BUPRENORPHINE:
`
`COMBATTING DRUG ABUSE
`WITH A UNIQUE OPIOID
`
`
`Editors
`
`ALAN COWAN
`
`Department of Pharmacology
`Temple University School of Medicine
`Philadelphia, Pennsylvania
`
` 4km;
`
`
`
`rm“firs-£5.14.'era:death-m"
`
`JOHN W. LEWIS
`
`School of Chemistry
`University of Bristol
`Bristol, England
`
`@WILEY-Liss
`A JOHN WILEY & SONS, INC. , PUBLICATION
`New York ' Chichester 0 Brisbane 0 Toronto 0 Singapore
`
`RB Ex. 2022‘
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`Page 1
`
`Page 1
`
`RB Ex. 2022
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`

`Address All Inquiries to the Publisher
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`Copyright © 1995 Wiley-Liss, Inc.
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`Foreword
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`in the most current issue of “Permissions to Photocopy" (Publisher's Fee List, distributed by
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`
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`I
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`.5
`‘
`
`.
`'
`
`Preface
`
`AmnCMfi
`
`CHEMIS
`'-
`
`While the authors. editors, and publisher believe that drug selection and dosage and the
`specifications and usage of equipment and devices. as set forth in this book, are in accord
`with current recommendations and practice at the time of publication, they accept no legal
`responsibility for any errors or omissions. and make no warranty, express or implied, with
`respect to material contained herein. in view of ongoing research, equipment modifications,
`changes in govemmental regulations and the constant flow of information relating to drug
`therapy. drug reactions and the use of equipment and devices, the reader is urged to review
`and evaluate the information provided in the package insert or instructions for each drug,
`piece of equipment or device for, among other things, any changes in the instructions or
`indications of dosage or usage and for added warnings and precautions.
`
`Library of Congress Cataloging-in-Publication Data
`
`Buprenorphine : combatting drug abuse with a unique opioid / edited by
`Alan Cowan and John W. Lewis.
`p.
`cm.
`
`
`
`
`
`Buprenor
`John W. L:
`.
`
`i
`I
`
`f
`‘
`
`Richard 8.
`
`_;
`
`.
`
`Update 0'
`
`
`
`Includes bibliographical references and index.
`ISBN 0-471-56198-3
`l. Opioid habit—Chemotherapy.
`2. Buprenorphine—Therapeutic use.
`I. Cowan, Alan, 1942—
`;
`II. Lewis John W.
`[DNLM:
`l. Buprenorphine—therapeutic use.
`2. Narcotic Dependence—
`therapy. QV 92 B9443
`1994]
`RC568.058BS7
`1994
`616.86’32061 —dc20
`DNLM/DLC
`for Library of Congress
`
`g ;
`'
`~
`.
`a
`3
`=
`1
`=
`
`.
`
`.
`
`94-28470
`ClP
`
`The text of this book is printed on acid-free paper.
`
`HH illHill“iii“Williill
`
`Alli-ll]: 651.733
`
`]
`
`
`
`Page 2
`
`;}
`.
`a
`Behavuorfi
`Buprenorl
`Linda A. of}
`i
`- Reinforciti
`and Physi‘
`.Ssmme
`‘8
`
`
`Page 2
`
`

