Psychopharmacology (2001) 154:230–242
`DOI 10.1007/s002130000637
`
`O R I G I N A L I N V E S T I G AT I O N
`
`Kenneth B. Stoller · George E. Bigelow
`Sharon L. Walsh · Eric C. Strain
`Effects of buprenorphine/naloxone in opioid-dependent humans
`
`Received: 2 February 2000 / Accepted: 16 October 2000 / Published online: 27 January 2001
`© Springer-Verlag 2001
`
`Abstract Rationale: Buprenorphine is a partial mu opi-
`oid agonist under development as a sublingual (SL) med-
`ication for opioid dependence treatment in the United
`States. Because buprenorphine may be abused, tablets
`combining buprenorphine with naloxone in a 4:1 ratio
`have been developed to reduce that risk. Low doses of
`injected buprenorphine/naloxone have been tested in opi-
`oid-dependent subjects, but higher doses (more than
`2 mg of either medication) and direct comparisons to SL
`buprenorphine/naloxone have not been examined. Objec-
`tives: To assess and compare the effects of intramuscular
`(IM) versus SL buprenorphine/naloxone in opioid-de-
`pendent volunteers. Methods: Opioid-dependent volun-
`teers were maintained on 40 mg per day of oral hydro-
`morphone while on a residential research ward. After
`safety testing in two pilot subjects, participants (n=8)
`were tested with both IM and SL buprenorphine/nalox-
`one (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); IM hydromor-
`phone (10 mg) and naloxone (0.25 mg); both IM and
`SL buprenorphine alone (8 mg); and placebo. Test
`sessions were twice per week; dosing was double-
`blind. Results:
`Intramuscular buprenorphine/naloxone
`produced dose-related increases on indices of opioid an-
`tagonist effects. Effects were consistent with naloxone-
`precipitated withdrawal, and were short-lived. As with-
`drawal effects dissipated, euphoric opioid agonist effects
`from buprenorphine did not appear. Sublingual bupre-
`
`Some of these data were presented at the annual meeting of the
`College on Problems of Drug Dependence, Scottsdale, Arizona,
`June 1998
`K.B. Stoller (✉
`) · G.E. Bigelow · S.L. Walsh · E.C. Strain
`Behavioral Pharmacology Research Unit,
`Department of Psychiatry and Behavioral Sciences,
`The Johns Hopkins University School of Medicine,
`5510 Nathan Shock Drive, Baltimore, MD 21224, USA
`e-mail: kstolle@jhmi.edu
`Tel.: +1-410-550-0094, Fax: +1-410-550-0060
`K.B. Stoller
`Addiction Treatment Services at Hopkins Bayview,
`Mason F. Lord Building, 6 East, Johns Hopkins Bayview Campus,
`4940 Eastern Avenue, Baltimore, MD 21224, USA
`
`norphine/naloxone produced neither opioid agonist nor
`antagonist effects. Conclusions: Intramuscular injection
`of buprenorphine/naloxone precipitates withdrawal in
`opioid dependent persons; therefore, the combination has
`a low abuse potential by the injection route in this popu-
`lation. Sublingual buprenorphine/naloxone by tablet is
`well tolerated in opioid dependent subjects, and shows
`neither adverse effects (i.e., precipitated withdrawal) nor
`a high abuse potential (i.e., opioid agonist effects).
`
`Keywords Agonist-antagonist · Buprenorphine ·
`Buprenorphine/naloxone · Hydromorphone · Naloxone ·
`Opioid dependence · Opioid
`
`Introduction
`
`Buprenorphine is an opioid mixed agonist-antagonist
`that is effective in the treatment of opioid dependence
`(Bickel et al. 1988; Johnson et al. 1992, 1995; Kosten et
`al. 1993; Strain et al. 1994; Ling et al. 1996, 1998;
`Schottenfeld et al. 1997). The analgesic form of bupre-
`norphine is approved in the United States for use only by
`injection, but this method of delivery is not optimal
`when treating opioid dependent outpatients on a daily or
`near-daily basis. Buprenorphine has relatively poor oral
`bioavailability; hence, development has focused upon a
`sublingual delivery system, because good bioavailability
`is possible by this route. Early clinical studies of bupre-
`norphine used an SL solution, but this form has practical
`limitations (i.e., preparation, storage and administration,
`and easier abuse by injection). For these reasons, interest
`has focused upon the development of a buprenorphine
`tablet for SL administration. Such a formulation is
`currently marketed in France, where an estimated
`55,000 patients were receiving buprenorphine as of 1998
`(Auriacombe 2000).
