Subjective, Psychomotor, and Physiological Effects of Cumulative Doses of Opioid m Agonists in Healthy Volunteers

The subjective, psychomotor, and physiological effects of three opioid m-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM’s effects were stronger than MOR’s, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study. Research in our laboratory has sought to characterize the subjective, psychomotor, and physiological effects of opioids in healthy, normal volunteers with no history of drug abuse (Zacny et al., 1992; 1993; 1994a, b; 1997a, b; 1998). Through randomized, double-blind, placebo-controlled crossover designs, dose-response curves have been constructed that include doses of opioids that are typically prescribed for pain relief. We have characterized the subjective, psychomotor, and physiological effects of a variety of opioid agonists [morphine (MOR), codeine, meperidine (MEP), fentanyl] and opioids with mixed actions (buprenorphine, butorphanol, nalbuphine, pentazocine) in different studies. These studies consisted of four to five sessions in which a placebo and different doses of the opioid were tested, one dose per session. This single-dosing method allows the effects of a range of doses of one drug to be studied within the same individual. However, the method does not easily allow for dose-response curves to be constructed for multiple drugs within the same subjects because a single-dosing study would require numerous sessions to test a range of doses of three or four drugs. Because we administer opioids no more than once per week, such a study would require months to conduct, and subject recruitment and retention would be problematic. In addition, the ethics of exposing healthy volunteers to different opioids on many occasions are questionable. In the present study we sought to characterize the effects of a range of doses of three full m agonists, MOR, hydromorphone (HM), and MEP, within the same subjects using a cumulative-dosing procedure. Cumulative dosing allows the effects of different doses of a drug to be assessed within the same session. First, the effects of a small dose are assessed early in the session. Then more drug is added periodically to determine the effects of larger doses (cumulative doses, or total amount of drug administered up to that point). This procedure allows an entire dose-response curve to be constructed in one session. By using this procedure, dose-response curves can be determined for several different drugs (plus placebo) within the same subjects in one study. Cumulative dosing has been used for many years in behavioral Received for publication September 3, 1998. 1 This research was supported by National Institute on Drug Abuse Grant DA-08573. Portions of these data were presented at the 60th Annual Scientific Meeting of the College on Problems of Drug Dependence, Scottsdale, Arizona; at the 11th Annual Scientific Meeting of the Great Lakes Chapter-American Society for Pharmacology and Experimental Therapeutics, Chicago, Illinois; and at the 72nd Clinical and Scientific Congress of the International Anesthesia Research Society, Orlando, Florida. ABBREVIATIONS: ARCI, Addiction Research Center Inventory; PCAG, pentobarbital-chlorpromazine-alcohol group; BG, benzedrine group; AMP, amphetamine; LSD, lysergic acid diethylamide; MBG, morphine-benzedrine group; VAS, visual analog scale; DEL, Drug Effect/Liking; OAC, Opiate Adjective Checklist; DSST, Digit Symbol Substitution Test; HM, hydromorphone; MEP, meperidine; MOR, morphine; SAL, saline; BL, baseline. 0022-3565/99/2893-1454$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 289, No. 3 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 289:1454–1464, 1999 1454 at A PE T Jornals on July 9, 2017 jpet.asjournals.org D ow nladed from pharmacology to generate dose-response functions rapidly in both nonhumans (Wenger, 1980; Winger et al., 1989) and humans (de Wit et al., 1989; Preston and Bigelow, 1993). Besides the efficiency of the procedure, another advantage is that even though multiple doses of each drug are examined within the same subject, the amount of time subjects are under the influence of each drug is much less than if subjects received single weekly injections of each dose of opioid tested. The present study examined mood, psychomotor, and physiological effects of MOR, HM, and MEP in healthy volunteers with no history of drug abuse. These opioids are commonly prescribed for pain relief, and although each acts predominantly at the m receptor, they may produce somewhat different profiles of effects (Reisine and Pasternak, 1996). Singledosing studies conducted in our laboratory showed that i.v. doses of MEP (17.5–70 mg/70 kg) had more intense effects on mood (e.g., increased ratings of “sedated”, “high”, “coasting or spaced out”) than did MOR (2.5–10 mg/70 kg). Interand intrasubject variability in ratings of drug liking was observed with both drugs: both produced ratings indicative of liking, disliking, and neutrality in different subjects and, to some extent, within the same subjects at different time points. Both opioids had mild effects on cognitive/psychomotor performance (Zacny et al., 1993, 1994a). In one of two studies examining HM effects in healthy volunteers, oral HM (1–6 mg/70 kg) did not significantly affect self-reported sedation, stimulation, or strength or liking of the drug effect (Oliveto et al., 1994). These doses did not impair performance on the Digit Symbol Substitution Test (DSST), and in another study oral HM (1 and 3 mg) produced mild performance impairment on only 1 of 14 measures of cognitive/psychomotor performance (Pickworth et al., 1997). Our goals in the present experiment were to systematically replicate our previous studies with MOR and MEP by testing the effects of a range of doses of each opioid within the same subjects and determine the viability of our cumulative-dosing procedure as an efficient way of determining dose-response functions. We included HM because, like MOR and MEP, it is a m agonist that is commonly prescribed for pain relief. Materials and Methods