`

`BUPRENORPHINE KINETICS
`IN HUMANS
`
`H. J. McQUAY
`
`Oxford Regional Pain Relief Unit, Churchill Hospital, Oxford OX3 7LJ, and Nuffield
`Department of Anaesthetics, Radcliffe Infirmary, Oxford, UK
`Fl. A. MOORE
`
`Oxford Regional Pain Relief Unit, Churchill Hospital, Oxford OX3 7LJ, Nuffield
`Department of Anaesthetics, Radcliffe Infirmary, Oxford, and Euro/DPC Ltd, Glyn
`Rhonwy, Llanberis, Caernarton, Wales, UK
`__—____—__—.—_—————-—
`
`
`
`© 1995 Wiley-Liss, Inc.
`
`This chapter reviews kinetic data for single—dose parenteral and sublingual
`buprenorphine and data on single—dose 0.6-mg intravenous (i.v.) buprenorphine,
`single—dose 0.3-mg i.v. buprenorphine in end-stage renal failure, single-dose 0.4-
`mg oral buprenorphine, chronic sublingual kinetics after dosing with 0.4 mg three
`times daily, iv infusion kinetics in patients with renal dysfunction, and cerebrospi-
`nal (CSF) and plasma concentrations after intrathecal and extradural doses of
`buprenorphine. In all of these studies, plasma buprenorphine concentrations were
`measured by a sensitive and specific radioimmunoassay [Bartlett et al., 1980] and
`single-dose studies used arterial samples exclusively.
`
`INTRODUCTION
`
`'Buprenorphine is a synthetic opiate analgesic with partial agonist properties [Heel et
`al., 1979]. Its slow dissociation from the receptor [Hambrook and Rance, 1976] and
`its long (6— 10 hr) duration of clinical effect [McQuay et al. , 1980] lead to particular
`interest in its kinetics.
`
`INTRAVENOUS KINETICS
`
`Single~dose pharmacokinetic data for intravenous buprenorphine at 0.3—mg and 0.6-
`mg doses are summarized in Table I and Figure l . Sufficient samples, including early
`
`Buprenomhine: Combam‘ng Drug Abuse With a Unique Opioid, pages 137—147
`
`Page 3
`
`

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`Page 4
`
`Page 4
`
`
`
`
`

`

`Fig. 1. Mean plasma buprenorphine concentrations fo
`dose of 0.3 mg intraveno
`
`dose.
`
`.
`'
`
`,
`
`r 10 patients given a postoperative
`et al., 1980] (El); 10 patients given a
`Bullingham et al., 1980] (A);
`ual buprenorphine [Bullingham
`raoperative 0.3-mg intravenous
`
`points, were taken to allow
`1980; Watson et al.,
`.
`2—3 hr;
`'
`
`'
`
`-hr data [Bullingham et al.,
`erminal half-life estimate of
`
`9441:5"..héafle-.‘--A~
`
`_. 0
`
`BUPFIENOHPHINE KINEI'ICS IN MAN
`
`139
`
`
`
`
`
`PlasmaBuprenorphine(ng/ml)
`
`Single-Dose Intravenous Kinetics in Renal Failure
`
`for anae
`values in the same patients were significantly different; the
`lower clearance in the anaesthetized
`
`Page 5
`
`

`

`140
`
`MCQUAY AND MOORE
`
`INTRAMUSCULAR KINETICS
`
`Plasma buprenorphine concentrations after a postoperative 0.25-mg intramuscular
`(i.m.) dose showed very rapid absorption [Bullingham et a1. , 1980]. Average peak
`plasma concentrations of 3.6 ng/ml occurred 2—5 min after the dose was given; by
`ten minutes there was no significant difference from the plasma concentrations seen
`after the same dose given intravenously. The mean kinetic data for the i.m. dose are
`summarized in Table I and are shown in Figure 1. Even though 2- and 5-min
`samples were taken, absorption was too fast to allow calculation of an absorption
`rate constant. Systemic availability of the 0.3-mg i.m. dose was greater than 90% in
`7 of the 11 patients; in the other 4 it was between 40% and 60%.
`
`SUBLINGUAL KINETICS
`
`Single Dose
`
`The mean peak plasma buprenorphine concentration, time to peak concentration,
`and systemic
`availability for 0.4-mg and 0.8-mg single-dose
`sublingual
`buprenorphine are shown in Table 2, and for the 0.4-mg dose are shown in Figure 1.
`After sublingual doses there was no significant rise in mean plasma buprenorphine
`concentration for 20 min [Bullingham et al., 1981a; Bullingham et al., 1982a]. The '
`pattern of the rise varied greatly between patients; peak plasma buprenorphine
`concentration occurred anywhere between 20 and 360 min, but generally at about 3
`hr. From about 2 hr, the plasma concentrations were sustained for some hours at a
`higher level than seen after comparable parenteral doses (Fig. 1). Similar plasma
`concentrations were reported by an enzyme immunoassay method [Tiong and Olley,
`1988].
`
`The average maximum increase in plasma concentration of 0.50 ng/ml after a
`
`TABLE II. Pharmacokinetic Data for Sublingual and Oral Buprenorphine“E
`
`23.rn
`
`rue-sage:-
`
`*x:
`
`Systemic
`Study
`Route
`availability
`Cm“
`duration Weight
`No.
`dose
`
`
`
`(hr)of pts(mg) (%)a(kg) (ng/ml) '
`
`
`Sublingualb
`0.4
`0.8
`0.4
`Oral
`
`5
`5
`10
`
`10
`10
`3
`
`66 i 3
`65 i 4
`69 1‘ 3
`
`0.50 1‘ 0.06
`1.04 i 0.27
`0.74 i 0.16
`
`
`
`6
`l
`
`57.7
`
`31
`
`
`
`
`
`nValues are mean 1 SEM. No Tm“ quoted for 3-hr sublingual study because concentrations were still
`rising for some patients. Values (with ranges) shown for the oral study because two patients had no
`measured absorption.
`bBullingham et al. [l98la, 1982a].
`
`2.7
`
`0.4 14 (0—33)H“6 3 70 i 4 0.25 (<0.1—0.62) 20 (?—180)
`
`
`
`
`
`
`
`
`
`Page 6
`
`

