Psychopharmacology (1999) 141 : 37 46
© Springer-Verlag 1999
O R I G I NA L I N V E S T I G AT I O N
John Mendelson · Reese T. Jones · Susette Welm Matthew Baggott · Isabella Fernandez Ann K. Melby · Rajneesh P. Nath
Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers Received : 9 February 1998 / Final version : 8 May 1998
Abstract Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist e¤ects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The e¤ects of three intravenous (IV) buprenorphine and naloxone combinations on agonist e¤ects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2 : 1, 4 : 1, and 8 : 1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist e¤ects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist e¤ects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2 : 1 and 4 : 1 produced moderate to high increases in global opiate withdrawal, bad drug e¤ect, and sickness. These dose ratios also decreased the pleasurable e¤ects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8 : 1 produced only mild withdrawal symptoms. Dose combinations at 2 : 1 and 4 : 1 ratios may be useful in treating opiate dependence. This study was supported by US Public Health Service grants DA01696 and DA00053 and contract No. N01DA-4-8306 from the National Institute on Drug Abuse, National Institutes of Health and carried out in part in the General Clinical Research Center at University of California, San Francisco, with support of the Division of Research Resources, National Institutes of Health (RR-00079) J. Mendelson (*) · R.T. Jones · S. Welm · M. Baggott I. Fernandez · A.K. Melby · R.P. Nath Drug Dependence Research Center, Langley Porter Psychiatric Institute, University of California, San Francisco, CA 94143-0984, USA e-mail :
[email protected], Fax : +1-415-476-7690
Key words Buprenorphine · Naloxone · Dose ratio · Opiate dependence · Human
Introduction Sublingual (SL) buprenorphine is a synthetic, oripavine, partial l opioid analgesic with a relatively low abuse liability (DEA Schedule V) (Lewis 1985). Buprenorphine reduces the physiologic and subjective e¤ects of opiates (Jasinski et al. 1978) and heroin selfadministration by heroin-dependent men (Mello and Mendelson 1980). Buprenorphine has recently been reported to be e¤ective in the treatment of opiate dependence (Kosten et al. 1991; Johnson et al. 1992; Ling et al. 1994; Strain et al. 1994; Amass et al. 1996). However, buprenorphines l opioid agonist e¤ects increase the potential for illicit diversion and reports of intravenous (IV) abuse in opiate-dependent populations have appeared (OConnor et al. 1988; Lavelle et al. 1991; Robinson et al. 1993; Nigam et al. 1994). For patients treated with (and presumably dependent on) SL buprenorphine, parenteral abuse may be limited by ceiling e¤ects at higher doses due to buprenorphines partial agonist properties (Walsh et al. 1994). Buprenorphine may be available for take-home dosing, and parenteral abuse or illicit diversion is possible. Injection drug abusers are at risk for serious, even fatal, bacterial and viral diseases, including human immunodeÞciency virus (HIV). Methods which diminish the parenteral abuse liability of treatment medications have the potential to decrease transmission of infections between injection drug abusers. Buprenorphine and naloxone combinations may diminish parenteral abuse liability in opiate-dependent individuals by precipitating opiate withdrawal when taken parenterally but not sublingually (SL). Naloxone has a relatively low SL absorption of 810 % (Weinberg et al. 1988; Preston et al. 1990; Mendelson et al. 1997b),
38
whereas buprenorphine is better absorbed (approximately 30 50%) and has signiÞcant pharmacologic activity when given SL (Olley and Tiong 1988; Weinberg et al. 1988; Jasinski et al. 1989; Mendelson et al. 1989). The rapid and intensely unpleasant e¤ects of naloxone when administered IV to opiate-dependent people (OBrien et al. 1978; Gilman et al. 1990; Mendelson et al. 1997a) suggest that it would be an ideal candidate for a combination formulation. An ideal ratio of buprenorphine to naloxone in a combination dose would preserve the therapeutic e¤ects of buprenorphine and minimize opiate antagonist e¤ects of naloxone when given SL. However, if the same combination is taken illicitly by the IV route, it would have the opposite e¤ects, precipitating substantial opiate withdrawal. Combination opioid agonist and antagonist formulations have been marketed but rarely tested for abuse liability in opiate abusers. Precedents for combination agonist and antagonist opioid formulations include pentazocine and naloxone mixtures, which signiÞcantly reduced parenteral pentazocine abuse (Ghodse 1987). A methadone and naloxone oral dose combination was tested but not widely prescribed (Nutt and Jasinski 1974; Loimer et al. 1991). A survey of New Zealand opiate abusers suggested that a marketed buprenorphine and naloxone combination appeared to decrease abuse liability for lower, analgesic buprenorphine doses (0.3 0.6 mg) (Robinson et al. 1993). Buprenorphine doses in the range of 4 32 mg per day are needed for opiate addiction treatment in most patients (Ling et al. 1996). The lowest e¤ective dose is 2 mg (Johnson et al. 1992). Combinations with naloxone in this dose range have received less study. In opiate-dependent daily heroin users, an IV dose of a 1 : 1 ratio of buprenorphine to naloxone (2 mg) produced opiate withdrawal and decreased the estimated illicit street value of the combination (Mendelson et al. 1996). Buprenorphine alone produced opioid agonist e¤ects and was considered liable to abuse by