Download intravenous buprenorphine in humans

Subjective and physiologic effects of
intravenous buprenorphine in humans
The pharmacologic profile of sublingual and subcutaneous buprenorphine, a partial opioid agonist, indicates it may be useful as a maintenance drug in the treatment of opioid dependence. However, illicit
intravenous self-administration suggests that it may have a greater abuse potential by this route of administration. Physiologic and subjective effects of intravenous buprenorphine (0.0, 0.3, 0.6, and 1.2 mg)
were determined in a dose-escalation study in six nondependent volunteers with histories of opioid use.
Buprenorphine caused miosis and decreased respiratory rate, increased diastolic blood pressure, and
transiently increased heart rate. Buprenorphine increased positive responses on a "feel drug" question
and scores on scales of "liking," "good effects," euphoria, and apathetic sedation. Physiologic and subjective responses were not consistently dose related, a finding compatable with the pharmacologic profile
of a partial agonist. The findings indicate that buprenorphine has substantial potential for abuse when
administered intravenously. (CLIN PHARMACOL THER 1993;53:570-6.)
Wallace B. Pickworth, PhD, Roney E. Johnson, PharmD,a
Barbara A. Holicky, RN, and Edward J. Cone, PhD Baltimore, Md.
Buprenorphine is a partial opioid agonist1'2 with an
analgesic potency 25 to 40 times that of morphine.3
Buprenorphine has a high therapeutic index and low
toxicity even at high doses.4'5 These characteristics
led Jasinski et al.6 to study the effects of short- and
long-term subcutaneous administration of buprenorphine in former opioid addicts. They found that single
doses of buprenorphine produced morphine-like effects, including miosis and elevations of the morphine-benzedrine group (MBG) and pentobarbitalchlorpromazine-alcohol group (PCAG) subscales of
the Addiction Research Center Inventory (ARCI).7
During long-term administration of buprenorphine, the
effects of subcutaneously administered morphine (120
mg) were attenuated, and on abrupt discontinuation of
buprenorphine a mild and delayed abstinence syndrome was observed. These findings suggested that
buprenorphine may be effective for the treatment of
opioid addiction.6 Subsequently, Mello and MendelFrom the National Institute on Drug Abuse, Addiction Research
Center.
Received for publication Sept. 21, 1992; accepted Dec. 26, 1992.
Reprint requests: Edward J. Cone, PhD, Clinical Pharmacology
Branch, NIDA, Addiction Research Center, P.O. Box 5180, Baltimore, MD 21224.
'Present address: The Johns Hopkins School of Medicine, Department of Psychiatry and Behavioral Sciences, Behavioral Pharmacology Research Unit, 5510 Nathan Shock Dr., Baltimore, MD
21224.
13/1/45127
570
son8 reported that subjects maintained on daily sublin-
gual doses of buprenorphine self-administered fewer
opioids than those maintained on placebo. Bickel
et al.9 compared the efficacy of daily administration of
buprenorphine (2 mg, sublingual) and methadone (30
mg, oral) in a double-blind outpatient detoxification
study. They concluded that buprenorphine was acceptable to patients and as effective as methadone. In a
second study, Bickel et al.1° reported that long-term
buprenorphine treatment caused dose-dependent blockade of hydromorphone challenges. These findings were
extended in studies that assessed a rapid-dose induction
procedure," and once daily versus every-other-day dosing of sublingual buprenorphine.12 Further, in an outpatient clinical trial, buprenorphine (8 mg, sublingual)
was as effective as methadone (60 mg, oral) in decreasing the number of opioid-positive urine samples.13 The
findings from these and other pharmacologic and treatment studies led to the initiation of a multicenter trial
with buprenorphine to assess its usefulness in treating
opioid-dependent patients.
The increased availability of buprenorphine could
lead to its abuse, particularly if the dosage form could
be injected intravenously. Self-administration of buprenorphine has been reported to occur in countries
in which buprenorphine is easily available. Pharmacists and physicians in New Zealand noted increasing demands for buprenorphine.14'15 Subsequently,
abuse of buprenorphine among opioid addicts was
reported in Ireland,16 Germany,17 Scotland, /8 and
CLINICAL PHARMACOLOGY & THERAPEUTICS
VOLUME 53, NUMBER 5
Australia. 19 In most instances, addicts reportedly
preferred the intravenous route of administration 20
Typically the user would obtain one or more 0.2 mg
tablets, manufactured for sublingual administration,
dissolve them in water, and inject the solution intravenously.21
In the present study, the pharmacologic and subjective effects of high intravenous doses of buprenorphine were evaluated. For safety reasons, placebo and
three doses of buprenorphine were administered in as-
cending order. Subjects were aware that they were
participating in a dose run-up safety evaluation study
of intravenously administered buprenorphine, but they
were not aware of actual doses.
