National Institute on Drug Abuse
Director's Report to the National Advisory Council on Drug Abuse
September, 1997
Research Findings
Clinical and Services Research
Buprenorphine, Morphine, and Naloxone Effects Attenuated During Ascending Morphine Maintenance in Humans
In an inpatient study six opioid dependent volunteers were chronically maintained on ascending morphine doses of 15, 30, 60, and 120 mg/kg/day. Each morphine dose level was maintained for two weeks; acute doses of test drugs (morphine 30 mg i.m., buprenorphine 6 mg i.m., and naloxone 0.3 mg) were administered during the second week of maintenance. The acute doses of both morphine and buprenorphine constricted pupils and produced reports of opiate-like subjective effects. The magnitude of these effects was inversely related to the maintenance dose of morphine, with no effects detected at higher maintenance levels. This attenuation of effects indicates development of tolerance and cross tolerance during ascending dose morphine maintenance. At high maintenance doses of morphine, naloxone but not buprenorphine precipitated withdrawal. That buprenorphine did not act as an antagonist under these dosing conditions further supports the clinical observation that there are conditions under which patients dependent upon short-acting opiates can be comfortably transferred directly onto buprenorphine maintenance doses. On the other hand, these results suggest that individuals with relatively low levels of dependence will experience opioid-like subjective effects from buprenorphine, which may support abuse liability in this population. Schuh, K.J., Walsh, S.L., Bigelow, G.E., Preston, K.L., & Stitzer, M.L. Journal of Pharmacology and Experimental Therapeutics, 278, pp. 836-846, 1996.
Less-Than-Daily Buprenorphine May Be Clinically Feasible
The clinical utility of administering buprenorphine on a less-than-daily basis was assessed in 8 outpatients maintained on 8 mg buprenorphine in a placebo-controlled study. Pupil diameter and subjective measure of opioid withdrawal were collected at pre-test and at 0.5, 1, 2, 3, 25, 49, and 71.5 hr after test dose administration. The lack of subjective withdrawal during 71.5 hrs of dose omission suggest that less-than-daily dosing may be clinically feasible. Eissenberg T. et al., Drug and Alcohol Dependence, 45, pp. 81-91, 1997.
Effectiveness of Over-the-Counter Transdermal Nicotine for Smoking Cessation
Dr. Scott Leischow at the University of Arizona conducted a study to compare the effectiveness of the nicotine patch in smoking cessation when used in an over-the-counter (OTC) setting with no adjunct behavioral support versus a physician-based minimal behavioral intervention setting (MI)-- both reflecting "real life" situations. The OTC group received only a patch package insert. The MI group received in addition to the package insert, minimal behavioral support and patch use guidelines from a physician at the screening and week 2 visit. No significant differences in abstinence rates were found. Abstinence rates for both groups were quite low: 7.4%, 5.4%, 5.4% and 4.7% and 6.6%, 9.3%, 5.3%, and 4.0% at weeks 2, 6, 26, and 52 for the OTC and MI groups, respectively. The use of OTC transdermal nicotine in smoking cessation is just as efficacious as its use in a physician-based minimal intervention setting with neither of the two treatment strategies being very effective. One implication of this study is that valid behavioral support programs in addition to nicotine replacement need be encouraged.
Dose-Related Efficacy of Levo-Alpha Actylmethadol (LAAM) for Treatment of Opioid Dependence
Dr. George Bigelow and colleagues at Johns Hopkins University School of Medicine conducted a 17-week randomized, double-blind, parallel group clinical trial to compare the clinical efficacy of different oral doses of LAAM. Male and female opioid-dependent patients (N=180) were assigned to one of three thrice-weekly LAAM dose conditions: low (25/25/35 mg), medium (50/50/70 mg.) or high (100/100/140 mg). Primary outcome measures were retention-in-treatment, self-reported heroin use and opioid-positive urine specimens. Although study results indicated that treatment retention was independent of dosage level, heroin use was not. For both men and women, self-report and urinalysis data showed that heroin use decreased in a dose-related manner. Thirty-four percent of the patients in the high dose condition remained opioid-abstinent for 4 consecutive weeks, as compared to 14% in the medium dose and 11% in the low dose condition (ps<.01). Eissenberg, T., Bigelow, G.E., Strain, E.C., Walsh, S.L., Brooner, R.K., Stitzer, M.L., Johnson, R.E. Dose-Related Efficacy of Levomethadyl Acetate for Treatment of Opioid Dependence: A Randomized Clinical Trial. Journal of the American Medical Association, 277(24), pp. 1945-1951, 1997.
