance dose every 48 h, and triple the maintenance dose every 72 h, were then partitioned into their individual
days for analysis purposes. Thus, measurements taken under the
double the maintenance dose every 48 h condition were partitioned into those obtained 24 h after an active double dose and
24 h after placebo (48 h after the administration of double the
maintenance dose), while measurements obtained under the triple
the maintenance dose every 72 h condition were divided into those
obtained 24 h after an active triple dose, 24 h after the first placebo (48 h after the administration of triple the maintenance dose),
and 24 h after the second administration of placebo (72 h after the
administration of triple the maintenance dose). The means were
derived by averaging the scores across participants taken at various intervals post active drug administration. These five conditions plus measurements taken 24 h after administration of the
maintenance dose defined a total of six treatment conditions for
each subject. In addition, the repeated measures ANOVA included
the subjects’ daily maintenance dose (4 mg or 8 mg) as an acrosssubject factor, along with its interaction with treatment condition.
The baseline maintenance period was not included in the repeated
measures analysis as it did not represent a treatment condition that
was randomized with respect to order within subjects. Data from
this portion of the trial is presented for descriptive purposes without statistical comparisons. The Student-Newman-Keuls (SNK)
procedure, which controls type I error rate experiment-wise, was
used to perform pairwise comparisons among treatment means, if
the overall F-test from the ANOVA was significant. Analyses
were performed using SAS statistical software. For all analyses,
statistical significance was determined using α=0.05.
Results
Comparisons across the three dosing conditions showed
no significant effects; that is, none of the measures
showed statistical difference on any of the measures
when collapsed across treatment days. Further, no significant effect of buprenorphine dose were observed. However, averaging measures obtained 24, 48, and 72 h following the triple the maintenance dose may have obsfucated important differences that occurred across the
72-h interval. Thus, the remainder of the Results section
will report on the five comparisons outlined in the Statistical methods section. The results of these analyses are
provided in Table 1.
Double the maintenance dose
Twenty-four hours following
Three measures showed significant differences when assessed 24 h, following the administration of double the
maintenance dose (condition double the maintenance
dose every 48 h) when compared to the maintenance
dose every 24-h condition. The ARCI PCAG (“Sedation”) scale, and “percent identifications as placebo measure” were lower 24 h following the administration of
double the maintenance dose than those measures obtained from the maintenance dose every 24-h condition.
The third measure, “percent identification as greater than
maintenance dose, “was significantly greater 24 h after
double the maintenance dose than was that same measure obtained 24 h after the maintenance condition.
Thus, these measures showed greater agonist effects relative to the maintenance dose alone, an effect consistent
with doubling the maintenance dose.
Forty-eight hours following
Only the measure of “percent identification as placebo”
was significantly higher 48 h after double the maintenance dose than identifications obtained 24 h after the
maintenance dose. Although this result indicates that
placebo doses were detected more frequently 24 h after a
placebo (i.e., 48 h after double the maintenance dose of
buprenorphine), it was not accompanied by significant
increases in measures of agonist or withdrawal effects.
Triple the maintenance dose
Twenty-four hours following
Eight measures showed significant differences between
measures obtained 24 h following administration of triple