our subjects. Evaluation of more than one dose ratio of buprenorphine to naloxone in this population was considered impractical, due to varying levels of opiate dependence inherent in untreated heroin injectors. Although some degree of opiate withdrawal is usually precipitated by parenteral administration of buprenorphine and naloxone combinations, there is considerable variability in withdrawal intensity between subjects. Some of this variability is probably due to di¤ering self-administered opiate doses and resulting levels of dependence. For example, in subjects with relatively more consistent levels of opiate dependence, such as those on 30 mg or more of methadone, parenterally administered Þxed ratio (2 : 1, 1.5 : 1, and 1 : 1) low dose buprenorphine (0.2 0.3 mg) and naloxone (0.10.2 mg) combinations produced predominantly opiate withdrawal and seemed to have a low abuse lia-
bility (Preston et al. 1988; Mendelson et al. 1997a). In contrast, in opiate-dependent subjects stabilized for 7 days on 8 mg / day of SL buprenorphine (Mendelson et al. 1997b), SL buprenorphine, 8 mg with naloxone 4 or 8 mg (2 : 1 and 1 : 1 ratios), did not precipitate opiate withdrawal. In this experiment, variability in the level of opiate dependence was decreased by stabilizing research subjects on morphine. We felt the use of morphine would be analogous to use of the short-acting opiate heroin. With this paradigm, volunteers physically dependent on variable but always uncertain self-administered doses of illicit opiates are given repeated known doses of morphine to achieve a stable level of dependence. Thus, when the experimental medication is substituted for morphine, opiate agonist and antagonist e¤ects are measured under pharmacologically controlled laboratory conditions. Substitution trials have used daily doses as large as 240 mg morphine (Fraser and Isbell 1960) given in equal doses [60 mg subcutaneous (SC) doses every 6 h]. More recent substitution and challenge studies of partial agonists of morphine were conducted with volunteers dependent on 60 mg morphine sulfate given in four daily 15 mg SC or intramuscular (IM) doses. At this dose, su¦cient physical dependence was present reliably to quantify suppression of abstinence (Jasinski 1977; Schuh et al. 1996). The relative potency of this morphine maintenance level is approximately equivalent to a 30 mg daily oral methadone dose, and is generally assumed to be associated with moderate dependence. A substantial percentage of individuals currently abusing heroin or other opiates do not show any evidence of precipitated withdrawal to naloxone challenge (Kanof et al. 1991). Combination formulations might not be e¤ective in these individuals because naloxoneprecipitated withdrawal would not occur. Therefore, in non-precipitated abusers, an important additional feature of a combination would be the attenuation of any pleasurable and reinforcing e¤ects of buprenorphine if taken parenterally. In our study of heroin-dependent subjects, maximal opioid agonist e¤ects were always smaller and delayed following buprenorphine and naloxone when compared with buprenorphine alone (Mendelson et al. 1996). The magnitude of opioid agonist e¤ects was diminished for up to 3 h. The time course of e¤ects was biphasic on ratings of global intoxication, with opiate antagonist-like e¤ects dominating in the Þrst 90 min and opioid agonist-like e¤ects emerging only later in the second hour. In this study, we assessed the ability of three buprenorphine and naloxone combinations to attenuate opioid agonist e¤ects. The combination of precipitated opiate withdrawal in dependent abusers and attenuated pleasurable e¤ects in both dependent and non-dependent abusers would probably result in decreased illicit street value.
39
The primary goals of this study were to determine the dose range over which IV naloxone, in combination with IV buprenorphine, would precipitate opiate withdrawal signs and symptoms and attenuate the pleasurable e¤ects of buprenorphine in subjects with a moderate level of opiate dependence. Opiate-dependent volunteers were stabilized on a 60 mg daily dose of morphine given as four 15 mg IM doses and challenged with a 2 mg IV dose of buprenorphine alone and in combination with naloxone 1, 0.5, and 0.25 mg (ratios of 2 : 1, 4 : 1, and 8 : 1). Empirical evaluation of e¤ective dose combinations could guide formulation of a sublingual medication with low abuse liability for the treatment of opiate dependence.
buprenorphine and naloxone combinations, morphine, or placebo. Since the e¤ects of parenteral naloxone in opiate-dependent subjects have been well described (OBrien et al. 1978), to diminish unnecessary subject discomfort, a naloxone alone challenge was not performed. Moreover, naloxone at doses similar to those used in our study reliably precipitates opiate withdrawal in subjects maintained on 60 mg / day IM morphine (Schuh et al. 1996). Challenges with buprenorphine and naloxone combinations were performed every other day because of buprenorphines relatively long half-life and slow receptor dissociation (Lewis 1985). Intravenous morphine served as a control for the opioid agonist e¤ects of buprenorphine. After the last challenge dose on day 17, tapered daily doses of SL buprenorphine (6 or 8 mg on day 17, then in sequence 6, 4, 2, and 1 mg daily) were substituted for the daily IM morphine doses. Subjects were discharged on day 22. No SL buprenorphine was given on the day of discharge. After discharge, subjects were o¤ered paid admission to a local drug abuse treatment program for 21-day, methadone-assisted opiate detoxiÞcation.