METHOD
Subjects
Six healthy paid male volunteers participated in this
inpatient research study. All subjects had histories of
opioid abuse but were not opioid dependent at the
time of their admission to the clinical research ward of
the Addiction Research Center (NIDA, Baltimore,
Md.). Each subject was a current smoker (average, 16
cigarettes per day) and each self-reported regular ethanol use before admission. The subjects' mean age
was 34.1 years (age range, 27 to 40 years), and their
weight averaged 68.6 kg (weight range, 63.6 to 73.3
kg). Each subject signed a consent form approved by
the local institutional review board (Francis Scott Key
Medical Center, Baltimore, Md.) that described the
experiment's procedures, risks, and benefits. The
study protocol and consent form met Department of
Health and Human Services guidelines for human experimentation.
Drug administration
This dose run-up phase preceded a study of the bioavailability of buprenorphine. In the dose run-up
phase, each subject received intravenous injections in
the following ascending order: placebo (water for injection) and 0.3, 0.6, and 1.2 mg buprenorphine.
Drug solutions were prepared for injection by dissolving buprenorphine hydrochloride in water for injection; the pH was adjusted to 4.0 to 4.5 with 0.1 mol/L
hydrochloric acid. Drug solutions were administered
in a 1 ml volume over 1 minute through a catheter inserted into an antecubital vein. Drug administration
sessions were separated by at least 48 hours.
Study measures
Physiologic measures. Systolic and diastolic blood
pressure and pulse rate were recorded from an auto-
Pickworth et al.
571
mated recording device. The pupil diameter was determined from Polaroid (Polaroid Corp., Cambridge,
Mass.) photographs of the eye by use of methods described by Marquardt et al.22 Respiration rate was obtained from 15 second observations of chest excursion.
Subjective measures. Subjects rated the drug effect
by drawing a vertical line through a 200 mm visual
analog scale anchored with the adjectives "good" and
"bad." The opiate Single Dose Questionnaire (SDQ)23
and subscales of the ARCI,7 including the MBG (a
measure of euphoria), PCAG (a measure of apathetic
sedation), and the lysergic acid diethylamide (LSD; a
measure of drug-induced dysphoria) subscales24 were
administered by means of a computer.
Performance measure. The circular lights task,25 a
hand-eye coordination test, was used for evaluation of
drug-induced performance effects.
Data collection
Physiologic, subjective, and performance data were
collected before and up to 48 hours after drug administration. Measurement times differed for each dependent variable. The number of measurements varied as
follows: two in the hour before the drug (after the insertion of the venous catheter), seven in the first hour
after the drug, seven at 1/2-hour intervals between
1 and 4 hours, three at hourly intervals between 4 and
6 hours, and four at 2-hour intervals between 6 and 14
hours. On the second day, dependent measures were
collected at 22, 24, 26, 28, 32, and 38 hours after
drug administration.
Data analysis
Treatment conditions were presented in ascending
order and the subjects were aware of this aspect of the
experimental design. Because the treatments were not
administered randomly, subjective measures could
have been influenced by expectation and anticipation
of drug effect. It is also possible that residual effects
from previously administered doses of buprenorphine
influenced the response to subsequent administrations.
These considerations precluded the use of conventional ANOVA procedures. Consequently, the findings were presented with descriptive statistics.
RESULTS
Physiologic measures
Respiration. As shown in Fig. 1, A, intravenous
buprenorphine caused a dose- and time-related decrease in the respiratory rate. The effect was evident
within 15 minutes and reached a maximum at 45 min-
CLINICAL PHARMACOLOGY & THERAPEUTICS
572 Pickworth et al.
MAY 1993
Respiration
A
22B
o 20-
2
18-
2
16-
75
.73
r,
70
65
gi 14-
60
12
Pulse Rate
90
ID
0-M
Placebo
0.3 mg
0.6 mg
1.2 mg
5
g 80
4
oda
Pupil Diameter
6p
85
75
Diastolic Blood Pressure
80-
3
2
70
65
Pre-
Pre-
0
0
1
2
3
4
5 6
12
18
24
Hour
Fig. 1. Time-action curves for physiologic parameters: respiration (A), diastolic blood
pressure (B), pulse rate (C), and pupil diameter (D) after intravenous buprenorphine (0.3, 0.6,
and 1.2 mg) and placebo (n = 6).
utes after drug administration. Respiratory rate gradually increased and attained baseline levels after 6
hours.