`Buprenorphine is a partial mu agonist and kappa an-
`tagonist (Rothman et al. 1995). As with other mu agonist
`opioids, abuse of buprenorphine is possible, and has
`been reported from several countries (Strang 1985;
`
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`O’Connor et al. 1988; Gray et al. 1989; Singh et al.
`1992; Robinson et al. 1993). Since an SL tablet must be
`water soluble, it is possible that buprenorphine tablets
`could be dissolved and injected. Acute doses of parenter-
`al buprenorphine produce opioid agonist-like effects in
`opioid dependent subjects (Schuh et al. 1996; Strain et
`al. 1997).
`Because of this potential for abuse of buprenorphine
`tablets, interest has shifted to the development of a bu-
`prenorphine tablet that also contains naloxone. Unlike
`buprenorphine, low doses of naloxone have poor SL bio-
`availability (Preston et al. 1990). Thus, a buprenor-
`phine/naloxone tablet taken by the therapeutic route (i.e.,
`SL) should produce a predominant buprenorphine effect.
`However, if such a tablet were dissolved and injected by
`an opioid dependent person, naloxone would produce a
`precipitated opioid withdrawal syndrome.
`In opioid-dependent volunteers parenteral administra-
`tion of the buprenorphine/naloxone combination precipi-
`tates a withdrawal syndrome (Preston et al. 1988;
`Mendelson et al. 1996, 1997, 1999; Fudala et al. 1998).
`These studies have generally tested a low range of bu-
`prenorphine/naloxone doses; the highest parenteral bu-
`prenorphine dose tested has been 2 mg, and the highest
`parenteral dose of naloxone tested has also been 2 mg
`(both alone and combined with 2 mg buprenorphine;
`Mendelson et al. 1996). Based upon human laboratory
`studies of different dose ratios of buprenorphine to nal-
`oxone (e.g., Fudala et al. 1998; Mendelson et al. 1999),
`the United States National Institute on Drug Abuse
`(NIDA) has selected buprenorphine/naloxone tablets
`with a 4:1 dose ratio for clinical testing.
`While low doses of combination buprenorphine/nal-
`oxone precipitate withdrawal in dependent subjects,
`combinations incorporating the larger buprenorphine
`doses typically used in addiction treatment (8 mg and
`above) have not been previously tested. In addition, pre-
`vious studies of buprenorphine/naloxone have tested the
`effects of this combination when given by injection, but
`not sublingually. Low doses of SL naloxone may not
`precipitate withdrawal in opioid dependent subjects, but
`higher doses can. In a study of SL naloxone in opioid de-
`pendent volunteers, naloxone doses of 1–2 mg were
`identified as the approximate threshold above which sub-
`jects experienced precipitated withdrawal (Preston et al.
`1990). It is possible that some patients might experience
`precipitated withdrawal from the combination product
`taken by the SL route because dosing of buprenor-
`phine/naloxone is expected to be at least 8–16 mg per
`day of buprenorphine combined with 2–4 mg naloxone.
`The purpose of this study was to assess the effects of
`buprenorphine/naloxone combinations over a broad dose
`range when administered by both the SL and parenteral
`routes to opioid dependent volunteers. The study sought
`to determine how buprenorphine and naloxone might in-
`fluence the effects of each other, as a function of both
`dose and route of administration. In addition, the study
`included testing of doses of buprenorphine without nal-
`oxone, prototypic opioid agonist and antagonist control
`
`231
`
`conditions, and placebo. The results from this study pro-
`vide information about how the combination of an opioid
`agonist with an opioid antagonist produce differential
`predominating effects when administered by different
`routes of administration. These results are also relevant
`to the clinical development and use of buprenorphine
`and buprenorphine/naloxone in the treatment of opioid
`dependence.
`
`Materials and methods
`
`Subjects
`
`Ten adult male and female volunteers with heroin dependence
`were enrolled in the study. Recruitment of participants was per-
`formed by study staff, primarily through newspaper advertise-
`ments and responding to telephone inquiries. Inclusionary criteria
`included an age of 18–55 years, diagnosis of current opioid depen-
`dence as assessed using the Structured Clinical Interview for
`DSM-IV (First et al. 1995), and eligibility for (but not enrolled in)
`opioid agonist treatment. Exclusionary criteria included pregnancy
`and significant medical or non-substance use psychiatric illness
`(e.g., schizophrenia). Individuals seeking substance abuse treat-
`ment were not enrolled but were assisted in referral to community-
`based treatment programs.
