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National Institute on Drug Abuse

Director's Report to the National Advisory Council on Drug Abuse

February, 2000

Research Findings

Treatment Research and Development

Buprenorphine Dosing Every 3 or 4 Days

Dr. Warren Bickel and associates at the University of Vermont recently conducted a study comparing 24-, 48-, 72-, and 96-hour buprenorphine dosing regimens in opioid-dependent outpatients. Fourteen subjects received buprenorphine in a double-blind, placebo-controlled crossover trial. Daily sublingual maintenance doses were 4 mg/70 kg (n = 5) and 8 mg/70 kg (n = 9). After a stabilization period of maintenance administration, subjects received, in a random order, four dosing regimens for five repetitions of each regimen: a maintenance dose every 24 hours, a doubled maintenance dose every 48 hours, a tripled maintenance dose every 72 hours, and a quadrupled maintenance dose every 96 hours. In the latter three dosing regimens, subjects received placebo on the interposed day(s). Study participation was contingent on opioid abstinence and daily clinic attendance. Measures of subjective opioid agonist and withdrawal effects were assessed daily. Results indicated that relative to standard maintenance dosing, none of the higher doses induced agonist effects. Changes in indices of subjective withdrawal effects were noted as the time since the last active dose increased during intermittent dosing regimens, but the magnitude of these effects was relatively low and was comparable to those found in other alternate-day dosing studies. These results support the feasibility and safety of twice weekly buprenorphine dosing regimens. Petry, N.M., Bickel, W.K. and Badger, G.J. A Comparison of Four Buprenorphine Dosing Regimens in the Treatment of Opioid Dependence. Clin Pharmacol Ther, 66(3), pp. 306-314, 1999.

LAAM is Not Less Potent than Methadone

Levo-alpha-acetylmethadol (LAAM) and methadone are full mu-opioid agonists used to treat opioid dependence. Current labeling indicates that LAAM is less potent than methadone. Clinical studies have not determined the relative potency of these drugs. This study conducted at Johns Hopkins University compared the effects of acute doses of LAAM and methadone and also examined the ability of naloxone to reverse their effects. Five occasional opioid users received once weekly doses of either placebo, LAAM, or methadone (15, 30, or 60 mg/70 kg p.o.) in agonist exposure sessions and then received naloxone (1.0 mg/70 kg i.m.) 24, 72, and 144 h after agonist exposure. Subject-rated, observer-rated, and physiological measures were assessed regularly. Comparisons of physiological and subjective measures collected in agonist exposure sessions indicate that LAAM is not less potent than methadone under acute dosing conditions. For some measures, LAAM was significantly more potent. Three subjects who entered the study were withdrawn for safety reasons due to greater than anticipated and clinically relevant respiratory depression after receiving 60 mg of LAAM. Naloxone did not fully reverse the pupil constriction produced by 60 mg of LAAM. Acute agonist effects suggest that LAAM may be more potent than methadone and more potent than current labeling indicates. An accurate LAAM:methadone relative potency estimate will aid determination of adequate doses for opioid-dependent patients inducted onto LAAM and for methadone maintenance patients who choose to switch to more convenient thrice-weekly LAAM. Relative Potency of Levo-alpha-acetylmethadol and Methadone in Humans Under Acute Dosing Conditions. Eissenberg, T., Stitzer, M.L., Bigelow, G.E., Buchhalter, A.R., and Walsh, S.L. J Pharmacol Exp Ther., 289(2), pp. 936-945, 1999.

Smoking, Schizophrenia, and Clozapine

Of patients with schizophrenia, 70 to 80% smoke. Nicotine corrects certain information processing and cognitive psychomotor deficits seen in many patients with schizophrenia. Clozapine, but not conventional antipsychotics, has been shown to correct some of these deficits. Investigators from Duke University assessed psychopathology and smoking in 70 patients with treatment refractory schizophrenia (55 smokers and 15 nonsmokers) at baseline when they were receiving conventional antipsychotics and again after they were switched to clozapine. Smokers showed significantly greater therapeutic response to clozapine than nonsmokers. Smokers smoked less when treated with clozapine than when treated with conventional antipsychotics. The authors concluded that certain patients with schizophrenia have contributing pathophysiologic mechanisms that respond favorably to either nicotine or clozapine. McEvoy, J.P., Freudenreich, O., and Wilson, W.H. Smoking and Therapeutic Response to Clozapine in Patients with Schizophrenia. Biol Psychiatry, 1;46(1), pp. 125-9, 1999.