Materials and methods Subjects Subjects were recruited by newspaper advertisements. Eleven men and one woman, 27 45 years of age (mean ± SD, 37 ± 6), completed the study. Two subjects voluntarily left the study during morphine stabilization (one on day 2 and the other on day 3) because of unacceptable levels of opiate withdrawal. Subjects were included if they were between 21 and 45 years of age, met DSM-IV criteria for opiate dependence, had at least daily self-reported heroin use during the last 30 days with no more than 1 week of non-use in the last 6 months, had opiate positive urine toxicological screens on two separate occasions and were in good physical and mental health (other than opiate dependence). Subjects were excluded if they currently or within the past 3 months had received any treatment for opiate dependence (including methadone), were dependent (using DSM-IV criteria) on ethanol, cocaine, or other psychoactive drugs (except for nicotine or ca¤eine), had medical or psychiatric illnesses which might have impaired their ability to safely complete the study, had a history of sensitivity to study medications, or were unable to give informed consent. A negative serum pregnancy test and current use of an adequate method of birth control were required for women. Pregnancy tests were conducted during screening and immediately before admission to the study. A medical examination and laboratory screening tests (complete blood count, serum chemistries for hepatic, renal, and metabolic functions, urinalysis, and hepatitis B surface antigens) were performed. Subjects with clinically signiÞcant abnormalities were excluded. HIV status was not an inclusion or exclusion factor. Subjects were admitted to the General Clinical Research Center (GCRC) at UCSF Mo¦tt Hospital. They were compensated for their time. Subjects were informed of the possible e¤ects of study medications and written informed consent was obtained. The study was approved by the Committee on Human Research, University of California, San Francisco.
Buprenorphine / naloxone and morphine challenge procedures Each challenge session on days 6, 8, 10, 13, 15, and 17 was performed in the Drug Dependence Research Center Laboratories. Subjects arrived at the laboratory at 0800 hours approximately 1 h after a standard breakfast. Challenges were performed at 1000 hours, 4 h after the Þrst and 1 h before the second morphine maintenance dose. After baseline measurements, one of the following six treatments was given at each session in a double-blind, placebo-controlled, balanced crossover design : IV buprenorphine 2 mg and naloxone placebo IV buprenorphine 2 mg and naloxone 1 mg combined (2:1 ratio) IV buprenorphine 2 mg and naloxone 0.5 mg combined (4:1 ratio) IV buprenorphine 2 mg and naloxone 0.25 mg combined (8:1 ratio) IV morphine 15 mg Placebo Peak e¤ects of IV administered buprenorphine, morphine, and naloxone occur rapidly and, for naloxone, dissipate rapidly (OBrien et al. 1978; Gilman et al. 1990). Due to the complex interactions between distribution, elimination, and receptor e¤ects of our drug combinations, the relative agonist and antagonist potencies were expected to vary in intensity over the Þrst hour following challenge. Therefore, a su¦cient density of measures was obtained to characterize both the time course and peak e¤ects of the drug combinations. Because IM morphine has a short (4 6 h) duration of action, measures beyond 1 h were expected to reßect e¤ects of impending morphine withdrawal; the e¤ects of challenge doses were assessed for only the Þrst hour after dosing.
Measures Physiologic measures
General procedure After GCRC admission, subjects were immediately started on IM morphine, 60 mg daily. Morphine was administered in four 15 mg doses at 0600, 1100, 1600, and 2200 hours for the Þrst 16 days of hospitalization. Morphine was injected IM in the hip on alternating sides or occasionally into the deltoid muscle. Intramuscular administration was used because absorption is similar following both IM and SC administration (Gilman et al. 1990) and IM and SC morphine stabilization protocols are well described (Jasinski 1977; Schuh et al. 1996). After 5 days of stabilization on morphine, subjects were challenged, every other day, with IV doses of
Heart rate, systolic and diastolic blood pressure were measured with a cardiovascular monitor (VSM 2; Physio-Control Corporation, Redmond, Wash., USA). Rate pressure product was calculated as the product of systolic blood pressure and heart rate. Fingertip skin temperature was measured by a thermistor (Mon-a-Therm, Model 6500, Mallinckrodt, St Louis, Mo., USA). Respiration rate was measured by counting the number of inhalations / min. Measures were obtained before IV dosing and at 5, 10, 15, 30, 45, 60 min postdose. Pupil diameter was measured with an automated video system under three (dark, dim and bright) light conditions (Em / 2 System, Oculokinetics, Inc., Torrance, Calif., USA) predose and at 20 and 60 min postdose.
40 Subjective reports
ProÞle of Mood States
Data are presented as symptom clusters associated with opiate agonist, opiate withdrawal (antagonist), and non-opiate speciÞc drug e¤ects. Measures included verbal ratings, visual analog scales, observer and subject-rated scales, and spontaneous subject comments (Mendelson et al. 1996).
The POMS (McNair et al. 1971) assessed mood changes in tension, depression, anger, vigor, confusion, and fatigue on a 0 (no e¤ect) to 4 (extremely strong) scale. POMS ratings were obtained predose and at 55 min postdose.
Opiate agonist measures Global opiate intoxication was verbally estimated by subjects on a scale of 0 100. Zero was no e¤ect, and 100 the maximum e¤ect ever experienced after opiate drugs. Global intoxication ratings were obtained at the same time as physiologic measures. The opiate agonist scale included 16 typical opiate e¤ects (Bickel et al. 1988). Subjects rated on a 0 4 scale (0 = no e¤ect and 4 = maximum e¤ect) the intensity of the following : nodding, heavy or sluggish feeling, dry mouth, good mood, energy, upset stomach, itchy skin, relaxed feeling, coasting, talkativeness, pleasant sickness, drive, carefree feeling, drunkenness, friendly feeling, and nervousness. Visual analog scales were used to identify qualitative and quantitative drug e¤ects. Subjects rated the degree of drug e¤ects by moving an arrow along a 10 cm line marked at opposite ends as 0 (no e¤ect) and 100 (maximal e¤ect) on a hand-held computer (Tandy 102, Radio Shack, Fort Worth, Tex., USA). Items rated on the visual analog scale were drug liking and good drug e¤ect. Opiate agonist scale and visual analog rating for drug liking and good drug e¤ect were obtained predose and at 5, 15, 30, 45, and 55 min postdose.