`Participants underwent routine medical screening, including
`medical history and physical examination, psychiatric history,
`electrocardiogram, and basic chemistry, hematology and urinalysis
`testing. Results were reviewed by medical staff not involved in the
`study as investigators, and all subjects were found to be without
`significant medical or psychiatric problems. The study was ap-
`proved by the Institutional Review Board; volunteers gave written
`informed consent and were paid for their participation.
`The first two participants were pilot safety subjects who were
`tested in a non-randomized escalating dose order to ensure all con-
`ditions would be tolerated. Otherwise, all procedures for these two
`subjects were identical to those used for the remaining eight sub-
`jects. Data from these first two participants are excluded from ana-
`lyses.
`The two pilot subjects tolerated all dose conditions, and the
`remaining eight participants were tested with randomized dose
`sequences. Of these eight subjects, six were male, all were Afri-
`can-American, and they had an average age of 36 years (range
`27–45 years). The mean duration of illicit opioid use was 8.5 years
`(range 4–14 years), frequency of use was at least once per day, and
`amount spent on opioids ranged from $10 to over $150 per day.
`
`Study setting
`
`Subjects lived on a closed, 14-bed pharmacology residential re-
`search unit while participating in the study. Urine samples were
`collected at admission and intermittently throughout participation,
`and tested for the presence of illicit drugs using an EMIT system
`(Dade Behring, Inc.). Breathalyzer testing for alcohol was done on
`the day of admission and at least twice weekly. There was no evi-
`dence of unauthorized drug or alcohol use during study participa-
`tion.
`
`Study procedure
`
`Participants were screened on an outpatient basis to determine
`study eligibility. Subjects who fulfilled inclusion and exclusion
`criteria were admitted and oriented to the residential unit, gave
`consent, and were introduced to the session room and the staff
`who would conduct the laboratory sessions. Participants were
`started on oral hydromorphone as a maintenance substitution ther-
`apy (10 mg four times per day). Hydromorphone was chosen due
`
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`232
`
`to a pharmacologic and time-course profile that closely mirrors the
`pattern of use and the level of physical dependence observed with
`heroin. During the several days following admission, participants
`received training on the various tasks they would be required to
`perform. The first experimental session, a practice session, was
`scheduled at least 4 days after admission in order to achieve stabi-
`lization on hydromorphone and to rule out physical dependence on
`alcohol/sedatives.
`Each subject participated in a minimum of 16 experimental
`sessions (including a training session) and typically resided on the
`unit for 10 weeks. After completion of the inpatient study, subjects
`were discharged to an outpatient treatment/research clinic where
`they were maintained on buprenorphine or buprenorphine/nalox-
`one during participation in a pharmacokinetic study that will be
`reported separately. Subsequently, participants were assisted in en-
`rolling in a drug treatment program, during which they could be
`transferred to methadone maintenance, or detoxified off opioids
`and transferred to a drug-free treatment program.
`
`Laboratory sessions
`
`Sessions were conducted at the same time of day, twice weekly,
`with at least 72 h between sessions. The session room contained a
`desk, two chairs, a Macintosh computer, and physiological moni-
`toring equipment. Subject and observer questionnaires were pre-
`sented on the computer screen, and responses were entered using a
`keypad and mouse.
`Sessions lasted 3.5 h and were run by a research technician
`who was present throughout each session and blind to the drug
`and dose administered. During the first thirty minutes of each ses-
`sion, baseline physiological data were obtained, all subject and ob-
`server questionnaires were completed, and pupil photos were tak-
`en. Thirty minutes after the start of the session the participant was
`administered two intramuscular injections (one-half of the dose in
`each arm), followed by SL tablets. Injections were divided to pre-
`vent leakage and tissue damage due to the substantial volume of
`solution used. Before administration of SL tablets, the subject
`rinsed his/her mouth with water. The session then continued for
`3 h, with data collected as described below.
`In the first session for each subject, the drugs administered
`were saline IM injections and placebo SL tablets. This session fol-
`lowed the format of all subsequent sessions, including blindness
`of session staff to the drug administered; it served as a training
`session and was excluded from statistical analyses.