the maintenance dose and the maintenance dose every 24h condition. Significant decreases were obtained in the
PCAG and LSD scales of the ARCI, “percent identification as placebo,” and pupil diameter 24 h after triple the
maintenance dose when compared to 24 h after the maintenance dose. For example, the PCAG scale as illustrated
in Fig. 1 shows a decrease of approximately 1.8 points
from the maintenance condition as compared to that measure 24 h after the triple the maintenance dose of buprenorphine. Significant increases were obtained in the A
(“Amphetamine”) scale, BG (another stimulant), and
MBG (“Euphoria”) ARCI scales (percent identified as
greater than maintenance) scales 24 h following triple the
maintenance dose condition when compared to the maintenance dose every 24 h condition. As illustrated in Fig. 1,
the increase in the MBG scale 24 h following the triple
dose of buprenorphine was approximately 1 point greater
relative to the maintenance condition. These results suggest that greater agonist effects were observed in the 24 h
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Table 1 Mean scores (SEM) for 18 measures of agonist and withdrawal effects across baseline, maintenance, double dosing (double the
maintenance and placebo), and triple dosing (triple the maintenance dose, placebo) condition
Outcome
measure
Max
Visual analog scales
Bad*
100
Sick*
100
Good*
100
Drug effect*
100
Like*
100
High
100
Adjective rating scales
Withdrawal
144
effects
Agonist
144
effects
ARCI subscales
PCAG*
15
LSD*
13
A*
14
BG*
16
MBG*
11
Dose identification
% Identified
1.00
as placebo
% Identified
1.00
as greater
than maintenance
Observer rating
Agonist effects
Withdrawal
effects*
Pupil diameter*
(mm)
45
63
Baseline
24 h after
maint. dosing
24 h after
double dosing
48 h after
double dosing
24 h after
triple dosing
48 h after
triple dosing
72 h after
triple dosing
13.06
(4.10)
25.41
(4.85)
15.12
(4.09)
11.06
(2.72)
25.45
(5.10)
5.58
(1.60)
15.48ab
(4.47)
23.84bc
(4.44)
13.26ab
(3.58)
10.67ab
(2.74)
23.57ab
(4.84)
4.71
(1.42)
12.27ab
(3.80)
20.11c
(4.20)
13.11ab
(3.39)
10.82ab
(2.82)
20.03ab
(4.78)
6.04
(1.75)
15.13ab
(5.04)
28.22ab
(5.10)
8.92b
(3.24)
7.42b
(2.69)
16.48b
(4.62)
4.33
(1.53)
10.35b
(2.91)
19.29c
(3.81)
18.07a
(4.23)
13.29a
(3.11)
24.57a
(4.84)
8.12
(2.63)
16.27ab
(4.77)
28.03ab
(5.07)
10.55b
(3.98)
8.42ab
(2.76)
19.11ab
(4.92)
6.72
(2.17)
17.37a
(4.67)
34.51a
(5.84)
9.28b
(3.49)
7.99b
(3.02)
17.52ab
(5.59)
5.30
(1.70)
26.85
(4.32)
15.91
(2.84)
33.70
(5.41)
15.91
(2.88)
27.27
(4.91)
14.66
(3.00)
32.70
(5.45)
13.26
(3.02)
25.55
(5.04)
17.01
(2.91)
33.20
(6.05)
14.06
(2.93)
37.05
(5.75)
14.44
(3.06)
6.36
(0.67)
5.72
(0.43)
3.25
(0.53)
5.37
(0.62)
3.47
(0.85)
6.34b
(0.77)
5.77ab
(0.50)
3.15b
(0.58)
5.12bc
(0.69)
3.77b
(0.94)
5.01c
(0.59)
5.14bc
(0.46)
3.42b
(0.66)
5.85b
(0.65)
4.28ab
(1.04)
6.83ab
(0.79)
6.08ab
(0.62)
2.70b
(0.65)
4.93bc
(0.73)
3.03b
(0.95)
4.52c
(0.73)
4.54c
(0.44)
4.36a
(0.70)
7.19a
(0.69)
5.21a
(1.12)
6.90ab
(0.77)
5.77ab
(0.55)
2.77b
(0.56)
4.94bc
(0.69)
3.13b
(0.95)
8.06a
(0.86)
6.54a
(0.67)
2.36b
(0.57)
4.15c
(0.67)
2.71b
(0.80)
0.364
(0.049)
0.065
(0.025)
0.378b
(0.049)
0.058b
(0.014)
0.210c
(0.058)
0.177a
(0.046)
0.711a
(0.065)
0.013b
(0.009)
0.146c
(0.054)
0.224a
(0.061)
0.760a
(0.066)
0.038b
(0.017)
0.777a
(0.064)
0.018b
(0.012)
0.22
(0.09)
2.74
(0.52)
5.80
(0.19)
0.15
(0.05)
1.90ab
(0.40)
6.07ab
(0.18)
0.04
(0.02)
10.08b
(0.29)
5.84bc
(0.18)
0.06
(0.03)
2.49a
(0.75)
6.17a
(0.18)
0.05
(0.03)
0.96b
(0.28)
5.61c
(0.21)
0.06
(0.03)
1.64ab
(0.51)
6.03ab
(0.22)
0.10
(0.04)
2.59a
(0.52)
6.19a
(0.25)
*Significant differences among treatment means based on ANOVA, P<0.05. Means with a common letter are not significantly different
from each other, SNK procedure
after the administration of triple the buprenorphine maintenance dose, than 24 h after the maintenance.
Forty-eight hours following
Only the measure “percent identified as placebo”
showed significant differences, with an increase in this
measure 48 h following triple the maintenance dose
when compared to 24 h after the maintenance dose.