Opiate antagonist measures Global opiate withdrawal was verbally estimated on a scale of 0 (no e¤ect) to 100 (maximum e¤ect). Global withdrawal ratings were obtained at the same times as physiologic measures. The opiate withdrawal scale listed 21 typical opiate antagonist symptoms (Bickel et al. 1988). Subjects rated the following symptoms on a 0 4 scale (0 = no e¤ect and 4 = maximum e¤ect) : muscle cramps, ßushing, painful joints, yawning, restlessness, watery eyes, runny nose, chills or gooseßesh, sick to stomach, sneezing, abdominal cramps, irritability, backache, tense and jittery, sweating, depressed, sleepy, shaky or tremulous, hot or cold ßashes, bothered by noises, clammy and damp skin. Opiate antagonist scales and visual analog rating for bad drug e¤ect and sickness were obtained predose and at 5, 15, 30, 45, and 55 min postdose.
Non-opiate-speciÞc subjective measures Dollar value of drug Subjects estimated the potential dollar amount they would pay for the challenge doses if they were illicitly available. This value was relative to the amount usually spent for illicit heroin; no attempt was made to standardize dollar values or amounts usually spent on heroin. Subjects were asked, How much would you pay right now for the dose you received today if you could buy it on the street?
Visual analog Rating of any drug e¤ect was obtained at the same times as other analog ratings.
Observer-rated measures Opiate agonist and withdrawal scales were completed simultaneously by the subjects and a research assistant. In addition, the Clinical Institute Narcotic Assessment (CINA) rating scale was used by the observer to rate the intensity of opiate withdrawal signs and symptoms (Peachey and Lei 1988). The scale consists of 13 items. Ten are typical withdrawal signs (nausea, goose ßesh, sweating, restlessness, tremor, lacrimation, nasal congestion, yawning, changes in heart rate and systolic pressure), and three are typical opiate withdrawal symptoms (abdominal pain, muscle pain, and feeling hot or cold). Ratings were obtained at baseline, and at 5 and 15 min postdose. Cumulative change scores, calculated by summing the changes from baseline for the two postdose periods of observation, were used in the comparison of treatment e¤ect.
Morphine, buprenorphine, and naloxone dose preparation Commercially available morphine sulfate (Elkins-Sinn, Inc., Cherry Hill, N.J., USA), 15 mg / ml, was used for the IM morphine stabilization phase and the IV morphine challenge. Buprenorphine hydrochloride and buprenorphine and naloxone combinations for the IV challenges were supplied by the National Institute on Drug Abuse, Medication Development Division. The IV challenge treatments, in a 2 ml volume of 0.9 % NaCl, were injected into a forearm vein by infusion pump (Model #22, Harvard Apparatus, South Natick, Mass., USA) over 30 s. Saline (0.9 %) was used for the placebo condition. Sublingual buprenorphine hydrochloride tablets used in the morphine withdrawal phase of the study were manufactured by Reckitt and Colman Products (London, UK), and supplied by the National Institute on Drug Abuse, National Institutes of Health.
Statistical analysis On challenge days, the e¤ects of IV buprenorphine, buprenorphine and naloxone combinations, morphine, and placebo were analyzed by repeated measures ANOVA, with drug conditions (buprenorphine 2 mg and naloxone placebo, buprenorphine 2 mg and naloxone 1 mg, buprenorphine 2 mg and naloxone 0.5 mg, buprenorphine 2 mg and naloxone 0.25 mg, morphine 1 mg, or placebo) and observation times as within-subject factors. Change scores (post-minus pretreatment) were used in the analysis. After a signiÞcant F test, pairwise comparisons were performed using the least square means analysis. Sequence by dose interaction was not analyzed because of the sample size. With an n of 12 and only two subjects for each sequence of treatment, an adequate number for valid analysis of the treatment sequence did not exist. Session and order e¤ect was analyzed by repeated measures ANOVA, with session and observation time as the within-subject variables. To assess the total agonist and antagonist e¤ects of buprenorphine alone relative to the di¤erent buprenorphine and naloxone combinations, an AUC (0 60 min) for global withdrawal, global intoxication, opiate agonist and withdrawal scales, and visual analog scales (except any drug e¤ect) was calculated by the linear trapezoidal method. E¤ects of buprenorphine and naloxone combination ratios were contrasted with buprenorphine alone by comparison of
41 AUC and analyzed by one-factor ANOVA. Data were adjusted for sphericity using the Huynh-Feldt correction factor. HuynhFeldt corrected signiÞcance values are reported.