`
`Session drugs and doses
`
`Subjects were maintained on 40 mg per day of oral hydromor-
`phone (10 mg, four times per day). Each dose of hydromorphone
`(10 mg) was provided in a size 0, opaque capsule loose-filled with
`five, 2 mg hydromorphone tablets (Knoll Pharmaceuticals, Mount
`Olive, N.J., USA) and lactose (Amend Drug and Chemical Com-
`pany, Irvington, N.J., USA). Capsules were administered under
`nursing supervision at 6:00 a.m., 10:00 a.m., 4:00 p.m. and
`8:00 p.m. on non-test session days, or at 6:00 a.m., 12:15 p.m.
`(post-session), 4:00 p.m. and 8:00 p.m. on test session days.
`Fifteen experimental drug conditions were tested: placebo, hy-
`dromorphone 10 mg given by IM injection (an agonist control
`condition), naloxone 0.25 mg given by IM injection (an antagonist
`control condition), buprenorphine 8 mg given by IM injection, bu-
`prenorphine 8 mg given as SL tablet, and buprenorphine/naloxone
`combinations of 1/0.25, 2/0.5, 4/1, 8/2, and 16/4 mg, each given
`once by IM injection and once as SL tablets.
`A commercial preparation of hydromorphone hydrochloride
`(10 mg/ml; Knoll Pharmaceuticals) was used for the IM hydro-
`morphone dose condition.
`The three lowest doses of naloxone for injection (0.25, 0.5 mg,
`and 1.0 mg) were prepared from commercial naloxone hydrochlo-
`ride product (0.4 mg/ml and 1.0 mg/ml; DuPont Pharma, DuPont
`Merck Pharma, Manati, Puerto Rico), by diluting to the appropri-
`
`ate volume with bacteriostatic water for injection. The two higher
`doses of naloxone (2 and 4 mg) were prepared from naloxone
`powder (DuPont Pharmaceuticals, Wilmington, Del., USA), using
`bacteriostatic saline to make a 10 mg/ml stock solution. This stock
`solution was then diluted with bacteriostatic water in order to ob-
`tain the appropriate doses. Bacteriostatic water was used for place-
`bo injections.
`Buprenorphine was supplied by NIDA, Research Technology
`Branch (Rockville, Md., USA), from a supply provided by Reckitt
`and Colman (Hull, UK). Buprenorphine for injection was prepared
`as a stock solution from pure powder using doubly distilled water,
`and adjusted with hydrochloric acid to pH 4.0–4.5. This stock so-
`lution was then diluted using bacteriostatic water to obtain the ap-
`propriate concentrations.
`Buprenorphine for SL administration was delivered as SL tab-
`lets that were of two sizes. Small tablets weighed 100 mg and con-
`tained either placebo, or 2 mg buprenorphine combined with
`0.5 mg naloxone. Large tablets weighed 400 mg and contained
`placebo, 8 mg buprenorphine alone, or 8 mg buprenorphine com-
`bined with 2 mg naloxone. Tablets containing buprenorphine
`alone, buprenorphine combined with naloxone, and placebo were
`matched for color and taste.
`During every session, subjects received, all at once, two large
`tablets and two and one-half small tablets in each session (com-
`bining active tablets with placebo tablets to maintain blinding of
`each dose). Each split tablet was weighed before being divided,
`and half-tablets were within ±5% of one-half the whole tablet’s
`weight. The 1 mg buprenorphine plus 0.25 mg naloxone condition
`was delivered as one-half of one small tablet, and the 2 mg bupre-
`norphine plus 0.5 mg naloxone condition was delivered as one
`small tablet. The 4 mg buprenorphine plus 1 mg naloxone condi-
`tion was delivered as two small combination tablets. The 8 mg bu-
`prenorphine dose conditions (8 mg buprenorphine alone and 8 mg
`buprenorphine combined with 2 mg naloxone) were each deliv-
`ered as one large tablet, and the 16 mg buprenorphine plus 4 mg
`naloxone condition was delivered as two large tablets.
`The order of conditions for the sessions was derived from a
`Latin-square for thirty subjects. Subjects were assigned one of the
`schedules using a random number table.
`
`Dosing procedures
`
`On test session days, participants received their usual dose of hy-
`dromorphone at 6:00 a.m. Test drug administrations occurred at
`9:00 a.m. (i.e., 3 h after the last dose of hydromorphone). Subjects
`received IM injections, rinsed their mouth with tap water, then re-
`ceived the SL tablets. Participants did not receive their usual
`10:00 a.m. dose of hydromorphone until 12:15 p.m., when the ex-
`perimental test session was complete.