Again, although the placebo dose was more frequently
discriminated during the triple the maintenance dose every 72 h condition, significant differences were not observed in the other measures of agonist or withdrawal effects.
116
identified as placebo” were significantly greater 72 h following administration of triple the maintenance dose
than 24 h after the maintenance dose. These significant
increases were generally of small magnitude. For example, as shown in Fig. 2, the VAS sick scale increased
10.67 points after triple the maintenance dose increased
as compared to this measures taken 24 h after the maintenance dose. This profile of results suggests that some
withdrawal-like effects may increase 72 h after administration of the triple buprenorphine maintenance dose.
Discussion
Fig. 1a, b Addiction Research Inventory PCAG (a) scores assessing “sedation” and MBG scale (b) assessing “euphoria” are shown
across the three different dosing regimes, according to hours since
last active dose. The different dose conditions are maintenance
dose every 24 h, double the maintenance condition every 48 h and
triple the maintenance dose every 72 h. Values represent means
and SEM
This study examined whether chronic administration of
three times the maintenance dose of buprenorphine every
72 h produced opioid withdrawal symptoms and/or
whether appreciable opioid agonist affects resulted that
could preclude the utility of this dosing schedule in clinical setting. The study also replicated our prior findings
of administrating double the maintenance dose of buprenorphine every 48 h (Amass et al. 1994, 1998). The present results indicate that limited opioid withdrawal occurs
during conditions where triple the maintenance dose of
buprenorphine is administered every 72 h and that tripling the maintenance dose of buprenorphine does not
increase opioid agonist effects sufficient to preclude
clinical use of this dosing schedule. Thus, these data support the possibility of dosing a patient with three times
the buprenorphine maintenance dose every 72 h, and offers a potential mechanism for decreasing or eliminating
weekend clinic attendance for patients receiving buprenorphine.
Withdrawal effects
Fig. 2 Visual analog scale “sick” scores are shown across the
three different dosing regimes, according to hours since last active
dose. See Fig. 1 legend for other details
Seventy-two hours following
Three measures showed significant differences when
measured 72 h following administration of triple the
maintenance dose when compared to the maintenance
dose. While VAS “sick”, ARCI PCAG, and “percent
Our overall analyses did not show significant withdrawal
effects across the dosing conditions. Additional analyses
examining effects within conditions showed some significant withdrawal-related effects on a few measures. For
example, the PCAG and VAS “sick” scores increased
2.38 and 10.67 points, respectively, following the administration of the second placebo in the triple the maintenance dose every 72-h condition as compared to the
maintenance dose every 24-h condition. With regard to
the double the maintenance dose every 48 h condition,
these analyses only showed significant differences in one
out of the 17 measures employed in the study. These
findings suggest that some withdrawal is occurring.
However, given the small magnitude of the effects, and
that both subject-rated withdrawal and observer-rated
withdrawal measures did not show any significant effects, opioid withdrawal, to the extent it was observed,
was of a limited magnitude.
These results are generally consistent with our prior
studies. For example, our group has demonstrated in two
prior studies that administering double the maintenance
dose every 2 days resulted in minimal reports of with-
117
drawal (Amass et al. 1994, 1998). Further, subjects preferred double the maintenance dose when given the opportunity to choose either double the maintenance dose
every 2 days or the maintenance dose every day (Amass
et al. 1999).
Other blinded studies that have administered the
maintenance dose of buprenorphine every other day
found that withdrawal ratings following placebo administration increased a variety of withdrawal scores relative to the maintenance dose condition (Fudala et al.
1990; Johnson et al. 1995). For example, Fudala et al.
(1990) noted that ratings of withdrawal following placebo administration during the 48-h interval were approximately 3-fold greater than scores during the maintenance dose condition. Similarly, Johnson et al. (1995)
found patients receiving the maintenance dose every
other day had worse outcomes, even though those effects were not statistically significant. The results of the
present paper and prior studies in our clinic suggest that
better outcomes can be obtained during alternate-day
dosing schedules by administering multiples of the
maintenance dose.
The present study is apparently inconsistent with the
results of a recent laboratory study by Eissenberg and
colleagues (1997a). That study reported that administering 8 mg buprenorphine once across a 72-h period had
no effect on reports of opioid withdrawal using the same
profile of measures we used in the present study. As reviewed above, we found in the present study some evidence of increases in three withdrawal-sensitive measures across the 72-h period during triple the maintenance dose every 72-h condition when compared to the
maintenance dose every 24-h condition. The Eissenberg
et al. (1997a) findings are also inconsistent with the finding of Fudala et al., who abruptly discontinued buprenorphine at the end of the study and observed sufficient
withdrawal to warrant providing supplemental medication 72 h after 8 mg buprenorphine. The reason for this
inconsistency is unclear.