Results Buprenorphine and naloxone challenge days (day 6 through day 17) Physiologic measures Buprenorphine and naloxone in 2 : 1 and 4 : 1 ratios (1 and 0.5 mg naloxone) increased systolic and diastolic blood pressure, heart rate, and rate pressure product compared with buprenorphine alone, morphine, and placebo (P < 0.01). Peak e¤ects occurred at approximately 5 min, and conditions remained signiÞcantly di¤erent for the Þrst 30 min. A dose-dependent response was evident, with the 2 : 1 combination (1 mg naloxone dose) producing the greatest increase in cardiovascular e¤ects. Respiration rate at 5 and 10 min postdose was higher following the 2 : 1 combination (1 mg naloxone) than after buprenorphine alone (P < 0.01), morphine (P < 0.02), or placebo (P < 0.01). Peak changes are shown in Table 1. Skin temperature decreased following the administration of 2 : 1 and 4 : 1 buprenorphine and naloxone combinations (1 and 0.5 mg naloxone) compared to buprenorphine alone (P < 0.02), morphine (P < 0.02), and placebo (P < 0.01). E¤ects appeared at approximately 5 min after injection, peaked at 10 min, and disappeared within 30 min of drug administration. Buprenorphine diminished pupil size in all three light conditions compared to morphine (P < 0.01)
and placebo (P < 0.01) with peak e¤ects at 20 min. The 2 : 1 and 4 : 1 buprenorphine and naloxone combinations attenuated pupil constriction e¤ects of buprenorphine (P < 0.01). Peak changes are presented in Table 1. Overall, cardiovascular activity and pupil size increased following administration of buprenorphine and naloxone challenge doses compared to buprenorphine alone. A dose-dependent response was evident, with the 2 : 1 combination producing the greatest increase in cardiovascular e¤ects and pupil size. Subjective measures The time course of agonist and antagonist e¤ects is in Fig. 1. Area under the e¤ect-time curve for selected subjective measures is in Table 2. Summary and statistical results are in Table 3. Opiate agonist measures Buprenorphine and morphine produced similar agonist proÞles with no di¤erences between agents. No signiÞcant opioid agonist e¤ects followed any of the buprenorphine and naloxone combinations. When compared to buprenorphine or morphine, all three buprenorphine and naloxone combinations decreased global intoxication and opiate agonist ratings for at least 30 min postdose. When measured by AUC, global intoxication (P < 0.01), drug liking (P < 0.01), and good drug e¤ect (P < 0.01) were diminished for the 2 : 1 but not the 4 : 1 and 8 : 1 buprenorphine and naloxone challenge doses.
Table 1 Peak changes from baseline for cardiovascular measures and pupil size (mean ± SD, n = 12) Measure
Buprenorphine (2 mg)
Buprenorphine/ naloxone 2:1
Buprenorphine/ naloxone 4:1
Diastolic blood pressure (mmHg) Systolic blood pressure (mmHg) Heart rate (beats/min) Rate pressure product (SBP*HR) Respiration rate (Inhalations/min) Pupil size Bright light (mm) Pupil size Dim light (mm) Pupil size Dark light (mm)
[0.5 ± 4.3
17.6 ± 11.7a,b,c
10.2 ± 7.6a,b,c
2.6 ± 5.6
a,b,c
a
8.7 ± 10
Morphine (15 mg)
Placebo
5.0 ± 9.7
3.0 ± 9.3
0.3 ± 5.4
7.7 ± 15.6
3.4 ± 9.3
1 ± 4.2
[0.5 ± 4.9
[3.6 ± 3.4
[1.7 ± 2.8
7.4 ± 8.4a,b,c
0.3 ± 4.0
[50 ± 350
2509 ± 1586a,b,c
614 ± 855c
357 ± 1415
183 ± 775
[356 ± 361
2.2 ± 2a,b,c
1.4 ± 2.5a,c
0.7 ± 1.4
0.6 ± 1.9
[0.3 ± 1
a
a
[0.39 ± 0.61
[0.3 ± 0.61
0.03 ± 0.3
[0.2 ± 1.4
[1.4 ± 6.3
[0.62 ± 0.48
0.45 ± 0.68
[0.83 ± 0.49
0.75 ± 0.78a,b,c
0.07 ± 0.61a
[0.4 ± 0.72
[0.38 ± 0.86
0.01 ± 0.76
[1.21 ± 0.86
0.54 ± 0.61a,b,c
0.04 ± 0.61a
[0.84 ± 0.59
[0.39 ± 0.58
[0.2 ± 0.97
0.18 ± 0.73
SigniÞcantly di¤erent from buprenorphine (P ≤ 0.01; except for respiration rate, 4 : 1 ratio, P ≤ 0.3) SigniÞcantly di¤erent from morphine (P ≤ 0.01) SigniÞcantly di¤erent from placebo (P ≤ 0.01; except for respiration rate; 4 : 1 ratio, P ≤ 0.02)
b c
22.3 ± 11.6
Buprenorphine/ naloxone 8:1
42 Fig. 1 Time course of subjectrated opiate agonist and antagonist e¤ects. Each data point represents mean values for 12 subjects (Time = baseline value). Buprenorphine (2 mg) (, buprenorphine (2 mg) and naloxone (1 mg) l, buprenorphine (2 mg) and naloxone (0.5 mg) ▲, buprenorphine (2 mg) and naloxone (0.25 mg) u, morphine (15 mg) n, and placebo ¡
Table 2 Area under the curve (0 60 min) for subjective measures (mean ± SD, n = 12) challenge sessions Subjective measure
Buprenorphine (2 mg)
Buprenorphine/ naloxone 2:1
Buprenorphine/ naloxone 4:1
Buprenorphine/ naloxone 8:1
Morphine (15 mg)
Placebo
Gobal intoxication Global withdrawal
1340 ± 1447 150 ± 303
250 ± 309a,b,c 1365 ± 958a,b
756 ± 1689 318 ± 331
795 ± 1409 451 ± 543
1511 ± 1715 71 ± 202
462 ± 628 339 ± 418
