The effects of buprenorphine in buprenorphine-maintained volunteers

Transcription

1 Psychopharmacology (1997) 129 : Springer-Verlag 1997 ORIGINAL INVESTIGATION Eric C. Strain Sharon L. Walsh Kenzie L. Preston Ira A. Liebson George E. Bigelow The effects of buprenorphine in buprenorphine-maintained volunteers Received: 22 February 1996/ Final version: 23 August 1996 Abstract Buprenorphine is a mu opioid partial agonist currently used as an analgesic, and being developed for the treatment of opioid dependence. The purpose of this study was to determine the abuse liability of parenteral buprenorphine in volunteers maintained on daily sublingual (SL) buprenorphine (8 mg). In a residential laboratory, eight volunteers underwent pharmacologic challenges two times per week. Medication challenges were 16 h after the daily dose of buprenorphine, and consisted of double-blind IM injections of buprenorphine (4, 8, 16 mg), the prototypic mu opioid agonist hydromorphone (9 and 18 mg), or saline. Assessments consisted of physiologic monitoring, subjects self-reports, and a trained observer s ratings of drug effects, and were collected for 0.5 h before and 2.0 h following injection. Supplemental doses of IM buprenorphine produced opioid agonist-like effects, indicating some abuse potential of parenteral buprenorphine in buprenorphine-maintained patients. There was incomplete cross-tolerance to the effects of hydromorphone, suggesting that higher maintenance doses of buprenorphine may be needed to maximize clinical efficacy. However, there was a lack of graded dose-effects for hydromorphone, suggesting that buprenorphine s combination of partial agonist effects and high affinity for opioid receptors may limit the magnitude of effects of supplemental full agonists. Finally, participants tolerated cumulative doses of maintenance buprenorphine plus challenge buprenorphine without adverse effects, suggesting higher doses E.C. Strain (*) S.L. Walsh K.L. Preston I.A. Liebson G.E. Bigelow 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 K.L. Preston Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland, USA of buprenorphine can be safely administered to opioid dependent patients. Key words Abuse liability testing Agonist-antagonist Buprenorphine Hydromorphone Opioid dependence Introduction Buprenorphine is an opioid mixed agonist-antagonist currently marketed as an analgesic in over 40 countries, including the United States. Parenteral buprenorphine is approximately 25 times as potent as parenteral morphine (Wallenstein et al. 1986), and has a duration of action that is at least equal to, if not greater, than morphine (Lewis 1995). In addition to buprenorphine s use as an analgesic, considerable attention has focused upon buprenorphine s development as a treatment agent for opioid dependence (Cowan and Lewis 1995). Buprenorphine s pharmacological profile has several features that suggest it should be an effective and safe medication for the treatment of opioid dependence: acute doses are identified as opioid-like (Jasinski et al. 1978, 1989; Johnson et al. 1989; Pickworth et al. 1993), there appears to be a ceiling to the respiratory depression produced by acute doses (Walsh et al. 1994), and chronic buprenorphine dosing in humans can produce cross-tolerance to other opioids (Bickel et al. 1988a; Rosen et al. 1994) and can suppress self-administration of heroin by heroin abusers (Mello et al. 1982). However, liabilities of buprenorphine such as its poor oral bioavailability may limit its eventual use. Buprenorphine appears to act as a mu opioid partial agonist and kappa antagonist. Support for buprenorphine s mu agonist effects is derived from several lines of evidence. As noted, studies in humans have shown acute doses of buprenorphine are identified as opioid-like and produce opioid-like effects (Jasinski

2 330 et al. 1978, 1989; Johnson et al. 1989; Preston et al. 1992; Pickworth et al. 1993; Walsh et al. 1994). Similarly, laboratory studies have shown that acute doses of buprenorphine are discriminated as mu opioid agonist-like in drug discrimination trials (Leander 1983; France et al. 1984; Preston and Bigelow 1991; Pournaghash and Riley 1993), and can produce acute morphine-like effects (Cowan et al. 1977a; Filibeck et al. 1981). However, buprenorphine appears to function as a mu partial agonist, as demonstrated in studies showing it can precipitate withdrawal or increase spontaneous withdrawal in opioid-dependent laboratory animals (Martin et al. 1976; Fukase et al. 1994), and that it can antagonize the behavioral effects of opioid agonists (Filibeck et al. 1981; Leander 1983). In addition to these mu partial agonist effects, animal studies also have shown buprenorphine has kappa antagonist effects (Leander 1988; Negus and Dykstra 1988; Negus et al. 1989). Buprenorphine has been shown to have a bell-shaped dose-response curve for several measures, such as antinociception, precipitated opioid withdrawal, gastrointestinal motility, and respiratory depression (e.g., Cowan et al. 1977b; Dum and Herz, 1981; Doxey et al. 1982; Lizasoain et al. 1991; Strain et al. 1995), and one possible explanation for this bell-shaped dose-response curve is that there is an offsetting of mu partial agonist effects by kappa antagonist effects as the dose of buprenorphine increases that is, buprenorphine may demonstrate noncompetitive autoinhibition (Cowan et al. 1977a). This bell-shaped dose-response curve suggests both advantages and disadvantages in the clinical use of buprenorphine for the treatment of opioid dependence. A significant advantage is that overdosing with buprenorphine should not result in marked respiratory depression (unlike pure opioid agonists), and both a human laboratory study (Walsh et al. 1994) and a case report (Banks 1979) suggest there is a ceiling to the respiratory depression produced by acute, high doses of buprenorphine. However, a disadvantage is that there may also be a plateau in the cross-tolerance produced by buprenorphine, suggesting that the effects of high doses of illicit opioids may not be blocked by simply increasing the dose of buprenorphine. However, human laboratory studies have shown that there is an increase in the blockade of opioid effects as the