dependent individuals. Key words: Buprenorphine - Hydromorphone - Naloxone .... view Board of the Francis Scott Key Medical Center, and subjects gave their ...
Psychopharmacology
Psychopharmacology (1988) 94: 484490
© Springer-Verlag 1988
Buprenorphinc and naloxonc alone and in combination in opioid-dependent humans* Kenzie L. Preston, George E. Bigelow, and Ira A. Liebson Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA Abstract. Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 rag), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 rag) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 rain after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioiddependent individuals. Key words: Buprenorphine - Hydromorphone - Naloxone Methadone - Precipitated opioid withdrawal
One objective of opioid pharmacology research has been to develop potent analgesics with lower abuse liability than the prototypic analgesic morphine. One strategy which has led to some progress in this area is the development of drugs with limited opioid agonist-like effects, such as the mixed opioid agonist/antagonists pentazocine, butorphanol, nalbuphine, and buprenorphine (Jasinski et al. 1970, 1975, 1978; Jasinski and Mansky 1972). Even this class of compounds has, however, not been devoid of abuse problems. For example, abuse of pentazocine became a serious problem in the 1970s, leading to greater controls on its distribution (Poklis 1984; Senay 1985). Offprint requests to. K.L. Preston, Johns Hopkins University/Key Medical Center D-5-W; 4940 Eastern Avenue, Baltimore, MD 21224, USA * Supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse
A second strategy used to decrease the abuse of opioid analgesics has been to combine an opioid analgesic with an opioid antagonist. Examples of agonist and antagonist combinations which have been investigated include: morphine and nalorphine (Fraser et al. 1956), methadone and naloxone (Parwatikar and Knowles 1973; Nutt and Jasinski 1974), and pentazocine and naloxone (Legros et al. 1984). While the two former combinations are not marketed, the latter combination, pentazocine and naloxone, is available as an oral preparation in the United States. Indeed, the introduction of the pentazocine-naloxone combination product and withdrawal of pentazocine alone tablets from the market has been associated with a decline in reports of pentazocine abuse (Poklis 1984). Among the group of agonist/antagonist opioid analgesics is the partial agonist buprenorphine (Martin et al. 1976). Previous studies with buprenorphine in a post-addict population showed that buprenorphine produced morphine-like subjective effects, but that it had lower intrinsic activity than morphine and produced a lower level of physical dependence than morphine (Jasinski et al. 1978). These investigators suggested that buprenorphine has the potential to be abused, though probably less potential than that of morphine. In order to reduce further the likelihood that buprenorphine might be used as a substitute for other opioids such as heroin or morphine in opioid-dependent individuals, the strategy of combination with naloxone is being considered for parenteral and sublingual preparations of buprenorphine. The optimal ratio in such combination products should provide active doses of buprenorphine and an amount of naloxone sufficient to prove aversive to a narcotic addict by parenteral administration but insufficient to compromise the analgesic action of the buprenorphine. Preliminary work in an animal model of pain and withdrawal precipitation showed that parenteral dosage forms containing naloxone and buprenorphine with the weight ratio of 1 : 3 to 1 : 1 and sublingual forms within the ratio of 1 : 2 to 2:1 fulfill these therapeutic requirements (Reckitt and Colman Pharmaceutical Division, Hull, UK, unpublished data, 1986). Indeed, studies in postoperative pain patients have demonstrated that the analgesic effectiveness of parenteral buprenorphine 0.3 mg is not different from that of buprenorphine 0.3 mg plus naloxone 0.2 mg (Rolly et al. 1986; Vanacker et al. 1986). The purpose of the present study was to determine whether the requirement of low abuse potential (or aversiveness to opioid-dependent humans) when given parenterally
485 was met by the combination of buprenorphine and naloxone. The doses tested were those under consideration for therapeutic use, buprenorphine 0.3 mg/naloxone 0.2 mg for parenteral use and buprenorphine 0.2 mg/naloxone 0.2 mg for sublingual use. To provide a basis for the assessment of the potential for parenteral abuse of these combinations in opioid-dependent humans, the effects of buprenorphine plus naloxone, were evaluated in relation to buprenorphine alone and to two reference compounds, naloxone and hydromorphone. Naloxone 0.2 mg alone was included as a positive control for opioid withdrawal effects and to determine whether combination of naloxone with buprenorphine altered the response to naloxone 0.2 rag. Hydromorphone 6 mg served as a positive control for agonist effects and increased subject compliance. This comparative evaluation examined the profile and time course of subjective, physiological, and behavioral effects of acute doses of the test