Reliability and Validity of the Addiction Severity Index Among Seriously Mentally Ill Outpatients
Dr. Kate Carey, and her colleagues at Syracuse University collected data for the Addiction Severity Index (ASI) when administered to persons with serious and persistent mental disorders. Participants were 97 outpatients (71 men, 26 women, between the ages of 22 and 62) at a public psychiatric facility. The serious mental disorders were: schizophrenia (53%), schizoaffective disorder (13%), bipolar disorder (23%) and other (11%). A majority of the patients met the DSM-IIIR diagnosis of substance abuse or dependence. The psychometric evaluations shows that the internal consistency of the composite scores was lower in this psychiatric sample than in previous nonpsychiatric samples. Interrater reliability was acceptable for most composite scores, but low for many severity ratings. Several scores showed low temporal stability. Validity evidence was weak for the Employment and Family/Social scales, acceptable for Drug and Alcohol scales, and mixed for Psychiatric, Medical, and Legal scales. Due to mixed reliability and validity evidence, the authors concluded that caution should be exercised when using the ASI with seriously mentally ill patients. Carey, K., Cocco, K.M., and Correia, C.J., Psychological Assessment, In press.
Marijuana Use and Cancer Incidence
Sidney and his colleagues at Kaiser Permanente (Oakland, California) reviewed medical charts of approximately 65,000 patients, ages 15-49 years, who self-administered questionnaires about smoking habits, including marijuana use. The patients were enrolled in the HMO between 1979-1985. Follow-up for cancer incidence was conducted through 1993 (mean length 8.6 years). Among nonsmokers of tobacco cigarettes, ever marijuana use was associated with increased risk of prostate cancer (RR 3.1 [95% CI 1.0, 9.5] and nearly significantly increased risk of cervical cancer (RR 1.4 [95% CI 1.0, 2.1]. The investigators concluded that, in this relatively young study cohort, marijuana use and cancer were unassociated in overall analyses, but that associations in nonsmokers of tobacco cigarettes suggested that marijuana use might affect certain site-specific cancer risks Sidney, S., Charles P. Quesenberry, Gary D. Friedman, and Irene S. Takawa. Cancer Causes and Control, In press.
Effects of Intranasal Cocaine on Sympathetic Nerve Discharge in Humans
Cocaine-induced cardiovascular emergencies are thought to be mediated by excessive adrenergic stimulation. Animal studies suggest that cocaine not only blocks norepinephrine reuptake peripherally but also inhibits the baroreceptors, thereby reflexively increasing sympathetic nerve discharge. However, the effect of cocaine on sympathetic nerve discharge in humans is unknown. In 12 healthy volunteers, Victor and his colleagues (University of Texas Southwestern Medical Center) recorded blood pressure and sympathetic nerve discharge to the skeletal muscle vasculature using intraneural microelectrodes (peroneal nerve) during intranasal cocaine (2 mg/kg, n = 8) or lidocaine (2%, n = 4), an internal local anesthetic control, or intravenous phenylephrine (0.5-2.0 microg/kg, n = 4), an internal sympathomimetic control. Experiments were repeated while minimizing the cocaine-induced rise in blood pressure with intravenous nitroprusside to negate sinoaortic baroreceptor stimulation. The investigators found that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed. The sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation and that the interplay between these excitatory and inhibitory neural influences determines the net effect of cocaine on sympathetic discharge targeted to the human skeletal muscle circulation. Jacobsen, T.N., Victor, R.G., Hillis, L.D., Lange, R.A., Landau, C., Chavoshan, B., Hansen, J., Snyder II, R.W., and Grayburn, P.A. J Clin Invest, 99(4), pp. 628-634, February 15, 1997.