dose of buprenorphine is increased (Bickel et al. 1988a; Rosen et al. 1994; Walsh et al. 1995), although there is not complete blockade of opioid effects at buprenorphine doses as high as 16 mg sublingually SL per day. Several studies have shown that buprenorphine can be used safely and effectively in the treatment of opioid dependence (for review, see Bickel and Amass 1995). Chronic dosing with buprenorphine in humans produces varying degrees of cross-tolerance to other opioids (Bickel et al. 1988a; Rosen et al. 1994) and can suppress heroin self-administration (Mello et al. 1982). Rapid dose induction with buprenorphine is well tolerated (Johnson et al. 1989), and acute doses of buprenorphine do not readily precipitate withdrawal in opioid dependent subjects (Strain et al. 1992, 1995). Several clinical trials comparing the efficacy of buprenorphine to methadone in the outpatient treatment of opioid dependence have shown the two medications produce comparable outcomes on measures of treatment retention and rates of opioid-positive urine samples (Bickel et al. 1988b; Johnson et al. 1992; Strain et al. 1994), although some studies have shown methadone can have superior efficacy when compared to buprenorphine (Kosten et al. 1993; Ling et al. 1996). However, these differences in efficacy between buprenorphine and methadone may reflect comparisons of nonequivalent doses. A placebo-controlled clinical trial found buprenorphine was superior to placebo (Johnson et al. 1995a). While evidence suggests buprenorphine may be an effective treatment agent for opioid dependence, the abuse liability of buprenorphine may compromise its eventual development as a treatment for opioid dependence. Indeed, there is extensive preclinical evidence supporting buprenorphine s abuse potential (for review, see Negus and Woods 1995). Further complicating buprenorphine s use, and possibly increasing its abuse potential, is the need for a sublingual formulation (since it has poor oral bioavailability), thus requiring that the drug composition be soluble. As a consequence, diverted buprenorphine could be abused, and anecdotal reports from several different countries have already described buprenorphine abuse [e.g., Ireland (O Connor et al. 1988), India (Singh et al. 1992), New Zealand (Robinson et al. 1993), Scotland (Morrison et al. 1989), and Spain (San et al. 1989)]. Because of this abuse potential, buprenorphine for addiction treatment in the United States is currently provided only under directly supervised dose administration (i.e., no take-home doses are provided); this is clinically inconvenient. A buprenorphine/naloxone combination product is being developed in an effort to decrease this abuse potential. The addition of naloxone, with its relatively poor sublingual bioavailability, would theoretically result in a predominant buprenorphine effect by the therapeutic sublingual route. However, abuse via the parenteral route should result in a predominant naloxone effect. While this combination product should decrease the abuse potential of buprenorphine, buprenorphine monotherapy (that is, without naloxone) continues also to be a focus of development and marketing attention, as evidenced by its recent introduction in France as an outpatient treatment agent for opioid dependence. Buprenorphine monotherapy may also be eventually used as a bridging agent between illicit opioid use and eventual buprenorphine/naloxone combination treatment. The abuse liability of buprenorphine in buprenorphine-maintained subjects has not previously been

3 331 determined. It is possible, given buprenorphine s doseresponse curve, that supplemental doses of buprenorphine administered to a subject maintained on buprenorphine would produce no further opioid agonist effect (and hence have minimal abuse liability). The purpose of this study was to determine the abuse liability of parenteral buprenorphine in buprenorphinemaintained volunteers. Thus, the study addresses the consequences of the injection of a take-home dose of buprenorphine, using a human laboratory assessment procedure in which subjects maintained on daily sublingual buprenorphine receive supplemental parenteral doses of buprenorphine. Since such supplemental dosing of buprenorphine in buprenorphine-maintained volunteers could produce opioid agonist-like effects, the study includes a prototypic mu agonist opioid (hydromorphone) as a control condition, so that the relative magnitude of buprenorphine agonist effects could be compared to this known pure mu agonist. Materials and methods Subjects Subjects were eight adult opioid-dependent volunteers. Demographic features are summarized in Table 1. All were diagnosed as Opioid Dependent using the Structured Clinical Interview for DSM- III-R (SCID) (Spitzer and Williams 1985), were otherwise free of major mental illness, and presented with evidence of active intravenous opioid use (i.e., urinalysis test positive for illicit opioids, evidence of acute and chronic needle use). Subjects underwent routine medical screening which included history and physical examination, EKG, and 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 problems. The study was approved by the Institutional Review Board, and volunteers gave written informed consent and were paid for their participation. Study procedure The present study followed procedures developed by this laboratory for similar studies examining the effects of mixed agonist-antagonist opioids in opioid-dependent volunteers (e.g., Preston et al. 1988a, 1989; Strain et al. 1992, 1993, 1995). After having the study procedures explained to them, applicants underwent screening procedures (e.g., laboratory tests, a background interview) to determine if they fulfilled the eligibility requirements for the study. Volunteers who consented and were eligible to participate were stabilized on buprenorphine (8 mg SL daily) as outpatients for a minimum of 2 weeks. During this 2-week stabilization phase subjects were assigned a counselor, had a treatment plan generated, and had urine samples collected and tested three times per week (Monday, Wednesday, Friday). No contingencies on urine results were enacted during this outpatient stabilization period. After the 2-week outpatient