Visual analog scales Good drug e¤ect Drug liking Bad drug e¤ect Sickness rating Opiate agonist scale Opiate withdrawal scale
2254 ± 2310 2251 ± 2492 123 ± 288 206 ± 413 970 ± 413 112 ± 134
611 ± 577a,b 646 ± 657a,b 1855 ± 1298a,b,c 1273 ± 1005a,b,c 655 ± 344a,b 588 ± 603a,b,c
1564 ± 1938 1465 ± 2081b 825 ± 891a,b,c 643 ± 626 788 ± 363 291 ± 270
1046 ± 1266a,b 1218 ± 1809a,b 446 ± 662 371 ± 425 869 ± 512 239 ± 176
2522 ± 2089 2973 ± 2630 160 ± 483 193 ± 420 968 ± 583 94 ± 183
597 ± 689 928 ± 1463 58 ± 169 408 ± 564 829 ± 486 249 ± 315
a
SigniÞcantly di¤erent from buprenorphine (P ≤ 0.01) SigniÞcantly di¤erent from morphine (P ≤ 0.01) SigniÞcantly di¤erent from placebo (P ≤ 0.01)
b c
Opiate antagonist measures Buprenorphine and naloxone combinations produced dose-dependent opiate antagonist e¤ects, with the 2 : 1 ratio (1 mg naloxone dose) eliciting the greatest e¤ect. All three buprenorphine and naloxone combinations signiÞcantly increased global opiate withdrawal rating and scores on the opiate withdrawal scale. The 2 : 1 combination (1 mg naloxone) produced signiÞcantly more intense withdrawal which persisted for a longer time (30 min) than the 4 : 1 or 8 : 1 combinations (0.5 or 0.25 mg naloxone). When evaluated by AUC, only the 2 : 1 combination increased withdrawal intensity; all other conditions did not di¤er signiÞcantly. Dose-dependent increases in bad drug and sickness ratings occurred. Ratings were greater with both the
1 mg (2 :1) and 0.5 mg (4 : 1) buprenorphine and naloxone doses when compared to buprenorphine and morphine. Ratings diminished as the buprenorphine to naloxone ratio increased. However, no statistical di¤erence was seen between the 4 : 1 and 8 : 1 combination. Peak e¤ects occurred at approximately 5 min and persisted for approximately 30 min. When evaluated by AUCs, only the 2 : 1 combination (1 mg naloxone) signiÞcantly increased ratings. Observer-rated measures (Clinical Institute Narcotic Assessment, CINA, Peachey and Lei 1988) All three buprenorphine and naloxone combinations signiÞcantly increased withdrawal signs compared to
43 Table 3 Buprenorphine versus buprenorphine / naloxone combination challenge phase. Statistical summary of agonist and antagonist e¤ects. NA not applicable; NS not signiÞcant Measures
Buprenorphinea Naloxone 2:1 P value time * course
Buprenorphineb Naloxone 4:1
Buprenorphinec Naloxone 8:1
P value AUC
*
P value time course
*
P value AUC
*
P value time course
*
P value * AUC
Opiate agonist measures Global intoxication Opiate agonist scale VAS drug liking VAS good drug
0.01 0.04 0.01 0.01
↓ ↓ ↓ ↓
0.01 0.01 0.01 0.01
↓ ↓ ↓ ↓
0.03 0.04 NS NS
↓ ↓ NS NS
NS NS 0.04 NS
NS NS ↓ NS
0.02 0.04 NS 0.04
↓ ↓ NS ↓
NS NS 0.04 0.03
NS NS ↓ ↓
Opiate antagonist measures Global withdrawal rating Opiate withdrawal scale VAS bad drug e¤ect VAS sickness rating
0.01 0.01 0.01 0.01
↑ ↑ ↑ ↑
0.01 0.01 0.01 0.01
↑ ↑ ↑ ↑
0.02 0.01 0.01 0.01
↑ ↑ ↑ ↑
NS NS 0.02 NS
NS NS ↑ NS
0.02 NS NS NS
↑ NS NS NS
NS NS NS NS
NS NS NS NS
$ Amount willing to pay
0.01
↓
NA
NA
NS
NS
NA
NA
0.03
↓
NA
NA
* Arrows indicate direction of signiÞcant drug e¤ect relative to the buprenorphine condition, based on analysis of variance of time course and area under the curve a Buprenorphine 2 mg, naloxone 1 mg b Buprenorphine 2 mg, naloxone 0.5 mg c Buprenorphine 2 mg, naloxone 0.25 mg
Dollar value of the drug Only morphine and buprenorphine were judged by subjects to have any signiÞcant illicit monetary value. Subjects would be willing to pay similar amounts for buprenorphine ($8 ± 10, mean ± SD) and morphine ($ 12 ± 10). The value of the buprenorphine and naloxone 4 : 1 and 8 : 1 combinations ($4 ± 7 and $4 ± 5, respectively) was less than buprenorphine or morphine. No subjects would be willing to pay anything for the 2 : 1 buprenorphine and naloxone combination. Fig. 2 Observer rating on the Clinical Institute Narcotic Assessment (CINA) Scale. Changes from baseline at 15 min postdose. Values are presented as means (n = 12). Error bars represent standard deviations. ∗ SigniÞcantly di¤erent from buprenorphine, morphine, and placebo (P ≤ 0.01) Bup (buprenorphine, 2 mg) MS (morphine sulfate, 15 mg), 8 : 1 (buprenorphine, 2 mg; naloxone, 0.25 mg), 4.1 (buprenorphine, 2 mg; naloxone, 0.5 mg), 2 : 1 (buprenorphine, 2 mg; naloxone, 1 mg), Plac (placebo)
the placebo, morphine, and buprenorphine conditions (P < 0.01). Compared to the 4 : 1 and 8 : 1 combinations, the 2 : 1 formulation obtained a more intense withdrawal rating. No signiÞcant di¤erence was found between the 4 : 1 and 8 : 1 ratios (Fig. 2). Non-opiate speciÞc measures Visual analog any drug e¤ect (0100 rating scale) All drug challenges except for the buprenorphine and naloxone 8 : 1 combination signiÞcantly increased rating of any drug e¤ect compared to placebo.