Prenatal Cocaine Exposure: Dose-Response Relationships with Newborn Neurobehavior
In a study of clinically healthy full-term infants, researchers in Boston have demonstrated dose-response relationships between cocaine exposure and 3-week neurobehavioral performance, with heavily-exposed infants showing poorer state regulation and greater excitability. These associations were not observed during the first few days after birth. Three prenatal exposure groups were involved: heavily-exposed (>75th percentile self-reported days of use during pregnancy and/or >75th percentile of meconium benzoylecognine concentration, n=44), lightly exposed (<75th percentile on both indicators, n=79), and unexposed (no positive self-report or biological marker, n=101). Factors controlled in the analyses included birthweight, gestational age, motherÕs age, perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use. The investigators point out the importance of determining how this behavior progresses developmentally, because regulation of arousal and attention is critical to learning. Tronick, E., Frank, D.A., Cabral, H., et al. Pediatrics, 98, pp. 76-83, 1996.
Prenatal Cocaine Exposure: Development of Children at School Age
Gale Richardson and colleagues at the University of Pittsburgh recently reported on the development, at 6 years of age, of children who have been studied since the prenatal period. Twenty-eight children whose mothers were considered light to moderate cocaine users during pregnancy (i.e., reported an average of 3.3 g per month during the first trimester, 0.1 g per month during the second trimester, and 0.2 g per month during the third trimester) were compared with 523 children whose mothers reported no cocaine use during pregnancy, and none for the year before pregnancy. The women were interviewed about cocaine, alcohol, marijuana, tobacco, and other drug use during the 4th and 7th months of pregnancy, at delivery, and at several times postpartum. At 6 years of age, the children were assessed regarding cognitive development, academic achievement, and behavior, and underwent a physical examination. There were no significant differences between the groups on growth, intellectual ability, academic achievement, or teacher-related classroom behavior. However, children prenatally-exposed to cocaine did show deficits in their ability to sustain attention on a computerized vigilance task. Richardson, G.A., Conroy, M.L., and Day, N.L. Neurotoxicology and Teratology, 18, pp. 627-634, 1996.
Characteristics and Pretreatment Behaviors of Clients Entering Drug Abuse Treatment: 1969 to 1992
This study summarizes historical changes in admission characteristics and pretreatment behaviors with particular attention to changes in the last decade. Data are drawn from three major studies of drug abuse treatment outcomes: The Drug Abuse Reporting Program (DARP), 1969-1972; the Treatment Outcome Prospective Study (TOPS), 1979-1981; and the Drug Abuse Treatment Outcome Study (DATOS), 1991-1993. According to the authors, declines in multiple drug use and the dramatic increase in admissions reporting cocaine use are the most notable changes. Other characteristics of the changing treatment population are the decreases in patients working full-time, in reports of suicidal thoughts and/or and attempts, and in predatory crime. However, there were some notable similarities across decades among treatment modalities. The authors suggest that those commonalities indicate the distinctiveness of client characteristics and there by reinforcing the importance of
studying differences among clients in different modalities when interpreting treatment outcomes. Craddock, S.G., Rounds-Bryant, J.L., Flynn, P.M., and Hubbard, R.L. Characteristics and Pretreatment Behaviors of Clients Entering Drug Abuse Treatment: 1969 to 1993. American Journal of Drug and Alcohol Abuse, 23(1), pp. 43-59, 1997.
