0022-3565/91/2593- 1 165$00.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 259, No. 3 Copyright C 1991 by The American Society for Pharmacology and Experimental Therapeutics Printed in USA. The Reinforcing and Subjective Effects of Morphine in Post- Addicts: A Dose-Response Study R. J. LAMB, K. L. PRESTON, C. W. SCHINDLER, R. A. MEISCH,1 F. DAVIS, J. L. KATZ, J. E. HENNINGFIELD and S. A. GOLDBERG Clinical Pharmacology Branch (R.J.L., K.L.P., RAM., F.D., J.E.H.) and Preclinical Pharmacology Branch (C.W.S., J.L.K., S.R.G.), National Instit ute on Drug Abuse, Addiction Research Center, Baftimore, Maryland; Behavioral Pharmacology Research Unit (K.L.P.), Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Division of Addiction Research & Treatment (R.J.L.), Department of Mental Health Sciences, Hahnemann University, Philadelphia, Pennsylvania Accepted for publication August 29, 1991 Downloaded from ABSTRACT The reinforcing and subjective effects of morphine were deter- Benzedrine Group scale of the Addiction Research Center Inven- mined in five human volunteers with histories of i.v. heroin abuse. tory, drug detection and identification. Subjects did not report jpet.aspetjournals.org Subjects responded under a second-order schedule of i.m. injec- subjective effects different from placebo for the lowest dose of tion. Under this schedule, every 1 00 lever presses produced a morphine; the intermediate doses of morphine produced incon- brief stimulus light [fixed ratio (FR) 100:s]; the 30th completion sistent effects, and the highest dose of morphine occasioned of the FR 1 00 requirement turned on the light for 1 5 mm and the reports of drug liking and “dope” identifications. These results subject received an i.m. injection of morphine [FR 30 (FR 100:5)]. indicate that there can be a significant dissociation of the rein- Once each weekday morphine or placebo was available under forcing and the subjective effects of opioids, which has implica- this schedule. Each drug dose was available for 1 week. Under tions for theories of opioid abuse, particularly those assuming these conditions placebo did not maintain responding; 3.75 mg that the reinforcing effects are causally related to the euphoric at Univ Of California San Diego on January 12, 2013 of morphine maintained responding in four of five subjects, and effects of opiolds. Furthermore, these results confirm that meas- higher morphine doses (7.5, 1 5 and 30 mg) maintained respond- ures of reinforcing effects and measures of subjective effects do ing in all five subjects. Subjective effects were measured con- not necessarily lead to identical predictions when used to assess currently: these included measures of drug liking, the Morphine the liability for abuse of a substance. To estimate the liability for abuse of new analgesics, a tamed by vehicle indicates that the drug has reinforcing effects, number of measures of pharmacological similarity to morphine which contribute to its abuse liability. have been developed (cf. Jasinski, 1977; Himmelsbach, 1988; Although there have been few formal comparisons, several Brady and Lukas, 1984; U.S. Department of Health and Human authors have indicated a relatively good agreement between Services, 1988). For example, the extent to which new analge- results obtained with measures of pharmacological similarity sics share certain physiologic and subjective effects with mor- to morphine in humans and measures of reinforcing effects in phine is generally used as an indication of whether these drugs animals (cf. Griffiths and Balster, 1979; Woods et at., 1982; have a morphine-like liability for abuse. Techniques for the Woolverton and Schuster, 1983). Nevertheless, direct compar- isons are needed. Such comparisons would be useful for at least direct laboratory assessment of the reinforcing effects of opioids two reasons: 1) determining if use of a particular pharmacolog- have also been devised (e.g., Headlee et at., 1955; Nichols et al., ical effect to predict the reinforcing effects of opioids leads to 1956; Weeks, 1962; Weeks and Collins, 1964; Thompson and an accurate prediction and 2) determining the extent to which Schuster, 1964). By using these techniques, completion of a certain pharmacological effects may covary with the reinforcing specified sequence of behaviors by the subject (e.g., pressing a effects of opioids. Because the reinforcing effects of drugs are lever 100 times) is followed immediately by drug injection. frequently assumed to be due to their pleasant or euphoric Maintenance of that behavior at levels exceeding those main- subjective effects, it is particularly important to assess agree- ment among measures of these effects. Received for publication January 5, 1990. In the present experiments, the reinforcing effects of various I Present Address: Department of Psychiatry and Behavioral Sciences, Uni- varsity of Texas Health Science Center at Houston, 1300 Moursand, Houston, morphine doses were examined in human volunteers with his- TX 77030. tories of heroin addiction; additionally, the physiologic and ABBREVIATIONS: ARCI, Addiction Research Center nventory; MBG, Morphine Benzednne Group; PCAG, Pentobarbital Chlorpromazine Alcohol Group; LSD, lysergic acid diethylamide; FR, fixed-ratio. 