ProÞle of Mood Scale No signiÞcant di¤erence was found in any of the mood scales (anger, confusion, depression, fatigue, tension, and vigor). Session and order e¤ect An analysis of session and order e¤ect revealed no signiÞcant dose-by-session order interaction on any measures.
Discussion The primary goals of this study were to evaluate the e¤ectiveness of IV naloxone in combination with buprenorphine in precipitating opiate withdrawal and attenuating the pleasurable e¤ects of buprenorphine.
44
This study can also be used to predict the safety and e¦cacy of parenterally administered buprenorphine and naloxone combinations in subjects with a moderate level of opiate dependence and to compare the relative pleasurable e¤ects of acute IV buprenorphine and morphine administration. The doses of buprenorphine and naloxone were similar to those currently being assessed for opiate dependence treatment in a Veterans Administration multicenter trial (Paul Fudala, PI, personal communication). E¦cacy of buprenorphine and naloxone combinations in precipitating opiate withdrawal All three buprenorphine and naloxone combinations studied produced opiate antagonist e¤ects when given IV. Naloxone produced a dose-dependent withdrawal response, with the 2 : 1 ratio (1 mg naloxone) producing the greatest and the 8 : 1 ratio (0.25 mg naloxone) the least opiate withdrawal. All indices of opiate withdrawal were increased by the 2 : 1 and 4 : 1 ratios, whereas with the 8 : 1 ratio only self-reports of global withdrawal were increased. Both subjective and objective withdrawal e¤ects peaked within 5 min after injection of naloxone plus buprenorphine, then dissipated within 30 min for all combinations. The duration of withdrawal e¤ects was also naloxone dose-dependent and lasted the longest after the 2 : 1 ratio. Buprenorphine-induced pupil constriction was signiÞcantly attenuated by the 2 : 1 and 4 : 1 buprenorphine and naloxone combinations, but not by the 8 : 1 ratio. In general, the 8 : 1 combination had a more variable between-subject response as well as less overall e¤ect. The 2 : 1 and 4 : 1 ratios were generally similar in producing antagonist e¤ects. Although the 2 : 1 ratio could be distinguished from the 4 : 1 ratio on many withdrawal measures, both the 2 : 1 and 4 : 1 precipitated substantial withdrawal. If buprenorphine was to be diverted from therapeutic to illicit use, our subjects would be typical potential purchasers. Because all our subjects were regularly purchasing illicit heroin, they were well qualiÞed to assess the potential illicit street value of buprenorphine and naloxone combinations. They judged IV buprenorphine and morphine equivalent in dollar value ($ 10 and $ 8, respectively). The monetary value of all combination ratios was substantially less than buprenorphine or morphine. Although some subjects would be willing to pay small amounts for the 4 : 1 and 8 : 1 combination ratios ($ 4), no one expressed any desire to pay for the 2 : 1 dose which precipitated maximal withdrawal. In a study similar to ours, opiate addicts were stabilized on the same daily dose of IM morphine sulfate (60 mg / day) and a single 4 : 1 dose ratio of buprenorphine and naloxone was evaluated (Fudala et al. 1996). SigniÞcant opiate withdrawal e¤ects were produced by
the IV dose of buprenorphine 2 mg and naloxone 0.5 mg, suggesting a decreased abuse potential for this 4 : 1 dose ratio. Their Þndings are concordant with our results, but the study was limited since the e¦cacy of higher or lower buprenorphine to naloxone ratios and doses was not examined (Fudala et al. 1996). In contrast, we examined a range of dose ratios. The results of our study are also consistent with our previous report of the e¤ects of IV buprenorphine and naloxone combinations (2 mg; 1 : 1 ratio) in opiatedependent daily heroin users not stabilized on morphine prior to challenge (Mendelson et al. 1996). When compared to our prior study (where a larger naloxone dose was utilized), the 2 : 1 combination produced more intense and less variable global withdrawal. The 4 : 1 ratio in this study produced global withdrawal comparable to the 1 : 1 ratio in our prior study. Although the pattern of visual analog ratings of antagonist e¤ects (bad drug, sickness) was generally similar in both studies, more variability was evident in the unstabilized heroin addicts. A major problem in developing any pharmacologic strategy to diminish illicit diversion and abuse of buprenorphine is that more than one population of opiate abusers is at risk for diversion. Buprenorphine abuse in patients treated with SL buprenorphine may be limited by the partial agonist properties of buprenorphine with ceiling e¤ects at higher doses (Walsh et al. 1994). It is well established that parenteral naloxone can precipitate withdrawal in patients maintained on SL buprenorphine, but relatively large doses are needed. For example, in patients on 23 mg / day SL buprenorphine, IM naloxone 35 mg / kg precipitated withdrawal (Kosten et al. 1990). Similarly, IM naloxone 3 mg / 70 kg precipitated withdrawal in patients on 8 mg / day