compounds. Measurements included both morphine-like effects and opioid abstinence signs and symptoms. Compounds which show a morphine-like profile of effects are viewed as possessing morphine-like abuse potential; compounds which precipitate abstinence symptoms are considered to have low potential for abuse by opioid-dependent individuals. For many years the abuse liability of new opioid analgesics was evaluated using prisoner volunteers at the USPHS Addiction Research Center (ARC) (Jasinski 1977). As part of the battery of testing done at the ARC the pharmacologic profiles of new opioid agonist/antagonist analgesics were evaluated in acute dosing cross-over studies comparing the new drug to a prototypic opioid such as morphine. In addition, the antagonist properties of these drugs were tested by measuring the drug's ability to precipitate withdrawal in volunteer prisoners made experimentally morphine-dependent. Legal restrictions have resulted in prisoner volunteers being no longer available to participate in such studies, and the need has arisen to develop alternative methods for clinical testing of opioid abuse liability. Thus, the second purpose of this study was to develop an assessment procedure to evaluate the morphine-like and antagonist properties of the mixed agonist/antagonist opioids in free volunteers recruited from the community. For this purpose we have recruited volunteers enrolled in methadone treatment for opioid addiction. Such volunteers have a prior history of opioid abuse and are currently maintained in a state of opioid tolerance and physical dependence for therapeutic reasons. The methods for measuring morphine-like effects were derived primarily from those traditionally used by the ARC in opioid drug abuse liability studies with institutionalized volunteers (Jasinski 1977), but were modified for use with volunteers recruited through community treatment centers. Measures of opioid abstinence were derived from those developed by Kolb and Himmelsbach (1938) and from other documented opioid abstinence signs and symptoms. Materials and methods
Subjects. The subjects were six adult, male, opioid-dependent volunteers with histories of narcotic drug abuse who were 27-43 years of age (mean 34) and weighed between 59.5 and 78.2 kg (mean 69.1). Subjects reported a range of 9-22 years (mean 13) of opioid abuse. Subjects were maintained on methadone HC1 (Methadose oral concen-
trate 10 mg/ml, Malinckrodt, St. Louis, MO) 30 rag/day, but were otherwise drug free at the time of their research participation. All subjects were stabilized on methadone 30 mg daily for at least 7 days prior to the initial experimental session. Methadone doses were administered once every 24 h, approximately 2 h after the experimental session. On the basis of physical examination, history, and laboratory chemistries, subjects were found to be without significant medical or psychiatric disturbance other than their drug abuse. This project was approved by the Institutional Review Board of the Francis Scott Key Medical Center, and subjects gave their written informed consent prior to beginning the study and were paid for their participation.
General procedures. Subjects participated while residing in an eight-bed behavioral pharmacology research ward which has been described previously (Griffiths et al. 1980). Urine specimens, which were collected prior to admission onto the research ward and at approximately weekly intervals during the study, were tested for the presence of illicit drugs on an EMIT system and/or using thin layer chromatography. Breathalyzer tests given to subjects on admission were negative for the presence of blood alcohol. Before research participation, subjects were informed that the study involved evaluation of the subjective and physiological effects of various doses of narcotic analgesics, narcotic antagonists, and a combination of a narcotic analgesic and an antagonist and that one of the drugs which they would receive included an investigational new drug which was not currently marketed in the United States. Subjects were also informed that they might experience effects similar to those which occur during withdrawal from opiates. Other than this general information, subjects were given no instructions of what outcomes might be expected. Drugs. Seven drug conditions were tested in randomized order for each subject: placebo; hydromorphone HC1 6 mg; naloxone HC1 0.2 mg; buprenorphine 0.2 and 0.3 rag; buprenorphine 0.2 nag plus naloxone HC1 0.2 rag, and buprenorphine 0.3 mg plus naloxone HC1 0.2 mg. Commercial preparations of hydromorphone HC1 (Knoll, Whippany, NJ) and naloxone HC1 (Du Pont, Wilmington, DE) were used. Buprenorphine HC1 was supplied by Reckitt and Colman Pharmaceutical Div (Hull, England) in ampules in the concentration of 0.2 and 0.3 mg (base) in 1 ml normal saline. The appropriate volume of drug solution from ampules was diluted to 1.5 rnl with 0.9% normal saline. Normal saline (1.5 ml) served as placebo. All doses were given subcutaneously as two 0.75 ml injections, one in each upper arm, under double-blind conditions. Hydromorphone and naloxone doses were calculated on the basis of the salts, and buprenorphine doses were calculated as the drug base.