Blood pressure. Diastolic blood pressure (Fig. 1,
B) increased after buprenorphine. The diastolic pressure increase was small (average, 5 mm Hg), and the
values returned to control levels within 4 hours. Systolic blood pressure (data not shown) was not significantly affected by buprenorphine.
Heart rate. Each dose of buprenorphine, but not
placebo, transiently increased the pulse rate (Fig. 1,
C). The effect was maximal 5 to 10 minutes after the
injection and returned to baseline level in approximately 3 hours. The response was not dependent on
the dose of buprenorphine.
Pupil diameter. Buprenorphine decreased pupil diameter (Fig. 1, D). The effect was evident within 10
minutes and persisted for 24 hours after the 0.3 and
0.6 mg doses and for 48 hours (data not shown) after
the 1.2 mg dose.
Performance measure
Buprenorphine caused a slight (7%) but sustained
decrease in response rate on the circular lights task between 1/2 hour and 3 hours after drug administration
(Fig. 2, A).
Subjective effects
Feel drug. Subjects consistently answered affirmatively to the question "Do you feel the drug?" from
the SDQ.23 As shown in Fig. 2, B, beginning 5 minutes after buprenorphine and lasting for 4 hours, at
least five of the six subjects reported positive responses. After placebo administration, there were no
affirmative responses to the question "Do you feel the
drug?"
Subject liking. Buprenorphine caused an orderly increase of scores on the drug-liking question of the
SDQ (Fig. 2, C). The effect peaked during the first
hour and gradually declined to values that were not
different from placebo at 8 hours.
Good and bad effects. Subjects reported no bad effects after placebo or at any time after buprenorphine,
but ratings of good effects increased after buprenorphine. Increases were evident 5 minutes after the injection, peaked at 1 hour, and gradually declined to
baseline values within 5 hours (Fig. 2, D). The 0.6
mg dose exerted a greater effect than the 1.2 mg dose,
but analysis of area under the curve indicated no difference.
ARC! subscales. Buprenorphine increased scores
on the MBG (Fig. 3, A) and PCAG (Fig. 3, B) subscales of the ARCI. There was a slight transient in-
CLINICAL PHARMACOLOGY & THERAPEUTICS
VOLUME 53, NUMBER 5
105
100
Pickworth et al.
Circular Lights
A
573
1.0
0.8
Aso
0.8
95.
0.4
90 -
0.2
e0
6
Subject's Liking
Pre-
0
1
2
3
4
5
12
0.0
Placebo
Good Effects
0.3 mg
0.6 mg
1.2 mg
18
24
Pre- 0
1
2
3
4
56
12
18
24
Hour
Fig. 2. Time-action curves for circular lights (A), feel drug (B), subject's liking (C), and good
effects (D) after intravenous buprenorphine (0.3, 0.6, and 1.2 mg) and placebo (n = 6) (maximal
score on subject's liking, 5; maximal score on good effects, 100).
crease in scores on the LSD subscale (Fig. 3, C). The
1.2 and 0.6 mg doses caused similar increases in the
MBG subscale; these scores were greater than after
the 0.3 mg dose. After all doses, MBG increases were
maximal within 30 minutes and declined to placebo
values within hour after the low dose and 21/2 hours
after the higher doses. The PCAG subscale score
gradually increased, reaching a peak 2 hours after the
high dose and 5 hours after the low dose. Increases in
scores on the PCAG subscale occurred later and persisted longer than those observed for the MBG or LSD
subscales.
1
DISCUSSION
Although there have been numerous reports of buprenorphine abuse,14-16.19'2° this appears to be the first
study that shows increases in scores for drug liking,
good effects, and drug-induced euphoria after intravenous buprenorphine administration. Intravenous buprenorphine changed physiologic and subjective measures that are valid predictors of the abuse liability of
opioids.24 However, the changes in subjective and
physiologic responses were not consistently dose related. This profile is compatible with the characterization of buprenorphine as a partial opioid agonist.