`
`Physiological measures
`
`Heart rate, blood pressure, skin temperature, respiratory rate, and
`oxygen saturation were monitored throughout the session. All of
`these measures were collected using a Criticare Non-Invasive Pa-
`tient Monitor (model 507S, Criticare Systems, Inc., Waukesha,
`Mich., USA). Skin temperature, respiratory rate, and oxygen satu-
`ration were recorded once per minute, and heart rate and blood
`pressure were recorded every third minute. The blood pressure
`cuff was placed on the subject’s dominant arm. Skin temperature
`was monitored using a skin surface thermistor taped to the ring
`finger of the non-dominant arm, and the oxygen saturation clip
`was placed on the middle finger of the same arm. Data for each
`measure were collected and stored using a Macintosh computer
`(Apple Computer, Inc., Cupertino, Calif., USA), and averaged
`across time intervals: baseline (the 15-min interval from 15 min to
`1 min before drug administration), and then 15-min intervals fol-
`lowing drug administration (1–15, 16–30, 31–45,...151–165, and
`166–180 min). Pupil diameter was determined from photographs
`taken in standardized ambient room lighting using a Polaroid cam-
`
`Page 3
`
`

`

`era with ×2 magnification. Pupil photographs were taken three
`times 15 min before drug administration, and at 15, 30, 45, 60, 75,
`90, 105, 120, 150, and 180 min after drug administration. The
`mid-value pre-drug pupil photo was used as the baseline measure.
`
`Subject and observer measures
`
`Subjective effect reports and observer rating questionnaires were
`completed 15 min before and at 15, 30, 45, 60, 75, 90, 105, 120,
`150 and 180 min after drug administration. Subjects were instruct-
`ed to respond describing how they felt at the time the question-
`naire was answered.
`Subjects completed visual analog scales and an adjective rating
`questionnaire. There were six visual analog scales: High, Drug Ef-
`fects, Good Effects, Bad Effects, Liking, and Sick. Each scale was
`a horizontal line on the computer screen, and the subject posi-
`tioned an intersecting vertical line along the horizontal line using
`the mouse. The ends of the horizontal line were labelled “None”
`and “Extremely,” and responses were scored proportionately on a
`100-point scale. The adjective rating questionnaire (Fraser et al.
`1961; Jasinski 1977) consisted of 37 items which the participant
`rated on a five-point scale from 0 (not at all) to 4 (extremely); the
`items constituted two scales: a 16-item opioid Agonist scale (ad-
`jectives associated with morphine-like effects), and a 21-item
`Withdrawal scale (adjectives associated with opioid withdrawal-
`like effects). The items in the Agonist scale were: nodding,
`heavy/sluggish feeling, dry mouth, carefree, good mood, energet-
`ic, turning of stomach, skin itchy, relaxed, coasting, soapbox (talk-
`ative), pleasant sick, drive, drunken, friendly, and nervous. The
`items in the Withdrawal scale were: muscle cramps, flushing,
`painful joints, yawning, restless, watery eyes, runny nose, chills or
`gooseflesh, sick to stomach, sneezing, abdominal cramps, irrita-
`ble, backache, tense and jittery, sweating, depressed/sad, sleepy,
`shaky (hands), hot or cold flashes, bothered by noises, and skin
`clammy and damp. The ratings for individual items were summed
`for total subjective agonist and withdrawal adjective rating scores.
`Observer ratings, done at the same times as the subject ratings,
`were performed by a research assistant trained to assess signs and
`symptoms of opioid agonist and withdrawal effects. Observer rat-
`ings included the same adjective rating scale, scored in the same
`way. In addition, an observer-rated assessment of seven signs of
`opioid withdrawal (lacrimation, rhinorrhea, perspiration, piloerec-
`tion, yawning, restlessness, and bowel sounds) was performed (de-
`rived from Kolb and Himmelsbach 1938). Each opioid withdrawal
`item was scored using standardized criteria, as 0, 1 or 2 (with
`higher scores corresponding to greater severity), and scores for all
`items were summed to produce a total observer Withdrawal Signs
`Score (WSS).