Agonist effects
The present study also provides support for the safety of
administering double and triple the maintenance dose of
buprenorphine. No subject was discontinued from participation as a result of administering double or triple the
maintenance dose of buprenorphine during dose run-ups
or during the double the maintenance dose every 48 h
and triple the maintenance dose every 72 h conditions,
indicating that these doses were safe and tolerable. Although several measures (e.g., MBG and pupil diameter)
showed evidence of increased agonist effects, there was
an absence of notable observer-rated agonist signs or
self-reported opioid intoxication (e.g., opioid agonist
questionnaire) following the doubling and tripling of the
maintenance dose. This limited profile of opioid agonist
effects is consistent with buprenorphine’s profile as a
partial agonist and its wide margin of safety (Jasinski et
al. 1978; Lange et al. 1990; Bickel and Amass 1995;
Walsh et al. 1995).
Consistent with our prior findings, there was an absence of any effect of buprenorphine dose when subjects
receiving 4 and 8 mg doses were compared. In both this
and the prior study’s result, this lack of dose effect was
somewhat unexpected. Certainly, the 4 mg dose is a low
dose not near the plateau of effects observed with this
partial agonist (Walsh et al. 1995). One explanation of
the results could be that we had insufficient power to detect an effect. Nonetheless, the clinical presentation of
the subjects did not indicate that subjects receiving 4 mg
were experiencing any more agonist or withdrawal effects than the 8 mg subjects. Although more research
will be necessary to replicate this finding, these results
may indicate that these dosing procedures could be used
with a variety of doses.
Implications
The present study raises several important research questions. For example, we do not know whether triple the
dose of buprenorphine every 72 h would be preferred to
daily dosing; that is, whether decreasing clinic attendance would mitigate against whatever withdrawal signs
and symptoms are incurred. Such a preference would
provide direct evidence of the acceptability of this dosing regimen. As we have already noted, our prior research has demonstrated that doubling the dose of buprenorphine every 48 h was preferred to daily dosing by
opioid-dependent patients (Amass et al. 1998). Also,
whether this profile of results would be obtained with the
buprenorphine-naloxone combination product currently
being developed needs to be addressed (Chaing and
Hawks 1994; Chaing et al. 1996a, 1996b; Mendelson et
al. 1996). Another important question is whether quadrupling the dose may permit clinic visits every 4 days.
However, how far this effect may be pushed is an important and empirical question. Finally, clinical pharmacology studies such as the present study do not address the
penultimate question; namely, the efficacy of different
dosing schedules in terms of treatment retention and the
use of illicit drugs under the different dosing schedules.
Nonetheless, the current study provides support for
the potential clinical utility of administering twice and
thrice the buprenorphine dose once every 2 and 3 days,
respectively. These dosing schedules appear to produce
limited withdrawal and are safe for patients. Development of alternate-day dosing is important because it may
facilitate better clinic attendance for patients who live far
from the clinic or for whom work or parental responsibilities make daily travel difficult. Another important advantage of such dosing procedures is that it permits less
frequent clinic visits without risk of illicit diversion
(Goldman and Thistel 1978). Such diversion may be a
contributing factor for a lack of neighborhood support
for new clinics that treat opioid dependence. In this regard buprenorphine may be able to provide the infre-
118
quent clinic visits that can be obtained with the long acting full opioid agonist LAAM (Ling et al. 1976; Eissenberg et al. 1997b). Finally, these dosing schedules may
permit existing treatment facilities to treat more patients
by having them attend less frequently.
Acknowledgements We thank John Brennan, Florian Foerg,
Beth Kubik, and Evangelos Tzanis for technical assistance, Marcia Dunham, David McGarry, and Susan A. C. Griggs for medications preparation, Rebecca Esch and Marlis Sorge for counseling
services, and John R. Hughes and John R. Brooklyn for medical
consultation. We thank Rebecca A. Esch, Eric Jacobs, Lisa A.
Marsch, and Nancy Petry for comments on earlier drafts of this
paper. Preparation of this report was supported by Grants
DA06969 and 5T32DA07242 from the National Institute on Drug
Abuse.
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