Relationship of Personality Characteristics to Drug Treatment Effectiveness
In a study of the relationship of personality characteristics to drug treatment effectiveness, Grossweiler and Martin analyzed data from a sample of 723 drug involved prison releasees who left prison between 1990 and 1994. Prison subjects in this study were released to one of three assigned interventions: (1) Assertive Community Treatment (ACT) which combined outpatient treatment and case management; (2) Therapeutic Community Work Release (TC) where releasees lived in a drug treatment facility, but could attend school or work in the community; or (3) a comparison group who were released to traditional parole or work release settings. As predicted, increased age, interpersonal sensitivity, and days in treatment were associated with decreased risk of relapse to drug use among those who were in the TC group. However, greater interpersonal sensitivity and attending an outpatient treatment group were associated with an increase in the likelihood of relapse to drug use and rearrest. The researchers suggest that future research should focus on common underlying traits that identify more global pathologies or personality types that severely limit treatment success. Grossweiler, R.S., and Martin, S.S. The Role of Personality in Treatment Outcome for Drug-Involved Offenders, International Journal of Sociology and Social Policy, 16(5/6), pp. 31-155, 1996.
Effect of Work Release TC and Aftercare on Drug Relapse and Criminal Recidivism
In a study of 448 patients involved in a corrections-based Therapeutic Community (TC) treatment, Dr. James Inciardi and his colleagues examined data from an 18-month follow-up for releasees who received (1) no treatment, but traditional parole or work-release settings; (2) treatment in a prison-based TC; (3) treatment in a work-release TC followed by aftercare (the 2 stage model); and (4) treatment in a prison-based TC followed by work-release TC and aftercare (the 3-stage model). According to the authors, a significantly greater percentage of respondents who received treatment in the 2-stage model (31%) and the 3-stage model (47%) were drug free (via self-report and urinalysis) at the 18-month post-release interview than respondents in the no treatment comparison group (16%, p<.01). Similarly, significantly greater percentages of respondents in the 2-stage model (57%) and the 3 stage model (77%) had no new arrests during the 18-month post-release period as compared to respondents in the comparison group (46%, p<.01). There were no significant differences in abstinence or rearrest rates between the no treatment comparison group and the prison TC-only group. These findings were supported even when adjusted for other risk factors (demographic, criminal and drug history). Inciardi, J.A., Martin, S.S., Butzin, C.A., Hooper, R.A., and Harrison, L.D. An Effective Model of Prison Based Treatment for Drug-Involved Offenders. Journal of Drug Issues, Spring 1997.
Relationship between Self-Efficacy Perceptions and In-treatment Drug Use among Regular Cocaine Users
This study, part of a national outcome study, investigates the relationship between self-efficacy and drug use in a subsample of 294 regular cocaine users who completed at least three months of community-based outpatient treatment programs. The results supported previous findings that increased self-efficacy in resisting drug use was associated with lower rates of drug use during treatment, and that self-efficacy enhancement may be an important intervention in the treatment of cocaine abuse. Although the results of this study compare favorably with results in other studies, the authors call for controlled studies of the effects of self efficacy on abstinence from drug use in outpatient settings. Rounds-Bryant, J.L., Flynn, P.M., and Craighead, L.W. Relationship between Self-Efficacy Perceptions and In-Treatment Drug Use among Regular Cocaine Users. American Journal of Drug and Alcohol Abuse, 23(3), pp. 383 395, 1997.
The Effect of an Enhanced Case Managed Intervention on Employment
Siegal and his colleagues examined the effectiveness of a strengths-based case management model for improving employment related outcomes in a sample of 632 veterans seeking treatment for substance abuse problems. They found that the patients who completed primary treatment showed significant gains in vocational functioning and that this improvement was generally correlated with improvement in each of the other areas measured by the Addiction Severity Index (ASI). These gains were reflected in three specific outcomes: average income earned, number of days worked, and the number of work-specific problems in the 30 days preceding the follow-up interview. Siegal and his colleagues also found that patients in the case managed group (CM) did significantly better than non-case managed group (NCM) in terms of average number of days employed in the last 30 days (15.6 vs. 12.1, p<.016). Further, CM patients reported fewer days of employment problems (7.95 vs. 12.27, p<.019), felt less troubled by employment problems (1.02 vs. 1.63, p<.008), and saw less need for employment counseling (.95 vs. 1.48, p<.023). Siegal, H.A., Fisher, J.H., Rapp, R.C., Kelliher, C.A., Wagner, J.H., O'brien, W.F., Cole, P.A. Enhancing Substance Abuse Treatment with Case Management: Its Impact on Employment. Journal of Substance Abuse Treatment, 13(2), pp. 93-98, 1996.