`
`Psychomotor/cognitive performance measures
`
`Subjects completed three psychomotor/cognitive performance
`tasks during the session: a computerized form of the Digit Symbol
`Substitution Task (DSST, McLeod et al. 1982), a Circular Lights
`task (Griffiths et al. 1983), and a computerized form of the Trail-
`Making Test (Strain et al. 2000). This latter test was a Macintosh-
`based version of the Trail-Making Test (Reitan 1958). In this task,
`the computer screen presented a distribution of squares that con-
`tained letters and numbers, and the subject was instructed to use a
`mouse to connect squares following an alternating sequence of
`numbers and letters (e.g., 1, A, 2, B, 3, C...). A total of 25 squares
`were presented (A-L and 1–13), and subjects had 4 min to com-
`plete the task. Results were summarized for sequence errors (i.e.,
`clicking on a number or letter out of order), and the total line
`length. Each of the three tasks was completed during the baseline
`period (15 min before drug administration), and at the same time
`periods as subject ratings.
`
`233
`
`Data analysis
`
`Peak values for each session were determined for each measure.
`For most measures this was an increased effect. However, since
`some measures may decrease in response to acute opioid agonist
`effects (e.g., pupil diameter, certain psychomotor tasks), the abso-
`lute nadir effect for these measures was examined.
`A conservative one-step procedure, Tukey’s honestly signifi-
`cant difference (HSD), was used to compare peak placebo values
`to the peak value of each active drug condition. The mean square
`error term needed to perform these tests was calculated using a re-
`peated measures, two-factor analysis of variance; main effects
`were the fifteen drug conditions and time (baseline versus peak ef-
`fect). Comparisons for which the Tukey q-value was greater than
`5.487 (P<0.05) are reported as statistically significant.
`
`Results
`
`Table 1 summarizes mean values and results of post hoc
`analyses comparing peak drug effect to peak placebo ef-
`fect for subjective, observer-rated, physiologic, and psy-
`chomotor measures obtained during the experimental
`sessions. Items shown had at least one condition that was
`significantly different from placebo.
`
`Subjective effects
`
`Mean peak visual analog scale ratings are presented in
`Fig. 1. Naloxone, the antagonist control condition, pro-
`duced mild, non-significant increases in ratings of Drug
`Effects. Hydromorphone, the opioid agonist control con-
`dition, significantly increased ratings of Drug Effects,
`High, Good Effects, and Liking.
`The effects of buprenorphine 8 mg (without nalox-
`one) varied as a function of the route of administration.
`When given by injection, it significantly increased rat-
`ings of Drug Effects, High, Good Effects, and Liking.
`This pattern and the magnitude of effects were similar to
`that seen with hydromorphone (which was also given by
`injection). When buprenorphine 8 mg was given by the
`SL route, the magnitude of ratings was virtually identical
`to that produced by the placebo condition.
`The combination of buprenorphine/naloxone when giv-
`en by the IM route produced dose-related increases in rat-
`ings of Drug Effects, Bad Effects, and Sick. For the higher
`doses of IM buprenorphine/naloxone (4/1–16/4 mg), these
`ratings significantly differed from placebo. Intramuscular
`buprenorphine/naloxone produced mild, non-significant
`increases on measures suggestive of opioid agonist effects
`(High, Good Effects, Liking). The pattern for these mea-
`sures appeared to be bell-shaped – that is, increased scores
`over the low-moderate dose range followed by decreased
`scores with the higher doses. However, none of these opi-
`oid agonist-like ratings was significantly different from
`placebo, and all were markedly lower than the corre-
`sponding ratings for the IM dose of buprenorphine alone.