Nicotine Withdrawal and PMS

Investigators at the University of Minnesota used an inpatient setting to test the hypothesis that withdrawal symptoms in short-term smoking cessation in women were increased in the late luteal phase when pre-menstrual symptomatology is the highest. Twenty-one female smokers with clinical, anatomical, and hormonal verification of their menstrual cycle phase were randomized to either a smoking abstinence group (n = 16) or a continued smoking group (n = 5). Participants were admitted during alternate phases of their cycle for two 7-day admissions with a 1-month interim period when they resumed smoking. Nicotine withdrawal scores, Smoking Urges scores and Pre-menstrual Assessment scores were collected during 2 days of baseline and 5 days of smoking deprivation. Smoking behavior was documented by self-report, breath CO levels and saliva cotinine measurements. Withdrawal symptomatology was not affected by menstrual cycle phase during short-term cessation in spite of increased pre-menstrual changes seen in the late luteal phase. In addition, no phase effect on smoking behavior was detected and cigarette consumption remained stable across the cycle in both groups. These results suggest that for some smoking cessation studies, complex strategies to control for menstrual cycle effects may not be necessary. However, Smoking Urges scores did suggest increased desire to smoke and desire to relieve negative affect in the late luteal phase when women have higher pre-menstrual symptomatology. This suggests women may have greater difficulty quitting smoking in late luteal phase, and it seems prudent to recommend that women quit during the follicular phase of their cycle. Allen, S.S., Hatsukami, D.K., Christianson, D., and Nelson, D. Withdrawal and Pre-Menstrual Symptomatology During the Menstrual Cycle in Short-Term Smoking Abstinence: Effects of Menstrual Cycle on Smoking Abstinence. Nicotine & Tobacco Research, 1, pp. 129-142, 1999.

Bupropion Helps Patch Prevent Smoking Relapse

Researchers from the University of Wisconsin conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant. Jorenby, D.E., Leischow, S.J., Nides, M.A., Rennard, S.I., et al. A Controlled Trial of Sustained-Release Bupropion, A Nicotine Patch, or both for Smoking Cessation. N Engl J Med, 340(9), pp. 685-691, 1999.

Smokeless Tobacco Cessation

Smokeless tobacco use is increasing in the United States, especially among young men, but there are few resources to assist users in quitting their use of moist snuff or chewing tobacco. This article reviewed some unique aspects of smokeless tobacco use and provided a systematic four-step clinical plan for providing a cessation program. The authors provided clear suggestions, measures, and aids for getting the user ready to quit, planning their quit, quitting, and staying quit. The procedures and measures were validated in randomized clinical trials and provide empirical support for the recommended cessation procedures. Finally, a review of brief cessation interventions in the context of health care was provided. Severson, H.H., and Hatsukami, D. Prim Care, 26(3), pp. 529-551, 1999.

Brain Metabolite Changes in Opiate Abusers in Methadone Maintenance

Dr. Marc Kaufman and colleagues at the Brain Imaging Center at McLean Hospital evaluated cerebral phosphorus metabolites using phosphorous magnetic resonance spectroscopy (P-MRS) in opiate-dependent polydrug abusers (6 men, 9 women; 40+5 years old) in methadone maintenance therapy (MMT) to determine if metabolite profiles differed based on treatment duration. Study subjects included two groups: one on MMT for an average of 39 weeks (n=7) and another on MMT for an average of 137 weeks (n=8). These groups were age-and body mass index (BMI)-matched. Results revealed that MMT subjects differed from controls in percent phosphocreatine (%PCr) levels and in both phosphomonoester (%PME) and phosphodiester (%PDE), which are thought to reflect abnormalities in energy and phospholipid metabolism, respectively. In short-term MMT subjects, abnormal %PCr (-18), % PME (+20), and %PDE (+17) levels were found compared to controls. However, in long-term MMT subjects, the only metabolite abnormality detected was in %PCr (-9) despite continued illicit drug abuse. From these data, the authors concluded that polydrug abusers in MMT have results consistent with abnormal brain metabolism and phospholipid balance. Interestingly, the nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT might be associated with improved neurochemistry. Kaufman, M.J., Pollack, M.H., Villafurte, R.A., Kukes, T.J., Rose, S.L., Mendelson, J.H., Cohen, B.M., and Renshaw, P.F. Cerebral Phosphorous Metabolite Abnormalities in Opiate-Dependent Polydrug Abusers in Methadone Maintenance. Psychiatry Research: Neuroimaging, 90, pp. 143-152, 1999.

Cerebral Alterations in Recreational MDMA Users

Dr. Linda Chang and colleagues at the UCLA School of Medicine evaluated the effects of recreational use of MDMA on brain neurochemistry. Twenty-two MDMA users were evaluated with magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) in the mid-frontal, mid-occipital, and parietal brain regions, and results were compared to matched controls. MRS showed normal N-acetyl (NA) compounds in all brain regions. The myo-inositol (MI) concentration and the MI to creatine (CR) ratio were increased in the parietal white matter in MDMA users. Cumulative lifetime dose of MDMA showed significant effects on MI concentration in the parietal white matter and occipital cortex. Normal NA concentration levels suggested a lack of significant neuronal injury in recreational MDMA users. However, the usage-related increase in MI suggests that exposure to MDMA, even at recreational doses, might cause increased glial content. Chang, L. et al. Cerebral 1H MRS Alterations in Recreational 3,4-Methylenedioxy-methamphetamine (MDMA, "Ectasy") Users. J. Mag Res Imaging, 10, pp. 521-526, 1999.