`

`
`
`new:4.“...2...‘
`
`BUPFIENORPHINE KINETICS IN MAN
`
`141
`
`0.4-mg single sublingual dose was doubled to 1.04 ng/ ml after a 0.8—mg dose
`(Table II). The increase in dose roughly doubled the average plasma concentrations
`and hence the area under the plasma concentration—time curve, but made no differ-
`ence to the systemic availability or to the time to reach peak plasma concentration.
`Average systemic availability, calculated as 30% by 3 hr [Bullingham et al., 1981a],
`rose to 55% by increasing study duration to 10 hr; in individual patients this varied
`from 16%—94% [Bullingham et a1. , 1982a]. The absorption half—life was estimated
`at 76 min based on a single—compartment model, first-order absorption, and mean
`plasma drug concentrations [Bullingham et al., 1982a].
`
`Chronic Dosing
`
`Four patients with chronic pain, who had been taking 0.4 mg sublingual
`buprenorphine three times a day for at least 4 weeks (median 2 months, range 1—12
`months), were studied when they stopped taking the drug to obtain decay kinetics
`from steady-state chronic dosing (Hand et al.,
`1986]. The mean plasma
`buprenorphine level on this 0.4—mg three times daily dose was 0.5 i 0.2 ng/mL
`(SEM) 2 hr after dose (i.e., close to peak). Venous samples were taken 2, 6, 10, 26,
`30, 50, 54, 74. 98, and 122 hr after the final dose. Kinetic analysis of the mean
`plasma concentrations revealed two components of this decay. The first had a half-
`life of 3.7 hr (similar to the terminal half-life reported in the 3-hr parenteral studies;
`Table I); the second had a much longer half-life of 45 hr, but only became evident
`when plasma buprenorphine concentrations were below 0.2 ng/ ml.
`
`‘Beams
`
`IORAL KINETICS
`
`Buprenorphine 0.4 mg was given orally to postoperative patients at the same sample
`times (over 3 hr) as a previous sublingual study [Bullingham et al., 1981a]. From 1
`to 3 hr, oral buprenorphine resulted in significantly lower plasma buprenorphine
`concentrations than after the same dose given sublingually (Fig. 2). The median
`systemic availability (Table II) was 16% (range 0%—36%), consistent with the mean
`availability of 15% calculated from the intravenous bolus kinetics [Bullingham et
`a1., 1980].
`
`SPINAL KINETICS
`
`There is little published information on the kinetics of intrathecal or extradural
`administration of buprenorphine. When buprenorphine 0.03 mg (diluted with saline
`to 1 m1 injectate) was given intrathecally at the lumbar level for treatment of painful
`spasm in 6 paraplegic patients [Glynn et al., 1984], there was a rapid fall in the
`mean CSF concentrations (Fig. 3).
`After an extradural dose of 0.3 mg of buprenorphine to three patients with
`painful paraplegic spasm a peak CSF concentration of 9.5 ng/ml was reached after
`
`Page 7
`
`