Buprenorphine increased scores on the MBG subscale of the ARCI to mean 5-hour total score of 60.
This score was comparable to that observed for intravenous morphine (20 mg/70 kg) or heroin (10 mg/70
kg).26 Other measures of drug-induced euphoria (e.g.,
liking scale of the SDQ23 and the visual analog "good
effects") were increased; these responses were similar
to those of intravenous morphine (30 mg).27 The lack
of increase in MBG subscale scores between the 0.6
and 1.2 mg doses suggests a ceiling effect occurred on
this measure. A curvilinear dose-response curve is
typical of the buprenorphine response in animal studies,2 and plateau effects have been reported for MBG
and drug-liking scales in human studies.6.28
The high dose of buprenorphine increased PCAG
subscales scores; the peak effect occurred between 2
and 5 hours after the intravenous administration of the
drug. In a study of long-term buprenorphine (Mello
et al.29), drowsiness and sedation occurred in three of
seven subjects during the first 6 days of subcutaneous
buprenorphine administration; however, tolerance
seemed to develop to the effect with continued daily
administration. Jasinski et al.6 also reported PCAG
score increases after subcutaneous buprenorphine. In
this study and the study by Jasinski et al.,6 increases
in PCAG subscales scores occurred later than the increases in MBG scores. Concurrent with the PCAG
score increase, there was a small decrement in circular
lights performance. Weinhold et al.3° also reported a
CLINICAL PHARMACOLOGY & THERAPEUTICS
MAY 1993
574 Pickworth et al.
A
MBG
161
12
10 -
8
6-
oAN
42
PCAG
15),
7
6
4
3
0 OE
2
LSD
--0
0-----
Placebo
0.3 mg
0.8 mg
1.2 mg
3-
2-
1
A
0
Pre-
0
2
4
5 6
12
18
24
Hour
Fig. 3. Time-action curves for the morphine-benzedrine
group (MBG) subscale (A), the pentobarbital-chlorpromazine-alcohol group (PCAG) subscale (B), and the lysergic
acid diethylamide (LSD) subscale (C) after intravenous buprenorphine (0.3, 0.6, and 1.2 mg) and placebo (n = 6).
Maximal scores are indicated on the ordinate.
small but significant decrease in performance on the
Digit Symbol Substitution Test after intramuscular
buprenorphine administration. Together, these findings suggest that high intravenous doses of buprenorphine cause drowsiness, sedation, and impaired performance.
In the present study, buprenorphine caused a small
decrease in respiratory rate that persisted for 6 hours.
This finding agrees with Weinhold et al.,3() who reported that intramuscular buprenorphine decreased
respiratory rates, and with the report by Ga1,31 who
found that intravenous buprenorphine (0.3 mg/70 kg)
reduced indexes of carbon dioxide responsiveness to
about one half of control values. Walsh et al.28 reported a small decrease in respiratory rate that appeared to plateau as the sublingual dose of buprenorphine was increased to 32 mg. However, after
subcutaneous administration of doses up to 8 mg, decreases in respiratory rate were not reported.° Our
findings differ from those of Budd,32 where intravenous buprenorphine (0.4 to 7 mg) did not change
depth, rate, or patterns of breathing in postoperative
patients. The lack of respiratory depression in the
Budd study32 might be explained by an inverted
U-shape dose-response curve.
A dose-dependent miosis was evident immediately
after intravenous buprenorphine administration and
persisted for 24 hours after the lower doses and up to
48 hours after the high dose. In these same subjects,
intravenous buprenorphine caused a long-lasting decrease in pupil size and a diminution in the constriction and dilation velocities and the amplitude of the
light reflex.33 Jasinski et al.° reported that 8 mg subcutaneous buprenorphine caused miosis. Sublingual
buprenorphine also caused miosis and decreased the
light reflex in heroin-dependent addicts.34
The findings of our study indicate that intravenous
buprenorphine has a pharmacologic profile similar to
other opioid agonists. Buprenorphine causes miosis, a
slight decrease in respiratory rate, and subjective effects that included elevation in drug liking, good effects, and increases in the MBG scores. These actions
are consistent with the suggestion that intravenous buprenorphine has substantial abuse potential. This suggestion is supported by worldwide reports of unauthorized intravenous administration of buprenorphine. On
the other hand, the respiratory rate decrease, MBG elevations, and estimates of good effects after the 1.2
mg dose were not significantly greater than those after
the 0.6 mg dose. It appears that a plateau exists for
these measures. Further increases in the dose of buprenorphine may not increase these effects. A decrease of effect could occur, as it does for electroencephalographic,35 analgesic,2 and operant behavior in
animal studies,36 and for respiratory and subjective effects after sublingual doses in humans.28 These effects
are characteristic of partial agonists. Thus the agonist
effects of buprenorphine may be self-limiting and the
abuse potential restricted to lower doses. If this is the
case, it is unclear how tolerance would affect the
abuse potential of buprenorphine under conditions of
long-term administration.