Neurochemical Adaptation to Cocaine Abuse

Drs. Shi-Jiang Li, Eliott Stein and their colleagues at the Milwaukee College of Medicine used an advanced brain imaging technique, magnetic resonance spectroscopy (MRS), to demonstrate a potential neurotoxic effect of chronic cocaine use in humans. Twenty-one cocaine abusers and 12 age-matched controls had in vivo proton MRS scans. Proton spectra were obtained from single voxels in the left basal ganglia and left thalamus. The cocaine users exhibited a 17% lower level of N-acetyl aspartate in the left thalamus, but not left basal ganglia compared to the control subjects. Since N-acetyl aspartate levels are thought to be an index of neuronal integrity, these results suggest that chronic cocaine use is associated with neurochemical dysregulation and possibly neurotoxicity in the thalamus. Since subjects were only abstinent from cocaine for 24 hours prior to the scan it will be necessary to determine whether this neurochemical abnormality disappears with continued abstinence from cocaine. It is also possible that the observed differences between cocaine users and controls existed prior to the onset of drug use. It also remains to be determined what impact this neurochemical abnormality has on behavioral or cognitive functioning, especially given the critical role of the thalamus in regulating input to the cerebral cortex. Li, S.-J. et al., Neurochemical Adaptation to Cocaine Abuse: Reduction of N-acetyl Aspartate in Thalamus of Human Cocaine Abusers. Biological Psychiatry, 45, pp. 1481-1487, 1999.

Dynorphin A1-13 Elevation of Serum Prolactin Levels through Opioid Receptor Mechanism in Humans: Gender Differences and Implications for Modulation of Dopaminergic Tone in Addictions Treatment

Dr. Mary Jeanne Kreek and colleagues at the Rockefeller University conducted a study to determine whether dynorphin peptides act to lower dopaminergic tone in the tuberoinfundibular system, resulting in elevated serum prolactin levels and, if so, whether such an effect is mediated by the opioid receptors. Dose-related increases in serum prolactin levels were observed after administration of dynorphin A1-13 in healthy human volunteers with no history of drug or alcohol abuse. Studies were then conducted to determine if this effect is opioid receptor-mediated and, if so, whether at the kappa or mu types. Pretreatment with the opioid antagonist, nalmefene, which has high affinity at both kappa- and mu-opioid receptors, caused a greater attenuation in dynorphin A1-13-stimulated increases in serum prolactin levels than pretreatment with similarly high doses of naloxone, an antagonist with lower affinity for both kappa- and mu-opioid receptors. These results suggest dynorphin A1-13 lowers tuberoinfundibular dopaminergic tone through action at kappa- and possibly mu-opioid receptors. Female subjects were significantly more responsive to the prolactin effects of dynorphin than were male subjects. Dynorphin gene expression, dynorphin peptides, and kappa-opioid receptor gene expression and binding have been shown to be altered in response to cocaine administration. Additionally, both dynorphin peptides and kappa-opioid agonists have been shown to lower dopamine levels in the nucleus accumbens and to attenuate cocaine-induced surges in dopamine levels. The authors suggest that a dynorphin-like compound that is capable of affecting critical mesolimbic-mesocortical and nigrostriatal dopaminergic systems might be effective in the management of cocaine addiction. Kreek, M.J. et al., Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: Gender Differences and Implications for Modulation of Dopaminergic Tone in the Treatment of Addictions. J. Pharmacol. Exp. Therap., 288, pp. 260-269, 1999.

Concurrent and Predictive Validity of Antisocial Personality Disorder Subtyping Among Substance Abusers

Three hundred and seventy inpatient and outpatient substance abusers were divided according to presence and subtype of antisocial personality disorder (APD) into groups comparing: a) adult antisocial behavior (AAB) versus full APD; b) APD with low versus high sociopathy; c) APD with versus without lifetime depression; and d) APD with versus without other axis II disorders. Multivariate regression was used to predict the unique contribution to the variance in baseline and 12-month follow-up measures of substance use, psychiatric severity, and personality. The presence of comorbid axis II pathology was the strongest predictor of baseline severity in all three domains. APD substance abusers with lifetime depression exhibited greater baseline to follow-up reductions in psychiatric severity than those APD substance abusers without a history of depression. All APD subtypes improved over time with treatment, suggesting that this diagnosis does not necessarily indicate poor prognosis. Cecero, J., Ball, S., Tennen, H., Kranzler, H., and Rounsaville, B. J. Nerv and Ment. Dis, 187, pp. 478-486, 1999.