stabilization phase, subjects were admitted to the inpatient research unit. This was a 14-bed human behavioral pharmacology residential research unit that included bedrooms, a day area with space for craft activities, exercise equipment, books and television, a kitchen area, and a nurses station. Nursing staff provided supervision 24 h per day, and no visitors were permitted. Urine samples were collected at admission and daily, and tested at least twice weekly for the presence of illicit drugs using an EMIT system (Syva Co.). Breathalyzer testing for alcohol was done on the day of admission and at least twice weekly. No evidence of unauthorized drug or alcohol use during study participation was observed. The daily dose of sublingual buprenorphine during both the outpatient and inpatient phases of the study was 8 mg in 1 ml, and was prepared in 30% (vol/ vol) aqueous ethanol solution. It was dispensed via a Ped-Pod oral dispenser (SoloPak Laboratories, Franklin Park, Ill., USA). Subjects were instructed to hold the buprenorphine solution under their tongue for 5 min. During the inpatient laboratory portion of the study subjects received their maintenance dose of buprenorphine at the same time each day (6:00 p.m.), which was 16 h before the test drug administration (10:00 a.m.). Buprenorphine was supplied by the National Institute on Drug Abuse (NIDA; Rockville, Md. from a supply provided by Reckitt and Colman, Hull, UK). After admission to the inpatient ward, each subject participated in a minimum of six experimental sessions (plus a training session), and typically resided on the unit for 4 weeks. Each session consisted of intramuscular injection challenges of one of two doses of the opioid mu agonist hydromorphone (9 and 18 mg), one of three doses of buprenorphine (4, 8, and 16 mg), or of saline placebo. Because of uncertainty about the tolerability of 8 mg of daily sublingual buprenorphine plus up to 16 mg of parenteral buprenorphine on a session day, a pilot subject had double-blind placebo substituted for sublingual buprenorphine on sessions days. This volunteer spontaneously complained of inadequate dosing on session days, and subsequent volunteers (reported here) received active sublingual buprenorphine doses on session days. After completion of the inpatient portion of the study, subjects transferred to the outpatient opioid treatment clinic and were offered Table 1 Demographics. B, Black (African-American); F, Female; M, Male Participant Age Race Sex Opioid Opioid use Amount spent Current other (years) use frequency on opioids substance (years) (times/day) a ($/day) a dependence diagnoses b 1 43 B M None 2 36 B F None 3 46 B M Alcohol, cocaine 4 44 B F Cocaine 5 40 B M Alcohol 6 41 B F None 7 40 B M Alcohol 8 43 B M Alcohol a Pre-buprenorphine treatment b Based upon the Structured Clinical Interview for DSM-III-R (SCID). All subjects met diagnostic criteria for opioid dependence

4 332 the opportunity to transfer to methadone and apply to long-term methadone treatment if they were eligible for such, or they received gradual detoxification from buprenorphine. Laboratory sessions Sessions were conducted at the same time of day, and no more than 2 days per week (i.e., separated by at least 72 h). The session room was located in a suite separate from the residential unit, and contained two chairs, an Apple IIe computer, and physiologic monitoring equipment. Subject and observer questionnaires were presented on the computer screen, and responses were entered using a key pad and joystick. Sessions lasted 2.5 h. Fifteen minutes after the start of each session, 10 min of baseline physiological data were obtained. All subject and observer questionnaires were completed, and a pupil photo was taken. Thirty minutes after the start of the session (16 h after the previous day s dose of SL buprenorphine) the participant received two IM injections, one in each arm. Blood pressure monitoring was halted during the injections, and the injection sites were massaged for 1 min before resuming blood pressure monitoring. The session then continued for 2 h with data collected as described below. The first session for each subject served as a training session; saline was administered and the data were excluded from statistical analyses. This session followed the format of all subsequent sessions, including staff s being blind to the drug administered. Antidepressants, Hallucinogens, Benzodiazepines, Stimulants, and Other. Examples for each drug class were listed. The adjective rating scale consisted of 37 items which the participant rated on a fivepoint scale from 0 (not at all) to 4 (extremely). The items were scored as two scales: a 16-item opioid Agonist scale (adjectives 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, energetic, turning of stomach, skin itchy, relaxed, coasting, soapbox (talkative), 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, irritable, backache, tense and jittery, sweating, depressed/sad, sleepy, shaky (hands), hot or cold flashes, bothered by noises, and skin clammy and damp. The ratings of individual items were summed for a total score for each scale. Observer ratings included the same adjective rating scale, as well as an assessment for the presence or absence of six signs of opioid withdrawal: lacrimation, rhinorrhea, yawning, perspiration, piloerection, and restlessness (Himmelsbach scale, derived from Kolb and Himmelsbach 1938). Ratings for the adjective rating scale and the Himmelsbach scale were made by a research technician who was present throughout the session and blind to the drug administered, and were done at the same time intervals as were the subject ratings. The adjective rating items were summed identically to the subject ratings, and a total score for the Himmelsbach scale (range 0 6) was derived by summing the responses for the six items. Physiological measures Physiological measures consisted of heart rate, blood pressure, skin temperature, and respiratory rate, and were monitored continuously throughout the session. Heart rate and blood pressure were collected once per minute using a Sentry II Automatic Blood Pressure Monitor (NBS Medical, Costa Mesa, Calif., USA). Skin temperature was monitored using a skin surface thermistor (Yellow Springs Instrument Co., Yellow Springs, Ohio, USA) taped to a finger on the arm without the blood pressure cuff. Respiratory rate was monitored using a bellows (Lafayette Instruments, Lafayette, Ind., USA) placed around the lower chest and connected to a pressure-sensitive switch. Data for each physiological measure were collected and stored in 1-min intervals using an Apple IIe computer (Apple Computer, Inc., Cupertino, Calif., USA). Pupil diameter was determined from photographs taken in constant ambient room lighting using a Polaroid camera with a 2 magnification. Pupil photographs were taken 15 min before drug administration, and at 15, 30, 45, 60, 90, and 120 min after drug administration. Subject and observer measures Subjective effect reports and observer rating questionnaires were completed 15 min before and at 15, 30, 45, 60, 90, and 120 min after drug administration. Subjects were instructed to respond describing how they felt at the time the questionnaire was being answered. Subjects completed visual analog scales (VASs), a pharmacological class questionnaire, and an adjective rating scale. There were six visual analog scales: High, Drug Effects, Good Effects, Bad Effects, Liking, and Sick. Each scale was a horizontal line on the computer screen, and the subject positioned an arrow along this line using a joystick. The ends of the line were labelled None and Extremely, and responses were scored proportionately on a 100-point scale. The pharmacological class questionnaire asked the subject to select one of ten drug classes to which the administered drug was most similar: Placebo, Opioids, Opioid Antagonists, Phenothiazines, Barbiturates and Sleeping Medications, Psychomotor/cognitive performance measures Two computerized psychomotor/cognitive performance measures were completed by the subject during the session: a recall (memory) task, in which the subject was required to recall eight-digit numbers, and a computerized form of the Digit Symbol Substitution Task (DSST: McLeod et al. 1982). The tests were completed during the baseline period (15 min before drug administration), and 15, 30, 45, 60, 90, and 120 min after drug administration. Drugs and doses Six drug conditions were tested: placebo, hydromorphone 9 and 18 mg, and buprenorphine 4, 8, and 16 mg. A commercial preparation of hydromorphone hydrochloride (10 mg/ ml; Knoll Pharmaceuticals, Whippany, N.J., USA) was diluted to the appropriate volume with bacteriostatic saline. Stock solutions of buprenorphine HCl 4 mg/ ml were prepared from bulk powder (obtained from NIDA see above) dissolved in Water for Injection (WFI), USP, ph adjusted to with 0.1 N HCl. Individual parenteral doses of buprenorphine were aseptically prepared by diluting the appropriate volume of buprenorphine stock solution with WFI. Bacteriostatic saline (4 ml) was used for placebo. All doses were given under double-blind conditions in two equal intramuscular injections of 2.0 ml each, one to each arm (4 ml total). The dose schedules for the six sessions were derived from two Latin squares for six subjects each (i.e., a total of 12 possible schedules). Subjects were assigned one of the 12 schedules using a random number table. Data analysis The maximum change from baseline was determined for each measure for each subject. For most measures this was a peak (increase) effect, although pupil diameter decreased in response to the active drug conditions. Thus, peak effect refers to the value associated with the maximum absolute change from baseline.

5 333 A conservative one-step procedure, Tukey s honestly significant difference (HSD), was used to compare peak saline values to the peak values of each active drug condition. The mean square error term needed to perform these tests was calculated using a repeated measures, two-factor analysis of variance; main effects were the six drug conditions and time (baseline versus peak effect). Comparisons for which the Tukey q-value was greater than (P < 0.05) are reported as statistically significant. Analysis for carry-over effects was conducted by examining baseline data from each session coded with the previous session s condition. Volunteers participated in an extra session at the end of the study, so all conditions were included in the analysis for each subject. Values were analyzed using analysis of variance. Results Table 2 provides a summary of peak and nadir values, and results from the post hoc analyses for peak drug effects compared to peak saline effects, for the subjectrated, observer-rated, and physiologic measures. In general, both doses of hydromorphone produced typical opioid agonist-like effects, with little difference in the magnitude of the effect across the two doses tested. Buprenorphine, on the other hand, tended to produce opioid agonist-like effects that were dose-related, with the highest dose tested yielding effects equivalent in magnitude to those produced by the two hydromorphone conditions. Subject-rated effects Both doses of hydromorphone produced significantly increased ratings on visual analog scales of High, Drug Effects, Good Effects, and Liking (Table 2). For all of these ratings except Liking, the lower (9 mg) dose of hydromorphone produced slightly greater ratings than the higher (18 mg) dose, although differences between the two doses were minimal and not significant (Fig. 1). While these peak VAS ratings were significantly greater than placebo, they were moderate in intensity (all less than 50 on the 100 point VAS score), and generally represented a typical profile of effects for an opioid agonist. Neither the 4 or 8 mg doses of buprenorphine produced significantly increased ratings on any of the VAS scales, although the 16 mg dose did produce significantly increased ratings of High, Drug Effects, Good Effects, and Liking (Table 2). There was an orderly dose-response effect seen for the ratings produced by buprenorphine (Fig. 1), and the magnitude of the effect for the highest dose of buprenorphine was approximately equivalent to that produced by one of the two doses of hydromorphone on several of the measures (e.g., Drug Effects, Liking; Fig. 1). Both doses of hydromorphone also produced significantly increased ratings for the peak adjective agonist score, as did the 8 and 16 mg doses of buprenorphine Table 2 Summary of peak drug effects a Saline Hydromorphone (mg) Buprenorphine (mg) Subjective measures Visual analog scales High 6 35** 29* * Drug effects 7 36** 32* * Good effects 7 36** 34** * Bad effects Liking 8 34* 37** * Sick Adjective rating scales Agonist 9 17** 18** 13 15* 16** Withdrawal ** 2 Observer-rated measures Adjective rating scales Agonist 10 20** 19** 12 17** 20** Withdrawal Total Himmelsbach score Physiologic measures Diastolic blood pressure (mmhg) 57 68** Systolic blood pressure (mmhg) ** Heart rate (bpm) Respiration (bpm) Skin temperature (ºF) Pupil diameter (mm) ** 2.8** 3.0** 3.2** 3.2** Psychomotor/cognitive tasks Recall (no. correct) DSST (% correct) a Mean values. Asterisks indicate significant results compared to saline: * P < 0.05; **P < 0.01