Functional MRI of Human Brain Activation during Cue-Induced Craving
Perry F. Renshaw, M.D., Ph.D. and colleagues at Harvard Medical School/McLean Hospital have used fMRI to demonstrate brain activation in areas associated with cocaine cue-induced craving. Six male subjects with a history of crack cocaine use and six control subjects were presented with audiovisual stimuli containing intervals of drug-related and neutral scenes, while brain activation was measured with fMRI. Significant activation was detected in the anterior cingulate and left dorsolateral prefrontal cortex in the cocaine-abusing group. In addition, self-reports of craving and activation also correlated in the same regions. Despite some procedural differences, the fMRI findings that presentation of cocaine cues activates the anterior cingulate and dorsolateral prefrontal cortex are consistent with previous PET studies conducted at NIDA's Intramural Research Program and at the University of Pennsylvania. The results suggest that fMRI may be an additional valuable tool to assist in the identification of the neurobiological basis of craving and may provide a means for the evaluation of new agents to modify or reduce craving. The consistent findings across different groups of researchers and different neuroimaging methods suggest that these findings are reliable and may be most helpful in further elucidating the neurobiological basis of drug addiction.
Maas, L.C., Lukas, S.E., Kaufman, M.J., Weiss, R.D., Daniels, S.L., Rogers, V.W., Kukes, T.J., Renshaw, P.F. Functional MRI of Human Brain Activation during Cue-Induced Cocaine Craving. American Journal of Psychiatry, In press.
Novel Approaches to Mapping the Brain
Fred L. Bookstein, M.D. at the University of Michigan has been involved in the application of statistics to neuroimaging and mapping of human brain structures. The major areas of work have been in terms of mapping discrete points (landmarks) in the normal human brain. Also, he has been exploring solutions to the problem of analysis of brain images where many of the landmarks are ambiguous or absent. Presently, the use of sophisticated multivariate statistical procedures in data sets with missing landmarks is being investigated. Preliminary results have shown reasonable estimates even when the extent of missing data is as high as 65%. Combining medical imaging analysis and statistics will allow investigators to study patterns of relationships between brain images and behavior. In the past, normal variation of brain shape has served as a serious confound that significantly hinders neuroanatomical data analysis. This project is assembling a tool kit of methods to address the shape variability issue. New methods of shape description can prove useful in identifying regions of interest in the human brain that are important for explaining the onset, course, treatment response and severity of brain diseases, such as drug abuse. Bookstein, F.L. Landmark Methods for Forms without Landmarks: Morphometrics of Group Differences in Outline Shape. Medical Image Analysis, 1, pp. 225-243, 1996/7; Bookstein, F.L. Shape and the Information in Medical Images: A Decade of the Morphometric Synthesis. Computer Vision and Image Understanding, 66, pp. 97-118, 1997.
Heritability of the Neurophysiological Drug-Taking Risk Factor, P300
In a study of monozygotic and dizygotic twins, critical amplitudes of visual evoked potential wave forms, including P300, N1, P2 and N2 were heritable. This finding is important because P300 has been found by several laboratories to be a physiological marker of risk in children of substance abusing persons. Thus, these data demonstrate a potential genetic component for such a physiological marker of drug abuse. Katsanis, J., Iacono, W.G., McGue, M.K., and Carlson, S.R. P300 Event-Related Potential Heritability in Monozygotic and Dizygotic Twins. Psychophysiology, 34, pp. 47-58, 1997.
Neurophysiological Changes after Smoking Marijuana
In a difficult auditory oddball task, N100 amplitudes were reduced and P300 latencies were shortened in cortical potentials evoked after smoking marijuana cigarettes. These changes were observed two hours after smoking, when subjective effects were not reported. As reported previously in studies on tobacco smoking acute marijuana administration may alter cognitive processing as assessed by electrophysiological measures. Orozco, S., and Lukas, S.E. Heart-Rate, Plasma, Subjective and Cognitive Changes after Marihuana Smoking. Presented at CPDD, 1997.
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