`

`142
`
`MCQUAY AND MOORE
`
`
`
`
`
`Plasmabuprenorphine(nglml)
`
`120
`so
`Time (min)
`
`Fig. 2. Mean (1 SEM) plasma buprenorphine concentrations against time for 6 patients
`given 0.4 mg oral buprenorphine (El) and 5 patients given 0.4 mg sublingually (0) [Bull-
`ingham et al., 1982a]. Patients had previously been given an intraoperative 0.3-mg intra-
`venous dose. The computed contribution from that close was subtracted from the measured
`concentrations to derive the data used in the figure.
`
`0.03 mg intrathecal buprenorphine in 1 m1 at the lumbar level [Jamous, 1987].
`
`45 min, with a mean concentration of 0.2 ng/ml at 24 hr (Fig. 4) [Jamous, 1987].
`The CSF absorption half-life was calculated at 3.5 min, with an elimination half-life
`of 84 min, a mean time to peak concentration of 16 min, and a mean maximum
`concentration of 13.2 ng/ml [Jamous, 1987]. The peak plasma buprenorphine con-
`centration was reached much earlier than in CSF (Fig. 4).
`CSF concentrations were measured after an intravenous dose of 0.6 mg of
`buprenorphine in three patients undergoing neurosurgery [Jamous, 1987]. CSF
`buprenorphine concentrations were very low, with 0.17 ng/ml measurable at the
`first sample time (10 min), and the highest mean value (0.3 ng/ml) occurring at 3 hr.
`
`
`
`
`
`CSFbuprenorphine(nglml)
`
`so
`
`120
`
`180
`
`240
`
`300
`
`360
`
`fig. 3. Mean (1 SEM) CSF buprenorphine concentrations against time for six patients given
`
`Time (min)
`
`Page 8
`
`

`

`
`
`
`
`0
`
`360
`
`BUPRENORPHINE KINETICS IN MAN
`
`143
`
`a 100
`5,
`0
`5 10
`.E.C
`
`1
`
`.1
`
`it
`.3
`In
`
`C 2a
`
`720
`Time (min)
`Fig. 4. Mean (i SEM) CSF (El) and plasma ( 6) buprenorphine concentrations against time
`for three patients given 0.3 m
`g extradural buprenorphine in 5 m1 at the lumbar level [Jamous,
`1987].
`
`1080
`
`1440
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The high systemic clearance ofbuprenorphine (> 1,000 m1/min) approaches hepat—
`
`
`'c blood flow and leads to the prediction [Wilkinson and Schenker, 1976] that drugs
`
`Kinetic analysis with 3-hr sampling after a single i.v. dose showed no change in the
`fate of buprenorphine in patients with impaired renal function [Summerfield et a1. ,
`1985]. In 9 dialysis-dependent patients there were no differences in buprenorphine
`kinetics with 24-hr sampling after a single i.v. 0.3-mg dose compared with 6
`patients with normal renal function [Hand et al., 1990]. Continuous i.v. infusion in
`8 patients with renal failure showed similar plasma buprenorphine concentrations
`and clearance values compared with values for infused patients with normal renal
`function [Hand et al., 1990]. Plasma concentrations of norbuprenorphine, however,
`were increased by a median of 4 times compared with normal renal function pa-
`tients, and buprenorphine-3—glucuronide concentrations were increased by a median
`of 15 times [Hand et al., 1990].
`
`
`
`METABOLISM
`
`Buprenorphine is metabolized in humans by N-
`dealkylation and conjugation of
`-dea1kyl buprenorphine and the parent drug;
`about 70% of a radioactive oral or
`intravenous dose is recovered in feces and most of the remainder appears in the
`urine [Heel et al., 1979]. The N-dealkyl metabolite has even slower elimination
`than the parent compound [Hand et a1. , 1986]. The red blood cell:p1asma buprenor-
`phine ratio is reported to be close to unity [Bullingham et a1. , 1980]. Buprenorphine
`and its glucuronide appear in urine in l —2 days, and the N-dealkyl metabolite and
`its glucuronide in 1—4 days [Cone et al., 1984; Blom et al., 1985].
`
`Impaired Renal Function
`
`IMPLICATIONS FOR CLINICAL USE
`
`Page 9
`
`