Understanding the abuse potential of intravenous
buprenorphine has practical and theoretic importance.
If buprenorphine becomes a widely used treatment for
CLINICAL PHARMACOLOGY & THERAPEUTICS
VOLUME 53, NUMBER 5
opioid dependence, drug diversion is likely to occur.
Combinations of buprenorphine with opioid antagonists may prevent illicit intravenous use. Preston
et al." reported that combinations of buprenoThine
and naloxone administered to opioid-dependent subjects produced fewer opioid withdrawal signs and
symptoms than naloxone alone. The authors suggested
that a buprenorphine-naloxone combination would
have a low potential for abuse in opioid-dependent
subjects. In another study, concurrent naloxone administration attenuated the opioid effects of buprenorphine in nondependent opioid users." The findings
from the present study indicate that buprenorphine formulations to be used in the treatment of opioid dependence should be examined carefully for abuse potential in both dependent and nondependent subjects.
We gratefully acknowledge the technical support of Ms.
Michelle Whitely and the editorial assistance of Ms. Patricia
Y. Thomas.
References
Cowan A, Doxey JC, Harry ETR. The animal pharmacology of buprenorphine, an oripavine analgesic agent.
Br J Pharmacol 1977;60:547-54.
Cowan A, Lewis JW, Macfarlane IR. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol 1977;60:537-45.
Houde RW. Analgesic effectiveness of the narcotic agonist-antagonists. Br J Clin Pharmacol 1979;7:297S308S.
Lewis JW, Rance MJ, Sanger DJ. The pharmacology
and abuse potential of buprenorphine: a new antagonist
analgesic. In: Mello NK, ed. Advances in substance
abuse: behavioral and biological research, vol. 3.
Greenwich: JAI Press, 1982:103-54.
Banks CD. Overdose of buprenorphine: case report. NZ
Med J 1979;89:255-6.
Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry 1978;35:501-16.
Haertzen CA. An overview of the Addiction Research
Center Inventory (ARCI): an appendix and manual of
scales. DHEW pub no (ADM) 79. Washington: Department of Health Education and Welfare, 1974.
Mello NK, Mendelson JH. Buprenorphine suppresses
heroin use by heroin addicts. Science 1980;207:657-9.
Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE. A clinical trial of buprenorphine: comparison with methadone in the detoxification
of heroin addicts. CLIN PHARMACOL TIER 1988;43:72-8.
Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE. Buprenorphine: dose-related
blockade of opioid challenge effects in opioid dependent humans. J Phannacol Exp Ther 1988;247:47-53.
Pickworth et al.
575
Johnson RE, Cone El, Henningfield JE, Fudala PJ. Use
of buprenorphine in the treatment of opiate addiction. I.
Physiologic and behavioral effects during a rapid dose
induction. CLIN PHARMACOL THER 1989;46:335-43.
Fudala PJ, Jaffe JH, Dax EM, Johnson RE. Use of buprenorphine in the treatment of opioid addiction. II.
Physiologic and behavioral effects of daily and alternate-day administration and abrupt withdrawal. CLIN
PHARMACOL THER 1990;47:525-34.
Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of
buprenorphine treatment for opioid dependence. JAMA
1992;267:2750-5.
Harper I. Temgesic abuse. NZ Med J 1983;777.
Rainey HB. Abuse of buprenorphine. NZ Med J
1986;72.
O'Connor JJ, Moloney E, Travers R, Campbell A. Buprenorphine abuse among opiate addicts. Br J Addict
1988;83:1085-7.
Richert S, Strauss A, von Arnim T, Vogel P, Zech A.
Medilcamentenabhangigkeit von buprenorphin. MMW
1983;125:1195-8.