`When given by the SL route these same five doses of
`buprenorphine/naloxone produced a different pattern of
`effects on VAS ratings (Fig. 1). Sublingual buprenor-
`phine/naloxone produced neither opioid antagonist-like
`
`Page 4
`
`

`

`234
`
`Table 1 Summary of peak drug effects. Values shown are the
`mean peak response (n=8). All doses shown are in milligrams. For
`subjective measures, observer-rated measures, diastolic and systol-
`ic blood pressure, heart rate, and Trails, the maximum positive in-
`crease was examined. For oxygen saturation and circular lights,
`the maximum decrease was examined. For pupil diameter, results
`
`are shown for both the maximum increase (max ↑) and the maxi-
`mum decrease (max ↓), since pupillary response could vary in ei-
`ther direction as a function of opioid antagonist versus agonist
`challenge. SL sublingual, IM intramuscular, N naloxone, H hydro-
`morphone
`
`Pla- N(IM) H(IM) Buprenorphine Buprenorphine/naloxone (IM)
`cebo
`0.25
`10
`
`8 (IM) 8 (SL)
`
`1/.25
`
`2/.5
`
`4/1
`
`8/2
`
`Buprenorphine/naloxone (SL)
`
`16/4
`
`1/.25
`
`2/.5
`
`4/1
`
`8/2
`
`16/4
`
`Subjective measures
`Visual analog scales
`High
`Drug effects
`Good effects
`Bad effects
`Liking
`Sick
`Adjective rating scales
`Agonist
`Withdrawal
`
`6.1
`8.8
`6.3
`6.4
`3.0
`6.1
`
`14.0
`27.3
`10.6
`18.5
`9.6
`19.0
`
`43.1**
`47.3**
`47.4**
`5.4
`48.4**
`2.4
`
`7.9
`38.5**
`38.6** 10.0
`37.3**
`8.4
`9.1
`7.0
`37.0**
`8.0
`8.4
`0.0
`
`7.1
`16.4
`5.3
`12.0
`3.5
`10.1
`
`12.4
`21.6
`17.1 17.4
`42.9** 60.9**
`20.1 31.3
`16.1
`8.6
`15.4 20.1
`16.9 29.3* 43.4** 59.0**
`23.6 19.1
`18.8
`5.8
`12.3 23.0
`35.0** 59.8**
`
`6.6
`9.9
`6.4
`3.5
`6.4
`0.0
`
`0.3
`5.6
`2.0
`5.9
`0.3
`5.9
`
`0.5
`6.8
`0.4
`6.6
`0.0
`0.0
`
`13.3 14.5
`14.4 13.0
`14.0 13.6
`0.3
`0.0
`14.4 14.5
`0.3 0.9
`
`13.6
`2.9
`
`12.1
`5.8
`
`19.6**
`2.0
`
`16.9*
`2.1
`
`14.6
`1.9
`
`13.6
`5.5
`
`13.3
`13.9
`13.1 14.1
`4.6
`9.0* 10.6** 19.0**
`
`13.0
`2.4
`
`11.9
`4.8
`
`12.9
`3.9
`
`14.0 14.5
`1.5
`1.6
`
`11.9
`3.3
`4.5
`
`10.4
`6.5
`4.9
`
`20.0**
`0.9
`2.6
`
`15.3
`2.4
`2.5
`
`13.1
`1.5
`2.9
`
`11.5
`4.3
`4.1
`
`13.5 12.1
`5.4
`7.5
`4.8
`5.8
`
`12.9
`9.4*
`7.0
`
`11.5
`17.5**
`9.1**
`
`12.9
`2.6
`3.8
`
`10.0 11.8
`3.9
`2.0
`4.4
`3.0
`
`13.4 13.8
`1.0
`1.3
`2.8
`2.5
`
`69.6
`
`72.8
`
`75.7
`
`71.2
`
`70.9
`
`74.0
`
`74.1 75.0
`
`76.9*
`
`81.3**
`
`73.0
`
`70.9 71.2
`
`71.2 73.8
`
`Observer-rated measures
`Adjective rating scales
`Agonist
`Withdrawal
`Withdrawal Signs
`Score
`Physiologic measures
`Diastolic blood
`pressure
`Systolic blood
`pressure
`Heart rate
`Pupil diameter
`(max ↑)
`Pupil diameter
`(max ↓)
`Oxygen saturation
`
`76.6
`5.5
`
`3.9
`
`79.5
`5.3
`
`84.2**
`3.9
`
`80.6
`4.3
`
`3.5
`
`2.7**
`
`3.2
`
`79.7
`4.9
`
`3.3
`
`79.6
`5.1
`
`78.9 80.8
`5.3
`5.4
`
`85.0** 84.4**
`5.5
`5.7
`
`78.6
`5.1
`
`77.0 78.6
`4.9
`5.0
`
`77.9 79.5
`4.9
`5.0
`
`3.5
`
`3.9
`
`3.4
`
`3.4
`
`3.2
`
`3.9
`
`3.7
`
`3.7
`
`3.5
`
`3.7
`
`98.0
`
`96.8**
`
`97.1*
`
`97.6
`
`97.4
`
`97.5 97.4
`
`97.2
`
`97.4
`
`97.8
`
`97.5 97.7
`
`97.4 97.5
`
`123.6 130.3 128.4
`
`127.2
`
`127.2
`
`127.3 130.7 133.0 134.2
`
`139.4** 126.4 125.9 127.2 126.9 129.9
`
`97.8
`
`Psychomotor tasks
`Circular lights
`Trails
`(sequence errors)
`
`71.4
`2.8
`
`65.8
`3.3
`
`56.3**
`4.9
`
`61.1
`4.8
`
`70.4
`3.8
`
`66.3
`3.4
`
`66.6 61.8
`3.9
`4.6
`
`64.0
`9.5**
`
`55.6**
`9.9**
`
`69.9
`2.4
`
`65.9 70.8
`4.0
`4.8
`
`67.5 66.5
`6.4
`3.1
`
`*P<0.05; **P<0.01 versus placebo
`
`effects nor opioid agonist-like effects as measured by
`these visual analog scale ratings. For all six of the visual
`analog scales, SL buprenorphine/naloxone produced low
`ratings with no clear dose-related pattern, and no signifi-
`cant differences from placebo.