6 334 (Table 2). Interestingly, the 8 mg dose of buprenorphine also produced a significant decrease (nadir) in the withdrawal scale score. However, the relative magnitude of this effect was small: the mean withdrawal scale score produced by saline was 4.13, while the mean score for the 8 mg dose of buprenorphine was 1.25 (maximal possible scale score was 84). These overall low withdrawal scores probably reflect the efficacy of buprenorphine as a maintenance agent in suppressing withdrawal. Responses on the pharmacological class questionnaire are presented in Table 3. Saline was identified primarily as placebo, and the two doses of hydromorphone were primarily identified as an opioid agonist. The lowest dose of buprenorphine was nearly evenly divided between identifications as an opioid agonist and placebo. As the dose of buprenorphine increased, the percentage of identifications as an opioid agonist increased, and identifications as placebo showed a corresponding decrease. There were occasional identifications both of buprenorphine and of placebo as other drugs (opioid antagonist, benzodiazepine, and stimulants), but there was no consistent pattern to these identifications. Examination of the time course of drug identifications revealed no apparent time-related changes in the pattern of responses. Observer-rated effects Fig. 1 Effects of acute intramuscular challenges of saline, hydromorphone and buprenorphine on subject-reported visual analog scale ratings in buprenorphine-maintained volunteers. The maximum possible score was 100. Each point (and bracket) represents the mean peak value (± standard error) for the eight subjects. S, saline; H, hydromorphone; B, buprenorphine Both doses of hydromorphone and the two higher doses of buprenorphine produced significantly increased ratings on the observer adjective agonist score, but none of the active drug conditions tested produced significant effects on observer-rated indices of withdrawal (Table 2). There were no significant effects on the observer adjective withdrawal scores, nor were there significant effects relative to placebo for the Total Himmelsbach score or for any of the six individual items from the Himmelsbach scale. Physiological and psychomotor effects Results from physiological indices are presented in Table 2. The 9 mg dose of hydromorphone produced a significant increase in the peak diastolic blood pressure relative to placebo (10 mmhg), and the 16 mg dose of buprenorphine produced a significant increase in the Table 3 Drug identification responses a,b Drug administered Number (%) Opioid Opioid Placebo Benzodiazepine Barbiturates and Stimulants agonists antagonists sleeping medications Saline 1 (2) 0 (0) 41 (85) 0 (0) 6 (13) 0 (0) Hydromorphone 9 mg 36 (75) 0 (0) 11 (23) 0 (0) 1 (2) 0 (0) 18 mg 33 (69) 0 (0) 15 (31) 0 (0) 0 (0) 0 (0) Buprenorphine 4 mg 25 (52) 0 (0) 23 (48) 0 (0) 0 (0) 0 (0) 8 mg 27 (56) 0 (0) 18 (38) 3 (6) 0 (0) 0 (0) 16 mg 31 (65) 1 (2) 14 (29) 0 (0) 0 (0) 2 (4) a Total identifications for each dose condition = 48 (8 subjects 6 times each) b There were no identifications as Antidepressants, Hallucinogens, Phenothiazines, or other

7 335 peak systolic blood pressure relative to placebo (13 mmhg). There were no significant effects for heart rate, respiration, or skin temperature, but all of the active drug conditions produced significant decreases in pupil diameter relative to placebo (ranging from 0.75 to 1.15 mm relative to placebo). None of the drug conditions produced significant effects on the psychomotor/cognitive performance tasks. Time course of drug effects The time course effects for three representative measures are shown in Fig. 2. The top two panels show the time course for pupil diameter. The baseline pupil diameter was approximately 3.9 mm, and both doses of hydromorphone produced rapid and marked pupillary constriction that was sustained through most of the session (top left panel of Fig. 2). While the three doses of buprenorphine also produced pupillary constriction, it was not as great as that produced by hydromorphone (top right panel of Fig. 2). However, like hydromorphone the constriction produced by buprenorphine was sustained throughout the session. The middle and lower panels of Fig. 2 show the time course effects for the subject-rated and observer-rated adjective agonist scores. For the subject-rated scores, both doses of hydromorphone produced significantly increased ratings that were sustained throughout the session (middle left panel of Fig. 2). The three doses of buprenorphine produced a similar pattern of effects (middle right panel of Fig. 2). The observer-rated adjective agonist scores showed a similar pattern (bottom two panels of Fig. 2). For hydromorphone the magnitude of the increase was nearly equivalent for the two doses tested; for buprenorphine, there was a clear doseresponse effect with the greatest scores produced by the highest dose of buprenorphine (bottom right panel of Fig. 2). For all doses of hydromorphone and buprenorphine tested, effects were sustained throughout the 2 h of the session. Individual subject responses Though there was considerable variability, visual inspection of the data showed individual subject results to be generally consistent with the average data. No patterns were observed that were suggestive of bimodal responses by participants, and analyses by gender also failed to find any differential