SL buprenorphine (Eissenberg et al. 1996). In regular buprenorphine abusers, injecting an average of 1.33 mg per day, naloxone 1.2 mg IV also precipitated withdrawal (Nigam et al. 1994). In contrast, subjects maintained for 45 52 days on 8 mg SC buprenorphine did not have opiate withdrawal following 4 mg SC naloxone (Jasinski et al. 1978). The combination of a ceiling on the pleasurable e¤ects of buprenorphine when administered by any route (Walsh et al. 1994) and precipitated withdrawal with increasing doses of parenteral (but not SL) naloxone may discourage illicit diversion in most l-opiate dependent abusers. Safety of buprenorphine and naloxone combinations Buprenorphine and naloxone combinations were safe in our opiate-dependent subjects. Naloxone produced an expected dose-dependent increase in sympathetic activation with statistically signiÞcant (but clinically insigniÞcant) increases in heart rate, blood pressure, and respiratory rate. No subject developed unstable
45
vital signs despite substantial subjective withdrawal. Therefore, although unpleasant, combination formulations are probably safe in opiate-dependent individuals. Because most heroin overdose deaths are due to respiratory depression (Gilman et al. 1990), illicit administration of formulations containing naloxone are probably safer than continued heroin abuse. In nonopiate abusers, lower doses of buprenorphine and naloxone combinations retain analgesic e¦cacy (Rolly et al. 1986; Vanacker et al. 1986) and suppress buprenorphine-induced stimulation of prolactin (Mendelson et al. 1989). Opiate agonist e¤ects in morphine-maintained subjects Opiate agonist e¤ects were substantial following morphine and buprenorphine administration, with 2 mg buprenorphine equivalent to 15 mg morphine. Buprenorphine and naloxone combinations may decrease the abuse liability of buprenorphine by attenuating the pleasurable e¤ects of buprenorphine. Diminishing the immediate reinforcing e¤ects of parenteral buprenorphine may be particularly important in non-dependent opiate abusers where naloxone-precipitated withdrawal would not occur. All three buprenorphine and naloxone combinations diminished the opiate agonist e¤ects of buprenorphine, with the 2 : 1 ratio decreasing all opiate agonist measures. The 4 : 1 and 8 : 1 ratios decreased global intoxication and opiate agonist scale indices but did not alter drug liking. All subjects rated all the buprenorphine and naloxone challenges as dysphoric, not euphoric. Our results are in agreement with reports in opiate abusers who are not physically dependent that the opiate agonist e¤ects of lower buprenorphine doses are attenuated by concurrent naloxone at dose ratios of 1 : 2, 1 : 1, and 2 : 1 (Weinhold et al. 1992). Although not tested in this experiment, diminished pleasurable e¤ects would be expected in non-dependent opiate abusers administered buprenorphine and naloxone combinations similar to the ones we tested. E¤ects of buprenorphine on opiate withdrawal Because buprenorphine is a partial l-agonist and could displace full l-agonists from receptor sites, l-opiate dependent people could experience precipitated withdrawal after buprenorphine. Precipitated withdrawal has been seen in morphine-dependent laboratory animals (Martin et al. 1976) and in methadone-maintained volunteers challenged with 1 and 2 mg buprenorphine (but not 4 or 8 mg) 20 h after methadone (Strain et al. 1995). In our study, opiate withdrawal did not occur after buprenorphine alone, consistent with the reports of others (Strain et al. 1992; Walsh et al. 1995; Schuh
et al. 1996 ). Only one subject reported mild subjective withdrawal symptoms after buprenorphine alone, similar to those reported after placebo injection. Conclusion Our results suggest that the abuse liability of buprenorphine in l-opiate dependent individuals can safely and e¤ectively be diminished by the use of buprenorphine and naloxone combination formulations. Intravenous administration of buprenorphine and naloxone combinations containing more than 0.5 mg naloxone in a 2 : 1 or 4 : 1 ratio of buprenorphine to naloxone reliably precipitates opiate withdrawal and has a low illicit street value for parenteral opiate abusers. In addition to precipitating withdrawal, these combinations substantially diminish the pleasurable e¤ects of buprenorphine. At the doses of buprenorphine needed to treat opiate dependence, combination formulations with 2 : 1 or 4 : 1 ratios of buprenorphine to naloxone should have lower abuse liability than buprenorphine alone. These ratios should be considered as potential sublingual tablet formulations for the treatment of opiate abuse. Acknowledgements The authors thank Nora Chiang PhD, NIDA Medication Development Division Project O¦cer, the sta¤ of the General Clinical Research Center at at the University of California, San Francisco, for assistance in conducting the study, Robert Jimison for data analysis, Nancy Mello, PhD, and Veronica Segredo, MD, PhD, for their helpful suggestions and Kaye Welch for editorial assistance.
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