Experimental session. Each subject participated in seven experimental sessions. Sessions were run at the same time of day for each subject and were separated by at least 48 h. Experimental sessions were conducted in a quiet testing room separated from the ward. All subjective effect and psychomotor performance measures were presented on a computer screen. Subjects used a key pad and joy stick to respond to subjective effect questions and to perform the psychomotor tasks. The subject was seated in the testing room for a 2.5-h session. After a 15-min stabilization period, 10 min of baseline physiological recording was taken;
486 a pupil photo was taken, and the subject answered subjective effect questionnaires and performed two psychomotor tasks. Approximately 30 rain after the start of the physiological recording, subjects received subcutaneous injections of saline or active drug. The session continued in the testing room for 2 h after drug dosing. Physiological, subjective, behavioral, and psychomotor/cognitive performance measures were collected as described below.
Physiological measures. Four physiological measures were monitored continuously in the experimental testing room: heart rate, blood pressure, skin temperature, and respiration. Heart rate and blood pressure were measured automatically once per min (Sentron Automatic Blood Pressure Monitor, Bard Biomedical Div., Lombard, IL). Skin temperature was monitored using a skin surface thermistor (Yellow Springs Instrument Co., Yellow Springs, OH) taped to the middle finger of one hand. Respiration was monitored using a bellows (Pneumo Chest Assembly, Lafayette, IN) placed around the lower chest and connected to a pressure sensitive switch (Micro Pneumatic Logic Inc., Fort Lauderdale, FL). Data for each measure were collected and stored in l-rain intervals using an Apple IIe microcomputer (Apple Computer, Cupertino, CA). Pupil diameter was determined from photographs taken in ambient room lighting using a Polaroid camera with a 3X magnification. Pupil photographs were taken 15 rain before drug administration and 6 times post-drug administration (15, 30, 45, 60, 90, and 120 rain). Subject-rated and observer-rated measures. Subjective effect and observer rating forms were completed 15 rain before drug administration and six times post-drug administration (15, 30, 45, 60, 90, and 120 rain post-drug). The subject was instructed to give answers describing how he felt at the time he filled out the questionnaires. The three questionnaires completed by subjects included visual analog scales, a pharmacological class questionnaire, and an adjective rating questionnaire. On the visual analog scales, the subject rated his current degree of " h i g h " and "sick" and the degree o f " any drug effect," " g o o d effects," " b a d effects," and "liking" of the drug effects by placing an arrow along a 100 point line marked at either end with " n o n e " and "extremely". On the pharmacological class questionnaire, the subject categorized the drug effect as being most similar to one of ten classes of psychoactive drugs; the questionnaire provided descriptive titles for and examples of each of the following classes: placebo, opiates (e.g., heroin, morphine), opiate antagonists (e.g., naloxone), phenothiazines (e.g., Thorazine), barbiturates and sleeping medications (e.g., pentobarbital), antidepressants (e.g., Elavil), hallucinogens (e.g., LSD), benzodiazepines (e.g., Valium), stimulants (e.g., amphetamine), and other. The adjective rating questionnaire consisted of 36 items (Table 1) which the subject rated on a 5-point scale from 0 (no effect) to 4 (maximum effect). The items in the rating scale were divided into three subscales: (1) the Fraser scale [adjectives previously shown by Fraser et al. (1961) to be sensitive to opioid effects], (2) an opioid agonist-like scale [adjectives in the Fraser scale plus additional adjectives associated with morphine-like effects], and (3) a withdrawal scale [adjectives derived from the Himmelsbach abstinence rating scale (Kolb and Himmelsbach 1938) plus other adjectives describing withdrawal symptoms]. Ratings for each item in
Table 1. Items in the adjective rating scales Fraser Scale * - Turning of stomach (1), skin itchy (2), relaxed (1), coasting (2), soapbox (1), pleasant sick (1), drive (2), sleepy (2), drunken (t), nervous (1) Agonist Scale Nodding, heavy or sluggish, dry mouth, carefree, good mood, energetic, turning of stomach, skin itchy, relaxed, coasting, soapbox, pleasant sick, drive, drunken, nervous Withdrawal Scale 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 * Values in parentheses are the weighting factors used in determining scale scores as described in the methods section the agonist and withdrawal scales were summed to determine a single total score for each scale. The Fraser scale score was determined as described by Fraser et al. (1961) with items rated as 0 (not at all) weighted as zero and items rated 1-4 weighted as either one or two; weights for individual items were then summed for a " t o t a l " Fraser score. The Fraser scale contains the same items as the opiate symptoms scale reported in many studies of opioid effects by the Addiction Research Center (Jasinski 1977), where it has been called the Single Dose Opiate Questionnaire or the opiate symptom scale. Observer ratings were completed by a research technician who rated the subject's drug effect at the same time intervals and using the same adjective list as the subject himself. The observer ratings were scored in the same way as the subject's adjective rating scales.