1165 1166 Lambetal. Vol. 259 subjective effects of the self-administered morphine were meas- ures were started at 1:00 P.M. Operant sessions started from 30 to 60 ured. A single i.m. morphine injection was available after the mm after the pretest. Post-test measures were collected 90 mm after completion of a long sequence of responses during each daily the operant sessions. Subjects returned to the day area between these three periods. The exact start time for the operant sessions was deter- experimental session. This schedule allowed for the assessment mined by the subject, who could ask the nurse to begin the session at of the reinforcing, physiologic and subjective effects of mor- anytime between 30 and 60 mm after the pretest. It was hoped that phine without the complications of multiple drug injections this variable (time to begin the operant session) might function as a within the session. Additionally, a range of morphine doses was measure of the reinforcing effects of morphine, but instead starting studied in the present experiments, allowing an assessment of time became entrained with ward routine and did not vary across the extent to which the physiologic and subjective effects of conditions. morphine paralleled its reinforcing effects. The physiologic measures collected were heart rate, blood pressure, oral temperature and pupil diameter. Materials and Methods The subjective effects measures collected before each session were a version of the ARC!, and a computerized analog rating scale that could Subjects. Five subjects participated in this study. Subjects were be resolved into 50 points. The ARCI scales that were collected were males greater than 21 years of age with histories of daily i.v. heroin use the MBG scale, the PCAG scale, the LSD scale (Martin et at., 1971) who had used opioids during the 14 days preceding study recruitment. and a group of items related to opiate withdrawal (opiate withdrawal scale, Higgins et at., 1988). On the analog scale subjects were asked to Subjects were not currently physiologically dependent on opioids or Downloaded from other drugs as determined by self-report and by observation for with- rate how well they liked the drug they had received yesterday. drawal signs for several days while subjects resided on the Addiction The subjective effects measures collected after each session were the Research Center Research Ward before beginning the study. Subjects same ARC! items as in the pretest session and in addition the single were not currently seeking treatment for their drug abuse, or had they dose questionnaire (Fraser et at., 1961; Martin and Fraser, 1961), a been in treatment in the last 6 months. Other than their drug abuse, series of analog rating scales and several additional questions and subjects were in good health as determined by history, physical exam- ratings. Subjects used analog scales to rate drug liking, good and bad jpet.aspetjournals.org ination, routine clinical chemistries and standardized psychological effects and drug strength. They were also asked to rate drug strength tests and interviews. in dollars and bags, and were questioned about whether they thought Written informed consent was obtained from all subjecta, and sub- they had received drug today. The Single-Dose-Questionnaire consisted jects were free to leave the study at any point. Subjects were informed of four scales. The first asked subjects if they felt the medicine. The that the purpose of the study was to learn why people abuse opioid second required subjects to categorize the drug received as most like drugs (e.g., heroin, morphine and pentazocine), and that placebo (a one of the following: 1) blank; 2) dope; 3) cocaine; 4) marijuana; 5) blank) as well as opioid drugs might be administered during the study. Valium; 6) downers; 7) alcohol; 8) speed; 9) LSD; 10) Thorazine; 11) glue; 12) PCP; 13) tobacco; and 14) other. The third asked subjects to Subjects were also informed that at the end of the study they would be at Univ Of California San Diego on January 12, 2013 given a naloxone test in order to ensure that they were not physiolog- rate on a five point Likert scale how much they liked the drug (0 = not ically dependent upon opioids. Subjects were paid for their participation at all and 4 = an awful lot). The fifth asked subjects to indicate which in the study. if any of the following symptoms they experienced 1) normal; 2) skin Subjects participated in this study while residing on the Residential itchy; 3) relaxed; 4) coasting’, 5) nodding-, 6) high; 7) sleepy; 8) drunken; Research Ward of the Addiction Research Center. This research ward 9) nervous; 10) drive; 11) soap box; 12) turning stomach; 13) pleasant consisted of subject bedrooms, a nursing station, study and examination sick; and 14) other.