`Results from the subject adjective rating question-
`naire showed that hydromorphone and IM buprenorphine
`8 mg both produced significant increases on the Agonist
`scale score (Table 1). None of the ten buprenorphine/nal-
`oxone conditions produced significant increases in Ago-
`nist scale scores, and the mean scores for the IM versus
`SL routes were generally in the same range. Finally, con-
`sistent with the pattern seen for the visual analog scales,
`the subject adjective rating scale scores for Withdrawal
`showed significantly increased scores for each of the
`
`three highest doses of IM buprenorphine/naloxone
`(4/1–16/4 mg; Table 1).
`
`Observer-rated effects
`
`Only the hydromorphone condition produced scores on
`the adjective Agonist scale completed by the trained ob-
`server that were significantly higher than placebo scores
`(Table 1). Peak scores on the observer adjective Agonist
`scale for the ten buprenorphine/naloxone conditions
`showed no pattern suggestive of dose-related effects for
`either the IM or SL conditions.
`Peak scores for the observer adjective Withdrawal
`scale showed dose-related increases for the IM buprenor-
`
`Page 5
`
`

`

`235
`
`Fig. 1 Mean peak values (±SE)
`for subject-reported visual ana-
`log scale ratings (n=8 subjects).
`Acute dosing conditions are
`shown along the x-axis as pla-
`cebo (P), naloxone (N), hydro-
`morphone (H), buprenorphine
`(B), and buprenorphine/nalox-
`one (B/N). All doses shown are
`in mg. Route of administration:
`im intramuscular, sl sublingual.
`The maximum possible score
`was 100. Conditions which dif-
`fered significantly from place-
`bo (Tukey test; P<0.05) are in-
`dicated by filled symbols
`
`phine/naloxone conditions, with significant elevations
`for the two highest doses tested (Table 1). None of the
`other drug conditions produced significant effects for
`this measure. A similar pattern was seen for the observer
`Withdrawal Signs Score (WSS), with dose-related in-
`creases for the five IM buprenorphine/naloxone condi-
`tions (Table 1); only the highest dose tested (16/4 mg)
`was significantly higher than placebo. None of the other
`drug conditions tested produced significant WSS effects
`in comparison to placebo.
`The mean peak scores for individual items from the
`WSS are shown for the placebo, naloxone, and the IM
`buprenorphine/naloxone conditions in Fig. 2. (The item
`“bowel sounds” is not shown, since peak ratings were
`consistently 2 for all subjects and all dose conditions.)
`As can be seen in Fig. 2, for most items the IM bupre-
`norphine/naloxone conditions produced dose-related in-
`creases in scores, with higher doses producing signifi-
`cantly elevated scores for several items (Perspiration,
`Piloerection, and Restlessness). Significant withdrawal
`
`effects were observed only when the buprenorphine/nal-
`oxone combination delivered IM naloxone doses of 2 mg
`or more. Interestingly, naloxone 0.25 mg alone did not
`produce significant changes for individual items or the
`total WSS scores (Table 1 and Fig. 2).
`Neither buprenorphine alone (8 mg IM or SL) nor SL
`buprenorphine/naloxone showed any suggestion of in-
`creasing withdrawal signs. Rather, their trend was to re-
`duce withdrawal signs; this achieved statistical signifi-
`cance for the 8 mg IM buprenorphine condition, which
`significantly decreased scores on Yawning (as did the IM
`hydromorphone condition and the two highest doses of
`SL buprenorphine/naloxone; not shown in Fig. 2).
`
`Physiologic effects
`
`None of the dose conditions tested produced significant
`changes on measures of respiratory rate. Diastolic blood
`pressure was significantly elevated for the two highest
`
`Page 6
`
`

`

`236
`
`Fig. 2 Observer ratings of opi-
`oid withdrawal signs, effects of
`acute doses of placebo (P), nal-
`oxone (N), IM buprenorphine
`(B) and IM