NEUROPSYCHOPHARMACOLOGY 1994-VOL. 10, NO.3 171 Morphine Effects on the Spontaneous Electroencephalogram in Polydrug Abusers: Correlations with Subjective Self-Reports Robert L. Phillips, Ph.D., Ronald Heming, Ph.D., and Edythe D. London, Ph.D. The spontaneous electroencephalogram (EEG) was on Morphine-Benzedrine Group (MBG) subscale of the recorded after the intramuscular (IM) injection of ARC!. Negative relationships were observed between morphine sulfate (15, 30 mg) or saline (0.9% NaCl). changes in alpha1, and beta2 and scores on the Correlations between changes in EEG spectral power and Pentobarbital Chlorpromazine Alcohol Group (PCAG) subjective self-reports, as measured on subscales of the subscale. The findings indicate that positive subjective Addiction Research Center Inventory (ARC!), were effects of opioids, as measured by the MBG subscale, are evaluated. Morphine increased alphaJ and alpha2 power related to increases in alpha and beta activity and are and theta power, and attenuated the increase in delta associated with reduction of opioid-induced sedation, as power observed after placebo. Positive correlations were measured by the PCAG subscale. found between the change in alpha1, alpha2, beta1, and [Neuropsychopharmacology 10:171-181, 1994] beta2 power in response to 30 mg of morphine and scores KEY WORDS: Electroencephalography; Morphine; Opiate; mal subjects (von Felsinger et al. 1955). Although con­ Reinforcement; Drug abuse siderable information about the actions of opioid drugs in the nervous system exists, little is known about the Thesubjective effectsof opioids have been studied ex­ central mechanisms underlying their effects on mood tensively in human volunteers (Martin 1983). Morphine and feeling state in human subjects. produces a wide variety of effects, including analgesia, Effectsof morphine on the electroencephalogram drowsiness, changes in mood, and mental clouding (EEG) have been tested in several species. In rats, opi­ Gaffe and Martin 1985). In detoxifIed volunteers with oids increase the abundance of low frequencies in the histories of opioid abuse, arousal is produced (Kay et EEG (Wikler 1954; Khazan and Colasanti 1971; Young aI. 1969), mental clouding is less prominent, and posi­ et al. 1980; Young and Khazan 1984, 1986). In the dog, tive effectson mood are more pronounced than in nor- periods of burst-slow activity have been observed (Wik­ ler 1952). Slowing of the EEG is observed in the cat as well (De Andres and Caballero 1989). From the Neuroimaging and Drug Action Section, Neuroscience Opioid-induced slowing of the EEG in human sub­ Branch (RLP, EDL) and the Medical AffairsBranch (RH), Addiction Research Center, National Institute on Drug Abuse, National Institutes jects was &rst discovered by visual observation of EEG ofHealth, Baltimore, Maryland; and Department of Radiology (EDL), tracings (Berger 1937; Andrews 1941, 1943; Gibbs and the Johns Hopkins Medical Institutions and Department of Pharma­ Maltby 1943). Slowing has been de&ned in several ways. cology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland. Earlier studies de&ned slowing as a decrease in the dom­ Address correspondence to: Edythe D. London, Ph.D., Chief, inant frequency of the EEG tracings (Fig. la) or as the Neuroimaging and Drug Action Section, NIDA Addiction Research appearance of bursts of slow wave activity (Fig. Ib). Center, P.O. Box 5180, Baltimore, Maryland 21224. Received August 18, 1993; revised December 28, 1993; accepted Later studies using more quantitative methods de&ned January 3, 1994. slowing as a decrease in the alpha frequency (Fig. lc) Published 1994 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 0893-133X/94/$0.00 172 R.L. Phillips et al. NEUROPSYCHOPHARMACOLOGY 1994-VOL. 10, NO.3 Decrease in dominant frequency Appearance of burst slow waves a b Voltage Voltage IlV IlV Time Time (sec) (sec) Decrease in alpha frequency Increase in delta power d Power )lVl Figure 1. Defmitions of EEG Frequency Frequency slowing. The four conditions (Hz) (Hz) presented are not mutually -- "Slowed" "Normal" exclusive. or as an increase in low frequency (delta and/or theta) These changes were accompanied by signihcant in­ power (Fig. 1d). A decrease in the dominant frequency creases in self-reports of drowsiness, lethargy, and men­ of the EEG tracing can be due either to a decrease in tal slowness. Opioid-naive subjects gave self-reports alpha frequency, a decrease in alpha power relative to of being dizzy, nauseous, itchy, warm, and headachy delta and/or theta power, or an increase in delta and/or more often in response to morphine than to placebo theta power (Lukas 1991). (Beecher 1959). Effects of opioids on the EEG of human subjects Despite differencesin the specilicopioid drugs and with a history of opioid abuse have been reported. Both doses and populations tested, increased EEG slow­ heroin and