Psychomotor/cognitive performance measures. At 15 rain pre-drug administration and three times post-drug administration (60, 90, 120 min) the following tests were completed: a computerized recall (memory) task in which subjects were required to recall 8-digit numbers displayed on the video screen for 3 s and a computerized Digit Substitution Test (DSST) developed in our laboratory and previously described by McLeod et al. (1982). Data analysis. All data were converted to change from predrug baseline. To assess differences in the time course among drugs, the data were analyzed using a two factor analysis of variance with repeated measures over time and drug condition. Change scores were then collapsed into the areas under the time course curve and further analyzed using an analysis of variance with repeated measures over drug condition to compare the overall effects of drug condition. Significant drug effects found in the area under the curve analyses and significant condition by time interactions found in the time course analyses were explored using Duncan's Multiple Range test. Effects were considered significant if P_< 0.05. Results
Categorization of drug effects. The results of the pharmacological class identification questionnaire which was administered to subjects six times in each 2-h experimental session are presented in Table 2. The table shows the numbers of
487 Table 2. Results of drug class identification questionnaire Drug categories
Drug conditions P
Blank Opiate agonist Opiate antagonist Other
36 0 0 0
H
18 t8 0 0
N
4 1 24 7
B0.2
28 1 0 7
B0.3
31 4 0 1
B0.2
B0.3
+N
+N
9 0 27 0
12 0 24 0
P placebo; H hydromorphone 6 mg; N naloxone 0.2 mg; B 0.2 buprenorphine 0.2 mg; B 0.3 buprenorphine 0.3 mg Values represent totals from six subjects over 2-h sessions; maximum possible score - 36
occasions o n which the v a r i o u s d r u g c o n d i t i o n s were identified as placebo, a n opioid, a n opioid a n t a g o n i s t , a n d the s u m of the identifications o f drug classes other t h a n these three categories. Subjects identified placebo as a b l a n k in 100% of opportunities. H y d r o m o r p h o n e was identified as a n opioid in 50% of opportunities. W h e n given alone b o t h doses o f b u p r e n o r p h i n e were p r i m a r i l y identified as being placebo (78 a n d 86% o f o p p o r t u n i t i e s ) with only occasional identifications as a n opioid or other. N a l o x o n e alone was identified p r i m a r i l y (67% o f o p p o r t u n i t i e s ) as a n opioid a n t a g o n i s t , as were b o t h b u p r e n o r p h i n e - n a l o x o n e c o m b i n a tions (81 a n d 67% o f opportunities). Subjective effect measures. T a b l e 3 presents a s u m m a r y o f the results for subject- a n d observer-rated b e h a v i o r a l effects, physiological indices, a n d p s y c h o m o t o r p e r f o r m a n c e tasks for areas u n d e r the t i m e - a c t i o n curves for the 2-h experimental sessions. The directions of drug effects (increase or decrease as indicated b y arrows) are given for o n l y those d r u g c o n d i t i o n s which p r o d u c e d changes that were significantly different (P_