`

`144
`
`McQUAY AND MOORE
`
`
`
`
`or interventions that lower hepatic blood flow should decrease buprenorphine clear-
`ance. The intraoperative fall in buprenorphine clearance [Bullingham et al., 1980]
`when halothane was used intraoperatively agrees with this. Another consequence of
`
`high clearance is the prediction of a substantial first-pass effect and low oral bio-
`availability. The median oral bioavailability for buprenorphine of 16% reported here
`is consistent with the prediction, as was the analgesic effect of oral doses of 1—2 mg
`[Bullingham et al., 1981b].
`Sublingual administration provides a way of avoiding the first-pass effect, and
`
`the systemic availability for sublingual doses up to 0.8 mg of 55% is borne out by
`the effectiveness of analgesia obtained by this route, which is equivalent to that seen
`with parenteral
`routes [Bullingham et al., 1981a]. Both oral and sublingual
`buprenorphine resulted in large variation in calculated systemic availability. Low
`
`availability after sublingual doses may result if the dose is swallowed rather than
`kept under the tongue; unexpectedly high availability after an oral dose might result
`if the dose were held up in the oesophagus and mucosal absorption, which is
`presumably like sublingual, should occur there.
`The long terminal half-life revealed by the chronic dosing kinetics suggests that it
`may take up to 10 days for steady-state plasma drug concentrations to be achieved
`
`by sublingual dosing alone." Equally, such a long half-life supports the use of
`buprenorphine in suppressing the use of heroin by addicts [Mello and Mendelson,
`
`1980]. The lack of withdrawal symptoms until Day 14 after 8-mg total daily dose
`may again reflect this long half—life [Jasinski et al., 1978].
`
`While the spinal route for opiates is capable of producing remarkable analgesia
`[Bullingham et al., 1982b; Bullingham et al., 1983], there is little spinal kinetic
`
`information available for buprenorphine. In vivo experiments showed that very high
`intrathecal doses of buprenorphine would be required to produce analgesic effect
`
`[Dickenson et al., 1990], and this was attributed to the high lipophilicity. The high
`
`doses necessary would be subject to systemic absorption, and it is doubtful whether
`
`there would be any measurable clinical gain from giving such high doses intra—
`
`thecally as opposed to systemically. By analogy with methadone it might also be
`
`unsafe [Jacobson et al., 1990]. In vitro experiments demonstrated that the per-
`
`meability of buprenorphine for both lumbar and cranial dura was the lowest of any
`
`opioid studied [Moore et al., 1982], and this was attributed to the relatively high
`
`molecular weight. Calculations indicated that only 0.2% of an extradural dose of
`
`buprenorphine would cross the dura, compared with 20% for extradural morphine
`
`[Moore et al., 1982]. The limited information in patients (Fig. 4) [Jamous, 1987]
`shows that CSF concentrations are considerably higher after an extradural dose than
`
`they are after the equivalent dose given i.v. The CSF concentration required for a
`
`spinal as opposed to a central effect is probably much greater again [Dickenson et
`
`al., 1990].
`‘
`
`The relative availabilities for intramuscular and sublingual buprenorphine quoted
`
`above agree well with the relative potency ratio for intramuscular and sublingual
`
`analgesia of 2:1 in postoperative or cancer patients [Wallenstein et al., 1982]. Such
`
`a direct relation between dose, plasma concentration, and effect may not always be
`
`so apparent with this drug.
`
`
`
`
`
`
`
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`
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`
`
`Page 10
`
`