pattern of effects for males versus females. Analysis for carry-over effects No evidence of residual effects from a previous session, such as sustained opioid agonist effects from the high dose hydromorphone and buprenorphine conditions, was found. Discussion Fig. 2 Time course of effects of saline, hydromorphone and buprenorphine on pupil diameter, subject-rated adjective agonist score, and observer-rated adjective agonist score, in buprenorphinemaintained humans. Each point represents the mean based upon one observation in each of eight subjects. BL, baseline This study examined the acute effects of parenteral buprenorphine, hydromorphone, and saline placebo in volunteers maintained on a daily dose of 8 mg of sublingual buprenorphine. The purpose was to assess the abuse potential of hydromorphone and of buprenorphine in buprenorphine-maintained subjects, using multidimensional measures of opioid agonist-like effects that have been developed for the assessment of abuse liability (Jasinski 1977; Bigelow 1991). The two doses of hydromorphone (9 and 18 mg) produced typical profiles of opioid agonist-like effects, with little dose difference noted in the profile or magnitude of effects produced. The three doses of buprenorphine tested (4, 8 and 16 mg) produced dose-related increases in typical opioid agonist-like effects, with the highest

8 336 dose of buprenorphine producing effects similar in magnitude to those produced by the hydromorphone conditions. The two doses of hydromorphone used in this study both produced a profile of opioid agonist-like effects on visual analog scale ratings of High, Liking, and Good Effects, subject and observer adjective rating scale scores of agonist effects, and physiologic measures such as pupil diameter (Table 2). This profile of hydromorphone effects is similar to that found in non-dependent opioid abusers (Bickel et al. 1989; Preston et al. 1992), demonstrating hydromorphone s typical opioid agonist-like effects in the present study. The present results show that 8 mg per day of maintenance buprenorphine does not produce sufficient cross-tolerance to block completely the effects of illicit opioids. A maintenance dose of 8 mg of daily buprenorphine was selected for this study because several large, outpatient clinical trials comparing buprenorphine to methadone used doses of buprenorphine in this range (e.g., Johnson et al. 1992; Strain et al. 1994; Ling et al. 1996). However, higher doses of buprenorphine may produce better outcomes in the treatment of opioid dependence, and human laboratory data and an outpatient clinical trial suggest doses of 16 mg per day can provide greater opioid blockade than 8 mg (Bickel et al. 1988a; Schottenfeld et al. 1993; Walsh et al. 1995). Interestingly, results from the present study and a previous human laboratory study with buprenorphinemaintained volunteers found similar outcomes in response to a hydromorphone challenge, for subjectrated and physiologic measures when participants were maintained on 8 mg per day of buprenorphine (Bickel et al. 1988a). While not the primary purpose of this study, the present results from the hydromorphone challenges provide important data supporting the use of buprenorphine doses greater than 8 mg per day in the treatment of opioid dependence, and at least one clinical report suggests higher doses of daily sublingual buprenorphine can produce better outcomes (Schottenfeld et al. 1993). The results from this study also suggest that higher doses of buprenorphine can be safely administered to patients. Sublingual buprenorphine has been estimated to have a relative potency of two-thirds compared to subcutaneous buprenorphine (Jasinski et al. 1989). Assuming there is little difference in the bioavailability of subcutaneous versus intramuscular buprenorphine, the 16 mg intramuscular dose used in this study is approximately equal to 24 mg of sublingual buprenorphine. Thus, subjects in this study received the equivalent of 32 mg of sublingual buprenorphine on some session days, and tolerated this total dose with no adverse effects. This sublingual dose of buprenorphine also has been administered with no significant adverse effects to volunteers who were experienced but not physically dependent opioid abusers at the time of study (Walsh et al. 1995). The lack of a graded dose-effect relation for hydromorphone effects is an interesting finding. This may be a consequence of buprenorphine maintenance. In similar studies in methadone-maintained patients hydromorphone effects have been clearly dose-related (e.g., Strain et al. 1992, 1993). It is well established that, as a partial agonist, buprenorphine itself does not always produce graded dose-effect relations, but has a ceiling on the magnitude of its agonist effects (e.g., Cowan et al. 1977b; Walsh et al. 1994). One of the pharmacological characteristics of partial agonists is the capability to function as an antagonist and attenuate the effects of full agonists. The partial agonist activity of buprenorphine, combined with its high affinity for opioid receptors, may explain the lack of graded hydromorphone dose-effects in the present study. In this conceptualization the magnitude of effects produced by full agonists such as hydromorphone, morphine or heroin is limited by the proportion of opioid receptors available for occupancy. In the present case of buprenorphine maintenance so many receptors may be occupied by buprenorphine that the remaining receptors provide little opportunity for supplemental full agonists to produce dose-related effects. This limited number of available receptors thus imposes a ceiling on the magnitude of effects that can be produced even by supplemental full agonists. One of the positive safety features of partial agonists such as buprenorphine in the treatment of opioid abuse and dependence is the fact that it would be difficult or impossible for a fatal overdose to result from misuse of the medication. The above interpretation of the present data suggests that a further benefit of partial agonist treatment may be reduction in the risk of fatal overdose from misuse even of illicit full agonists such as heroin. The doses of hydromorphone used in this study were considerably larger than typical analgesic