Substance Dependence Posttraumatic Stress Disorder Therapy: An Integrated Cognitive-Behavioral Approach

While substance abuse and PTSD are known to frequently co-occur, there have been few clinical trials evaluating integrated approaches for this form of dual diagnosis. Substance Dependence PTSD Therapy (SDPT) is the first manualized individual treatment to undergo a controlled clinical trial. SDPT is a 5 month, twice-weekly, two-phase individual cognitive-behavioral treatment utilizing (a) relapse prevention and coping skills training for substance abuse; and (b) psychoeducation, stress inoculation training, and in vivo exposure for PTSD. SDPT is also unique in having been designed for use in mixed-gendered civilians with varied sources of trauma. Preliminary data from this study indicates efficacy in reducing PTSD severity. Triffleman, E., Carroll, K., and Kellogg, S. J. Substance Abuse Treatment, 17, pp. 3-14, 1999.

Day Treatment Versus Enhanced Standard Methadone Services for Opioid-Dependent Patients: a Comparison of Clinical Efficacy and Cost

Dr. Kelly Avants and colleagues at Yale University evaluated the differential efficacy and relative costs of two intensities of treatment (intensive day treatment versus enhanced standard care) for methadone maintained opioid-dependent patients. 291 patients participated in a 12-week randomized clinical trial with 6-month follow-up. The day treatment was an intensive, 25-hour per-week program. The enhanced standard care was standard methadone maintenance plus a weekly skills training group and referral to services. Both interventions were manual-guided. No significant differences were found between the two groups in use of either opiates or cocaine. Drug use, drug-related problems, and HIV risk behaviors decreased significantly for patients assigned to both treatment intensities. Thus, the intensive day treatment program, which cost significantly more, was not cost effective, relative to an enhanced methadone maintenance program, which produced comparable outcomes. Avants, S.K., Margolin, A., Sindelar, J.L., Rounsaville, B.J., Schottenfeld, R., Stine, S., Cooney, N.L. Rosenheck, R.A., Ki, S.H., and Kosten, T.R. American Journal of Psychiatry, 156, pp. 27-33, 1999.

Validity of Diagnostic Criteria for Adolescent Alcohol and Cannabis Use Disorders

Until recently, few studies focused on adolescent drug abuse utilized formal diagnostic criteria for substance use disorders. Reluctance to use diagnostic criteria was, in part, based on concerns that adult-based criteria and related diagnostic instruments were not developmentally appropriate for adolescent patient populations. But utilization of a common set of criteria and related measures would facilitate cross-study comparisons and collaborations in drug treatment research. Toward identifying adolescent-appropriate criteria, Dr. Winters and colleagues at the University of Minnesota School of Medicine examined DSM-III-Revised and DSM-IV criteria for alcohol and cannabis use disorders in a sample of 772 adolescents (42% 12-15 years; 63% boys; 77% white) enrolled in outpatient drug treatment. Results indicate that, compared to DSM-III-Revised criteria, application of DSM-IV criteria for alcohol and cannabis use results in more abuse cases and fewer dependence cases, with the shift in diagnostic assignments largely due to a broadening of abuse criteria rather than a tightening of dependence criteria when applied to adolescents. Although further research is necessary, external validity supported the DSM-IV abuse and dependence distinction in this adolescent patient population. Winters, K.C., Latimer, W., and Stinchfield, R.D. J. Studies on Alcohol, 60, pp. 337-344, 1999.

Desipramine May Be A Useful Adjuctive Medication In Facilitating Opioid and Cocaine Abstinence In Opioid-Maintained Patients

The efficacy of opioid medications to treat opioid and cocaine dependence may differ by sex. A 13-week randomized, double-blind, placebo controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine (12 mg/d) or methadone (65 mg/day) in 180 opioid-dependent cocaine abusers (124 men and 56 women). Urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported weekly. In men, opioid dependence was increased more rapidly over time when treated with methadone than with buprenorphine, whereas cocaine abstinence was increased more with buprenorphine than with methadone. In women, opioid abstinence was increased the least rapidly when treated with buprenorphine plus placebo, while cocaine abstinence was increased more rapidly over time when treated with methadone than with buprenorphine. Regardless of sex or opioid medication, desipramine increased opioid and cocaine abstinence over time more rapidly than placebo. Desipramine plasma levels were higher in women than men. Higher desipramine plasma levels were associated with greater opioid but not cocaine abstinence. Desipramine in Opioid-dependent Cocaine Abusers maintained on Buprenorphine vs. Methadone, Oliveto, A., Feingold, A., Schottenfeld, R., Jatlow, P., and Kosten, T. Arch Gen Psychiatry, 56, pp. 812-820, 1999.

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