`

` BUPFIENOFIPHINE KINETICS IN MAN
`
`Buprenorphine is an intriguing and complicated drug; it is a potent partial ago-
`nist, is highly lipophilic, and dissociates slowly from the receptor. It has proved to
`be an effective, strong analgesic, and the apparent ceiling effect on respiration and
`unchanged kinetics in renal failure are two specific advantages for the drug. These
`properties make sublingual buprenorphine an important alternative for patients in
`both acute and chronic pain.
`
`ACKNOWLEDGMENTS
`
`
`
`145
`
`
`
`Doubling the intravenous dose from 0.3 to 0.6 mg produced a dose~related
`
`
`increase in analgesia and increased neuroendocrine effects without significant
`
`change in blood gases [Watson et al., 1982]. The same doses given as infusions over
`
`
`20 min to volunteers for rebreathing studies also produced no dose response for
`
`
`respiratory depression [De Klerk et al., 198]]. This suggests a ceiling effect in the
`
`
`therapeutic dose range for respiratory depression but not for analgesia. Although
`
`
`plasma concentrations after intravenous or intramuscular doses did not differ after
`
`
`10 min [Bullingham et al., 1980], the analgesia and the neuroendocrine effects were
`
`
`significantly greater after intramuscular use [McQuay et al., 1980] without greater
`
`respiratory effects.
`
`
`Men and women may respond differently to the same plasma buprenorphine
`
`
`concentration. Different analgesic and neuroendocrine effects were obtained in men
`
`
`and women who were given the drug by the same route; in men buprenorphine had
`
`
`less analgesic effect but produced a significantly greater suppressive effect on neu-
`
`
`roendocrine stress responses to surgery [McQuay et al., 1980; Moore et al., 1981].
`
`
`These differences could not be explained by any difference in plasma drug concen-
`tration or kinetic fate.
`
`
`
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`We wish to thank Mike Allen, Dene Baldwin, Martin Bennett, Roy Bullingham,
`Dawn Carroll, Peter Evans, Chris Glynn, Chris Hand, Ali Jamous, John Lloyd,
`Geraldine O’Sullivan, Patsy Poppleton, Brian Porter, John Sear, Richard Summer—
`field, and Jane Watson for their help in this work.
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`Bartlett AJ, Lloyd-Jones JG, Rance Ml, Flockhart lR, Dockray G, Bennett MRD, Moore RA
`(1980): The radioimmunoassay of buprenorphine. Eur] Clin Pharmaco 18:339—345.
`Blom Y, Bondesson U, Anggard E (1985): Analysis of buprenorphine and its N—dealkylated
`metabolite in plasma and urine by selected—ion monitoring. J Chromatogr 338289-98.
`Bullingham RES, McQuay HJ, Moore RA. Bennett MRD ([980): Buprenorphine kinetics.
`Clin Pharmacol Ther 28:667—672.
`Bullingham RES, McQuay HJ, Dwyer D, Allen MC, Moore RA (1981a): Sublingual
`buprenorphine used postoperatively: Clinical observations and preliminary pharmacokine-
`tic analysis. Br J Clin Pharmacol 12:117—122.
`Bullingham RES, McQuay H], Moore RA, Weir L (1981b): An oral buprenorphine and
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`buprenorphine with iodine label: Analysis of buprenorphine and metabolites in human
`plasma. Ann Clin Biochem 23:47—53.
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`disposition in patients with renal impairment: Single and continuous dosing, with special
`reference to metabolites. Br J Anaesth 64:276—282.
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`response study and comparison with intrathecal morphine 0.5 mg. Pain 43: 141—148.
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`analgesic buprenorphine. Arch Gen Psychiatry 35:501—516.
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`buprenorphine during and after surgery. BrJ Anaesth 52:1013—1019.
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`Mello N, Mendelson JH (1980): Buprenorphine suppresses heroin use by heroin addicts.
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`aesthesia 36:263—267.
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`n'prenorphine and morphine (abstract). Clin Pharmacol Ther 31:278.
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