methadone decreased alpha frequency and wave activity (delta and/or theta abundance) has been increased delta and theta abundance (Fink et al. 1971; the common response to opioids in human subjects. Volavka et al. 1979). Biphasic EEG effects of intrave­ However, there has been no previous attempt to corre­ nous heroin have been reported. Increased alpha power late the magnitude of EEG changes after opioid drug and decreased alpha frequency were found during the treatment to scores of mood and feeling state. In the fIrst 2 to 3 minutes; after 3 to 5 minutes, a decrease in present study, self-reports of mood and feeling state alpha amplitude and an increase in theta abundance oc­ were correlated with the quantitative changes in the curred (Volavka et al. 1970). Kay et al. (1969) reported EEG produced by morphine in polydrug abusers with diminished amplitude of delta waves with an increased histories of opioid use and dependence. incidence of unusual EEG patterns such as bursts of multiple frequency waves and mixtures of alpha and delta. MATERIALS AND METHODS Effects of opioids on the EEG vary with the drug Subjects histories of the subjects. In surgical patients, the inject­ able opioid anesthetics, fentanyl, sufentanil, and alfen­ Subjects were paid volunteers who resided on a closed tanil, increased abundance of EEG delta power and de­ research ward for the duration of the study. Nineteen creased abundance of alpha and/or beta power (Sebel subjects emolled in the study, but data were only avail­ et al. 1981; Bovill et al. 1983; Smith et al. 1984; Wau­ able for twelve. EEG data from seven of the subjects quier et al. 1984; Bromm et al. 1989; Scott et al. 1991). was not retained either because of equipment failure In contrast, in normal, pain-free human subjects, a small or because the subjects had subjective responses that decrease in delta, an increase in slow alpha with a de­ were not characteristic of polysubstance abusers that crease in relative fast alpha, and an increase in beta power are emolled in studies at the Addiction Research Cen­ occurred 1 to 2 hours after subcutaneous administra­ ter (i.e., extremely weak response to 30 mg intramus­ tion of morphine (4 and 8 mg) (Matejcek et al. 1988). cular (IM)morphine or strong response to placebo). The NEUROPSYCHOPHARMACOLOGY 1994-VOL. 10, NO.3 Morphine,EEG, and Subjective Self-Reports 173 Table 1. Effects of Morphine on Visual Analog Scale (VAS) Responses Morphine Morphine VAS Question Saline (15 mg) (30 mg) How strong is the drug effect?t§ 5 (7) 32 (19) 54 (18) Does the drug have good effects?t§ 4 (6) 32 (18) 59 (22) Does the drug have bad effects? 4 (5) 7 (7) 13 (17) How much do you like the drug?t§ 4 (6) 38 (24) 59 (28) How high do you feel?t§ 4 (6) 29 (17) 57 (21) How much do you want to take the drug again?t 9 (18) 51 (35) 70 (26) Numerical columns with mean (SO). t SignifIcant main effects of treatment (p < .0001) by repeated-measures ANOV A. § Response to 30 mg morphine signifIcantly different from response to 15 mg morphine, p < .05 by Bonferroni-corrected t-test. remaining 12 subjects were 26-39 years of age (mean that 60% and 95% of detoxifi.ed, previously opioid­ = 35; SD = 4.5). dependent, human subjects could correctly discrimi­ A recent history of intravenous usage of opioids nate 15 mg and 30 mg of morphine 1Mas an opioid drug was a criterion for admission. The time from the last rather than a sedative or marijuana (Kay et a1. 1967). use of opioids prior to admission to the study was 3 (4) (mean [SD]) weeks. Subjects were confi.rmed to be Test Sessions opiate-free by urine testing prior to admission and while in the study. Screening instruments included the Na­ Subjects were administered the Morphine-Benzedrine tional Institute of Mental Health (Bethesda, MD) Diag­ Group (MBG); Pentobarbital Chlorpromazine Alcohol nostic Interview Schedule (Robins et al. 1981), as mod­ Group (PCAG); and lysergic acid diethylamide (LSD) ifled forcomputerized administration. Full details of the subscales of the Addiction Research Center Inventory screening process are presented elsewhere (London et (ARCI) Oasinski et al. 1967; Haertzen 1974} and the Sin­ al. 1990). All but one subject met DSM-III (1980) criteria gle Dose Questionnaire (SDQ) (Fraser et al. 1961; Jasin­ for opioid dependence, although none showed signs ski et al. 1971). The MBG subscale consists of 16 ques­ of physical dependence at the time of admission or dur­ tions, which relate primarily to positive effectson mood. ing participation in the study. Most other diagnoses for The PCAG subscale primarily measures sedation and which Axis I criteria were met related to substance abuse lethargy. The LSD subscale is sensitive to weird feel­ disorders; however, one subject met criteria for psy­ ings, disorientation, and increased awareness of bodily chosexual dysfunction, one met criteria for simple pho­ sensations.