doses (1 2 mg parenterally), although the lower dose tested (9 mg) is similar to a hydromorphone dose used in previous abuse liability studies (10 mg) that have enrolled methadone-maintained volunteers (e.g., Strain et al. 1992, 1993). Thus, comparison of the present study results with these previous studies provides valuable information about the relative cross-tolerance to hydromorphone in buprenorphine versus methadone-maintained volunteers: patients maintained on 30 mg of daily methadone reported nearly two-fold greater agonist-like effects in response to acute hydromorphone challenge compared to patients maintained on 8 mg of daily sublingual buprenorphine. This suggests buprenorphine 8 mg/day SL may produce greater attenuation of illicit opioid effects than methadone 30 mg/day PO. While the effects produced by all doses of buprenorphine tested in this study were generally mild in intensity, the data also suggest that buprenorphine could be abused parenterally by patients maintained on a daily dose of 8 mg SL buprenorphine. Buprenorphine needs

9 337 to be available in a soluble formulation for buccal absorption, and such monotherapy is already available in one country (France). The present results suggest prescribed sublingual buprenorphine could be misused and administered via the parenteral route, producing opioid agonist effects, and thus having abuse potential. Two approaches to decrease the abuse of buprenorphine are being considered. The first is the development of a combination product containing buprenorphine plus naloxone that would decrease the abuse liability of parenteral buprenorphine, similar to the pentazocine-naloxone combination product developed in the 1980s (Polkis 1984). Preliminary work on buprenorphine-naloxone combination products has been reported (Preston et al. 1988b; Weinhold et al. 1992), and NIDA is actively pursuing this possibility (Chiang et al. 1996). The second is the development of buprenorphine as an alternate-day medication. Again, preliminary work on alternate-day buprenorphine dosing has been reported (Fudala et al. 1990; Amass et al. 1994; Johnson et al. 1995b), and this approach also appears promising. Thus, this study demonstrates that volunteers maintained on a daily dose of 8 mg sublingual buprenorphine can experience agonist-like effects from supplemental doses of parenteral buprenorphine, suggesting that buprenorphine could be abused by patients maintained on buprenorphine. The results also show that this daily dose of buprenorphine provides incomplete cross-tolerance to the effects of a prototypic mu agonist opioid (hydromorphone), suggesting that higher maintenance doses of buprenorphine may be needed to achieve the maximum clinical efficacy. Finally, subjects in this study tolerated cumulative doses of buprenorphine with no adverse effects noted, suggesting that higher doses of buprenorphine can be safely administered to opioid dependent patients. Acknowledgements The authors thank Michael Webb, Linda Felch and John Yingling for assistance in data collection and analysis. This study was supported by US Public Health Service Research Scientist Award K05 DA00050 (G.E.B.). Scientist Development Award K20 DA00166 (E.C.S.), R01 DA08045, and R18 DA06120 from the National Institute on Drug Abuse. Some of these data were presented at the annual meeting of the College on Problems of Drug Dependence, Palm Beach, Florida, June References Amass L, Bickel WK, Higgins ST, Badger GL (1994) Alternateday dosing during buprenorphine treatment of opioid dependence. Life Sci 54: Banks CD (1979) Overdosage of buprenorphine: case report. N Z Med J 89: Bickel WK, Amass L (1995) Buprenorphine treatment of opioid dependence: a review. Exp Clin Psychopharmacol 3: Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988a) Buprenorphine: dose-related blockade of opioid challenge effects in opioid dependent humans. J Pharmacol Exp Ther 247: Bickel WK, Stitzer ML, Bigelow GE, Liebson IA, Jasinski DR, Johnson RE (1988b) A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts. Clin Pharmacol Ther 43: Bickel WK, Bigelow GE, Preston KL, Liebson IA (1989) Opioid drug discrimination in humans: stability, specificity and relation to self-reported drug effect. J Pharmacol Exp Ther 251: Bigelow GE (1991) Human drug abuse liability assessment: opioids and analgesics. Br J Addict 86: Chiang CN, Bridge P, Hawks RL, Herbert S, Hill J, Maghrablian L, Terrill J, Walsh R (1996) The development of buprenorphine-naloxone products for treating opiate dependence. In: Harris LS (ed) Problems of drug dependence, 1995: proceedings of the 57th Annual Scientific Meeting, The College on Problems of Drug Dependence, NIDA Research Monograph 162. US Department of Health and Human Services, National Institute of Health, Rockville, Md. p 117 Cowan A, Lewis JW (1995) Buprenorphine: combatting drug abuse with a unique opioid. Wiley-Liss, New York Cowan A, Lewis JW, MacFarlane IR (1977a) Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol 60: Cowan A, Doxey JC, Harry EJ (1977b) The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol 60: Doxey JC, Everitt JE, Frank LW, MacKenzie JE (1982) A comparison of the effects of buprenorphine and morphine on the blood gases of conscious rats. Br J Pharmacol 75 [S]:118P Dum JE, Herz A (1981) In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions. Br J Pharmacol 74: Filibeck U, Castellano C, Oliverio A (1981) Differential effects of opiate agonist-antagonists on morphine-induced hyperexcitability and analgesia in mice. Psychopharmacology 73: France CP, Jacobson AE, Woods JH (1984) Discriminative stimulus effects of reversible and irreversible opiate agonists: morphine, oxymorphazone and buprenorphine. J Pharmacol Exp Ther 230: Fudala PJ, Jaffe JH, Dax EM, Johnson RE (1990) 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 47: Fukase H, Fukuzaki K, Koja T, Nagata R, Lukas SE (1994) Effects of morphine, naloxone, buprenorphine, butorphanol, haloperidol and imipramine on morphine withdrawal signs in cynomolgus monkeys. Psychopharmacology 116: Jasinski DR (1977) Assessment of the abuse potentiality of morphinelike drugs (methods used in man). In: Martin WR (ed) Drug addiction I. Springer, Berlin, pp Jasinski DR, Pevnick JS, Griffith JD (1978) Human pharmacology and abuse potential of the analgesic buprenorphine. Arch Gen Psychiatry 35: Jasinski DR, Fudala PJ, Johnson RE (1989) Sublingual versus subcutaneous buprenorphine in opiate abusers. Clin Pharmacol Ther 45: Johnson RE, Cone EJ, Henningfield JE, Fudala PJ (1989) Use of buprenorphine in the treatment of opioid addiction. I. Physiologic and behavioral effects during a rapid dose induction. Clin Pharmacol Ther 46: Johnson RE, Jaffe JH, Fudala PJ (1992) A controlled trial of buprenorphine treatment for opioid dependence. JAMA 267: Johnson RE, Eissenberg T, Stitzer ML, Strain EC, Liebson IA, Bigelow GE (1995a) A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Depend 40: 17 25