Robertson JR, Bucknall ABV. Buprenorphine: dangerous drug or overlooked therapy. Br Med J 1986;292:
1465.
Quigley AJ, Bredemeyer DE, Seow SS. A case of buprenorphine abuse. Med J Aust 1984;140:425-6.
Sakol MS, Stark C, Sykes R. Buprenorphine and
temazepam abuse by drug takers in Glasgow-an increase [Letter]. Br J Addict 1989;84:439-41.
Gray RF, Ferry A, Jauhar P. Emergence of buprenorphine dependence. Br J Addict 1989;84:1373-4.
Marquardt WG, Martin WR, Jasinski DR. The use of
the Polaroid CU camera in pupillography. Int J Addict
1967;2:301-4.
Fraser HF, Van Horn GD, Martin WR, Wolbach AB,
Isbell H. Methods of evaluating addiction liability. (A)
Attitude of opiate addicts toward opiate-like drugs, (B)
a short term direct addiction test. J Pharmacol Exp Ther
1961;133:371-87.
Jasinski DR. Assessment of the abuse potentiality of
morphine-like drugs (methods used in man). In: Martin
WR, ed. Handbook of experimental pharmacology:
drug addiction I, morphine, sedative-hypnotic and alcohol dependence. Heidelberg: Springer-Verlag, 1977:
197-258.
Heishman Si, Huestis MA, Henningfield JE, Cone EL
Acute and residual effects of marijuana: profiles of
plasma THC levels, physiologic, subjective, and performance measures. Phannacol Biochem Behav 1990;
37:561-5.
Jasinski DR, Preston KL. Comparison of intravenously
administered methadone, morphine and heroin. Drug
Alcohol Depend 1986;17:301-10.
Jasinski DR, Martin WR, Hoeldtke R. Studies of the
dependence producing properties of GPA-1657, profadol and propiram in man. CLIN PHARMACOL THER
1971;12:613-49.
576
CLINICAL PHARMACOLOGY & THERAPEUTICS
Pickworth et al.
Walsh SL, Preston KL, Stitzer ML, Bigelow GE, Liebson IA. The acute effects of high dose buprenorphine in
nondependent humans. In: Harris L, ed. Problems of
drug dependence 1991. NIDA Research Monograph
119;1992:245.
Mello NK, Mendelson JH, Kuehnle JC. Buprenorphine
effects on human heroin self-administration: an operant
analysis. J Phannacol Exp Ther 1982;223:30-9.
Weinhold LL, Preston KL, Farre M, Liebson IA, Bigelow GE. Buprenorphine alone and in combination
with naloxone in non-dependent humans. Drug Alcohol
Depend 1992;30:263-74.
Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. CLIN PHARMACOL THER 1989;45:
66-71.
Budd K. High dose buprenorphine for postoperative analgesia. Anesthesia 1981;36:900-3.
MAY 1993
Pickworth WB, Bunker E, Welch P, Cone E. Intravenous buprenorphine reduces pupil size and the light reflex in humans. Life Sci 1991;49:129-38.
Pickworth WB, Lee H, Fudala PJ. Buprenorphineinduced pupillary effects in human volunteers. Life Sci
1990;47:1269-77.
Kareti S. Moreton JE, Khazan N. Effects of buprenorphine, a new narcotic agonist-antagonist analgesic on
the EEG, power spectrum and behavior of the rat. Neuropharmacology 1980;19:195-201.
Leander JD. Opioid agonist and antagonist behavioral
effects of buprenorphine. Br J Pharmacol 1983;78:60715.
Preston KL, Bigelow GE, Liebson IA. Buprenorphine
and naloxone alone and in combination in opioiddependent humans. Psychophannacology 1988;94:48490.
Bound volumes available to subscribers
Bound volumes of CLINICAL PHARMACOLOGY & THERAPEUTICS are available to subscribers (only) for the 1993 issues from
the Publisher, at a cost of $52.50 for domestic, $69.18 for Canadian, and $65.50 for international subscribers for Vol. 53
(January-June) and Vol. 54 (July-December). Shipping charges are included. Each bound volume contains a subject and
author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue of the
volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine.
Payment must accompany all orders. Contact Mosby, Subscription Services, 11830 Westline Industrial Drive, St. Louis, MO
63146-3318, USA; phone (800)453-4351, or (314)453-4351.
Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.