10 338 Johnson RE, Eissenberg T, Stitzer ML, Strain EC, Liebson IA, Bigelow GE (1995b) Buprenorphine treatment of opioid dependence: clinical trial of daily versus alternate-day dosing. Drug Alcohol Depend 40: Kolb L, Himmelsbach CK (1938) Clinical studies of drug addiction. III. A critical review of the withdrawal treatments with method of evaluating abstinence syndromes. Am J Psychiatry 94: Kosten TR, Schottenfeld R, Ziedonis D, Falcioni J (1993) Buprenorphine versus methadone maintenance for opioid dependence. J Nerv Ment Dis 181: Leander JD (1983) Opioid agonist and antagonist behavioral effects of buprenorphine. Br J Pharmacol 78: Leander JD (1988) Buprenorphine is a potent κ-opioid receptor antagonist in pigeons and mice. Eur J Pharmacol 151: Lewis JW (1995) Clinical pharmacology of buprenorphine in relation to its use as an analgesic. In: Cowan A, Lewis JW (eds) Buprenorphine: combatting drug abuse with a unique opioid. Wiley-Liss, New York, pp Ling W, Wesson D, Charuvastra C, Klett J (1996) A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry 53: Lizasoain I, Leza JC, Lorenzo P (1991) Buprenorphine: bell-shaped dose-response curve for its antagonist effects. Gen Pharmacol 22: Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197: McLeod D, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Methods Instrum 14: Mello NK, Mendelson JH, Kuehnle JC (1982) Buprenorphine effects on human heroin self-administration: an operant analysis. J Pharmacol Exp Ther 223:30 39 Morrison V (1989) Psychoactive substance use and related behaviors of 135 regular illicit drug users in Scotland. Drug Alcohol Depend 23: Negus SS, Dykstra LA (1988) κ antagonist properties of buprenorphine in the shock titration procedure. Eur J Pharmacol 156: Negus SS, Woods JH (1995) Reinforcing effects, discriminative stimulus effects, and physical dependence liability of buprenorphine. In: Cowan A, Lewis JW (eds) Buprenorphine: combatting drug abuse with a unique opioid. Wiley-Liss, New York, pp Negus SS, Picker MJ, Dykstra LA (1989) Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats. Psychopharmacology 98: O Connor JJ, Moloney E, Travers R, Campbell A (1988) Buprenorphine abuse among opiate addicts. Br J Addict 83: Pickworth WB, Johnson RE, Holicky BA, Cone EJ (1993) Subjective and physiologic effects of intravenous buprenorphine in humans. Clin Pharmacol Ther 53: Polkis A (1984) Decline in abuse of pentazocine/ tripelennamine (T s and Blues) associated with the addition of naloxone to pentazocine tablets. Drug Alcohol Depend 14: Pournaghash S, Riley AL (1993) Buprenorphine as a stimulus in drug discrimination learning: an assessment of mu and kappa receptor activity. Pharmacol Biochem Behav 46: Preston KP, Bigelow GE (1991) Subjective and discriminative effects of drugs. Behav Pharmacol 2: Preston KP, Bigelow GE, Liebson IA (1988a) Butorphanol-precipitated withdrawal in opioid-dependent human volunteers. J Pharmacol Exp Ther 246: Preston KP, Bigelow GE, Liebson IA (1988b) Buprenorphine and naloxone alone and in combination in opioid-dependent humans. Psychopharmacology 94: Preston KP, Bigelow GE, Liebson IA (1989) Antagonist effects of nalbuphine in opioid-dependent human volunteers. J Pharmacol Exp Ther 248: Preston KP, Liebson IA, Bigelow GE (1992) Discrimination of agonist-antagonist opioids in humans trained on a two-choice saline-hydromorphone discrimination. J Pharmacol Exp Ther 261: Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN (1993) The misuse of buprenorphine and a buprenorphinenaloxone combination in Wellington, New Zealand. Drug Alcohol Depend 33: Rosen MI, Wallace EA, McMahon TJ, Pearsall R, Woods SW, Price LH, Kosten TR (1994) Buprenorphine: duration of blockade of effects of intramuscular hydromorphone. Drug Alcohol Depend 35: San L, Tremoleda J, Ollé, Porta Serra M, de la Torre R (1989) Prevalencia del consumo de buprenorfina en heroinómanos en tratamiento. Med Clin (Barc) 93: Schottenfeld RS, Pakes J, Ziedonis D, Kosten TR (1993) Buprenorphine: dose-related effects on cocaine and opioid use in cocaine-abusing opioid-dependent humans. Biol Psychiatry 34: Singh RA, Mattoo SK, Malhotra A, Varma VK (1992) Cases of buprenorphine abuse in India. Acta Psychiatr Scand 86: Spitzer RL, Williams JBW (1985) Structured clinical interview for DSM-III-R. New York State Psychiatric Institute, Biometrics Research, New York, NY Strain EC, Preston KL, Liebson IA, Bigelow GE (1992) Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther 261: Strain EC, Preston KL, Liebson IA, Bigelow GE (1993) Precipitated withdrawal by pentazocine in methadone-maintained volunteers. J Pharmacol Exp Ther 267: Strain EC, Stitzer ML, Liebson IA, Bigelow GE (1994) Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry 151: Strain EC, Preston KL, Liebson IA, Bigelow GE (1995) Buprenorphine effects in methadone-maintained volunteers: effects at two hours after methadone. J Pharmacol Exp Ther 272: Wallenstein SL, Kaiko RF, Rogers AG, Houde RW (1986) Crossover trials in clinical analgesic assays: studies of buprenorphine and morphine. Pharmacotherapy 6: Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994) Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther 55: Walsh SL, Preston KL, Bigelow GE, Stitzer ML (1995) Acute administration of buprenorphine in humans: partial agonist and blockade effects. J Pharmacol Exp Ther 274: Weinhold LL, Preston KL, Farre M, Liebson IA, Bigelow GE (1992) Buprenorphine alone and in combination with naloxone in non-dependent humans. Drug Alcohol Depend 30: