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Director's Report to the National Advisory Council on Drug Abuse - May, 2005

Research Findings - Research on Pharmacotherapies for Drug Abuse

Risperidone May Diminish Cocaine-Induced Craving

Dr. Richard De La Garza II and colleagues at UCLA examined the effects of the D2/5HT2A antagonist risperidone on cocaine-induced craving in a human laboratory study, based on the hypothesis that rispiridone would reduce cocaine-induced craving in individuals who experienced priming. Study participants were 7 non-treatment seeking, cocaine-dependent individuals. Subjects were administered cocaine to induce drug priming, then treated with rispiridone for five days. At the end of the treatment regimen, cocaine was again administered, and subjective responses to the cocaine challenge were assessed through rating craving for cocaine. In this study, risperidone blunted cocaine craving in those subjects who experienced cocaine-induced craving, suggesting that this medication might be effective in reducing relapse. De La Garza II, R., Newton, T.F. and Kalechstein, A.D. Risperidone Diminishes Cocaine-Induced Craving. Psychopharmacology, 178, pp. 347-350, 2005.

Modafinil As a Treatment for Cocaine Dependence

Dr. Charles Dackis and colleagues at the University of Pennsylvania in Philadelphia conducted a double-blind, placebo controlled outpatient study in 62 cocaine-dependent individuals to assess the efficacy of modafinil for cocaine abstinence. Modafinil was tested based on the hypothesis that its glutamate-enhancing action may be effective in treating cocaine dependence, as the repeated administration of cocaine depletes extracellular glutamate levels. This study found that modafinil reduced cocaine use in the outpatient setting. Dackis, C.A., Kampman, K.M., Lynch, K.G., Pettinati, H.M. and O'Brien, C.P. A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence. Neuropsychopharmacology, 30, pp. 205-211, 2005.

Role Played by the Smoking-related Stimuli that are Delivered by Denicotinized Cigarettes

Pharmacologically, pure nicotine suppresses tobacco abstinence symptoms partially, and non-nicotine, smoking-related stimuli suppress these abstinence symptoms fully, at least for 24 hours. The current study was designed to clarify the impact of smoking-related stimuli on tobacco withdrawal, and to explore the duration of their ability to suppress withdrawal in smokers. Three double-blind, within-subjects, Latin square-ordered, 5-day conditions in which participants smoked nicotinized, denicotinized or no cigarettes were conducted in 13 women and 19 men. Subjective, physiological and performance measures were collected daily and compliance with study conditions was verified objectively. The results showed that smoking-related stimuli are sufficient for suppressing some symptoms of tobacco abstinence over a 5-day period [i.e. Questionnaire of Smoking Urges (QSU) factor 1, -Desire for sweets', -Hunger' and -Urges to smoke'], while in this study a combination of nicotine and smoking-related stimuli suppressed other symptoms (i.e. -Difficulty concentrating', -Increased eating', -Restlessness' and -Impatient'). These results indicate that, while some tobacco abstinence symptoms may be suppressed with nicotine, suppressing others may also require strategies that address the absence of smoking-related stimuli. Buchhalter, A.R., Acosta, M.C., Evans, S.E., Breland, A.B. and Eissenberg, T. Tobacco Abstinence Symptom Suppression: The Role Played by the Smoking-related Stimuli that are Delivered by Denicotinized Cigarettes. Addiction, 100, pp. 550—559, 2005.

Urine Cotinine as an Index of Smoking Status

Biomarkers such as carbon monoxide (CO) and cotinine are used in tobacco cessation studies to assess smoking status. CO is easy to assess, is inexpensive, and provides immediate results. However, the short half-life of CO may limit its ability to identify smokers who have abstained for several hours. Quantitative methods (e.g., gas chromatography/mass spectrometry, or GC/MS) for measuring urine cotinine, which has a longer half-life, are valid and reliable, though costly and time consuming. Recently developed semi-quantitative urine cotinine measurement techniques (i.e., urine immunoassay test strips, or ITS) address these disadvantages, though the value of ITS as a means of identifying abstaining smokers has not been evaluated. The present study examined ITS as a measure of smoking status in temporarily abstaining smokers. A total of 236 breath and urine samples were collected from smokers who participated in two separate studies involving three independent, 96-hr (i.e., Monday-Friday), Latin-square-ordered, abstinence or smoking conditions; a minimum 72-hr washout separated each condition. Each urine sample was analyzed with GC/MS and ITS. Under these study conditions, CO demonstrated moderate sensitivity (83.1%) and strong specificity (100%), whereas ITS assessment showed strong sensitivity (98.5%) and weak specificity (58.5%). In this study of short-term abstinence, ITS classified as non-abstinent nearly half of the samples collected from abstaining smokers. However, it classified nearly all non-abstinent smokers as currently smoking. Acosta, M., Buchhalter, A., Breland, A., Hamilton, D. and Eissenberg, T. Urine Cotinine as an Index of Smoking Status in Smokers During 96-hr Abstinence: Comparison between Gas Chromatography/Mass Spectrometry and Immunoassay Test Strips. Nicotine.Tob.Res. 6(4), pp. 615-620, 2004.

Uptake of Lung Carcinogens by Smokers of Regular, Light, and Ultralight Cigarettes

Cigarette design has changed markedly over the past 60 years and sales-weighed levels of tar and nicotine have decreased. Currently, cigarettes are classified as regular (>14.5 mg tar), light (>6.5-14.5 mg tar), and ultralight (< or =6.5 mg tar), based on a Federal Trade Commission-specified machine-smoking protocol. Epidemiologic studies suggest that there is no difference in lung cancer risk among people who smoke light or ultralight cigarettes compared with regular cigarettes, but the uptake of lung carcinogens in smokers of these types of cigarettes has never been reported. We recruited 175 smokers, who filled out a tobacco use questionnaire in which their current brand was identified as regular, light, or ultralight. Urine samples were collected and analyzed for 1-hydroxypyrene (1-HOP), total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides) and total cotinine (cotinine plus its glucuronides). 1-HOP and total NNAL are biomarkers of uptake of polycyclic aromatic hydrocarbons and 4-(methylnitrosamino) -1-(3-pyridyl)-1-butanone, lung carcinogens in cigarette smoke. Total cotinine is a biomarker of nicotine uptake. There were no statistically significant differences in urinary levels of 1-HOP, total NNAL, and total cotinine in smokers of regular, light, and ultralight cigarettes, whether the results were expressed per mg urinary creatinine, per mL of urine, or per mg creatinine divided by cigarettes per day. Levels of machine measured tar were available for the cigarettes smoked by 149 of the subjects. There was no correlation between levels of tar and any of the biomarkers. These results indicate that lung carcinogen and nicotine uptake, as measured by urinary 1-HOP, total NNAL, and total cotinine is the same in smokers of regular, light, and ultralight cigarettes. The results are consistent with epidemiologic studies that show no difference in lung cancer risk in smokers of these cigarettes. Hecht, S.S., Murphy, S.E., Carmella, S.G., Li, S., Jensen, J., Le, C., Joseph, A.M. and Hatsukami, D.K. Similar Uptake of Lung Carcinogens by Smokers of Regular, Light, and Ultralight Cigarettes. Cancer Epidemiol Biomarkers Prev. 14(3), pp. 693-698, 2005.

Transdermal Nicotine Use in Postmenopausal Women and Hormone Replacement Therapy

Ninety-four postmenopausal female smokers were recruited according to HRT and non-HRT use (self-selecting) then randomized within strata to active nicotine or placebo nicotine patch. After 1 baseline week of smoking, participants quit smoking for 2 weeks. Women received cessation counseling and were monitored for abstinence. Dependent measures were collected during five clinic visits. Two-way analysis of covariance (ANCOVA) were run on change scores for dependent variables, with nicotine patch group (active/placebo) and HRT group (HRT/non-HRT) as independent variables and age as a covariate. No interactions were found between HRT and patch condition, but both showed specific effects. During the first abstinent week, women on active nicotine patch (compared with placebo) experienced less severe withdrawal, greater reductions in cigarette cravings, and lower (more favorable) Factor 1 scores on the Questionnaire of Smoking Urges. During the second abstinent week, women using HRT (compared with the non-HRT group) exhibited better mood (Profile of Mood States scores) and less depression (Beck Depression Inventory scores). These results suggest the following: First, the efficacy of transdermal nicotine replacement is not adversely modified by women's HRT use; second, ovarian hormones might influence women's responses to smoking cessation, and thus should be considered in developing effective strategies for women to quit smoking. Allen, S.S., Hatsukami, D.K., Bade, T. and Center, B. Transdermal Nicotine Use in Postmenopausal Women: Does the Treatment Efficacy Differ in Women Using and Not Using Hormone Replacement Therapy? Nicotine Tob. Res. 6(5), pp. 777-788, October 2004.

Urinary Biomarkers of Tobacco and Carcinogen Exposure in Smokers

The investigators report the comparison of urinary concentrations of tobacco alkaloid and tobacco carcinogen biomarkers in a subset of smokers during a 7-week period prior to any reduction in cigarette consumption. Urine samples were collected at four time points and analyzed for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and its glucuronide, 1-hydroxypyrene, anatabine, free nicotine, total nicotine (free plus glucuronidated), free cotinine, total cotinine (free plus glucuronidated), and total trans-3'-hydroxycotinine (free plus glucuronidated). Anatabine is a minor alkaloid that may be useful in assessing tobacco exposure in individuals using nicotine replacement therapies. Urinary anatabine levels were well correlated (P < 0.0001) with both free and total nicotine (r = 0.753 and 0.773, respectively). Anatabine levels were also correlated with free cotinine (r = 0.465; P < 0.001), total cotinine (r = 0.514; P < 0.001), and total NNAL (r = 0.633; P < 0.001). These data support the role of anatabine as a biomarker of tobacco exposure. 1-Hydroxypyrene is a biomarker of polycyclic aromatic hydrocarbon exposure, but unlike NNAL it is not tobacco specific. Whereas urinary concentrations of 1-hydroxypyrene were consistent across the four visits, the levels were not correlated with NNAL, anatabine, nicotine, or any nicotine metabolites. These results provide: (a) demonstration of a strong correlation between anatabine and urinary NNAL, a metabolite of the tobacco-specific carcinogen NNK, confirming the potential usefulness of anatabine as a biomarker of tobacco exposure for smokers using nicotine replacement therapy; (b) support for the use of total cotinine as the most consistent and reliable urinary marker of nicotine exposure; and (c) reiteration of the findings that CPD is not an adequate measure of tobacco toxin exposure. In addition, the data provide additional evidence that the percent glucuronidation of cotinine measured in urine is reproducible and potentially useful as a reflection of UDP-glucuronosyltransferase activity. Murphy, S.E., Link, C.A., Jensen, J., Le, C., Puumala, S.S., Hecht, S.S., Carmella, S.G., Losey, L. and Hatsukami, D.K. A Comparison of Urinary Biomarkers of Tobacco and Carcinogen Exposure in Smokers. Cancer Epidemiol Biomarkers Prev. 13(10), pp. 1617-1623, October 2004.

Re-emergence of Tobacco Smoking Using a Waterpipe

Waterpipes are increasing in popularity, and more must be learned about them so that we can understand their effects on public health, curtail their spread, and help their users quit. Research regarding waterpipe epidemiology and health effects is limited; no published studies address treatment efforts. Waterpipe use is increasing globally, particularly in the Eastern Mediterranean Region, where perceptions regarding health effects and traditional values may facilitate use among women and children. Waterpipe smoke contains harmful constituents and there is preliminary evidence linking waterpipe smoking to a variety of life threatening conditions, including pulmonary disease, coronary heart disease, and pregnancy related complications. More scientific documentation and careful analysis is required before the spread of waterpipe use and its health effects can be understood, and empirically guided treatment and public policy strategies can be implemented. Maziak, W., Ward, K. D., Afifi Soweid, R. A. and Eissenberg, T. Tobacco Smoking Using a Waterpipe: A Re-emerging Strain in a Global Epidemic. Tob. Control, 13(4), pp. 327-333, 2004.

Gender Effects of Reported in Utero Tobacco Exposure on Smoking Initiation, Progression and Nicotine Dependence in Adult Offspring

The investigators studied the relationship between self-reported in utero tobacco exposure and gender on smoking initiation, progression of cigarette use (i.e., telescoping), and current levels of nicotine dependence in adult treatment-seeking smokers. Subjects (N = 298) who reported "yes" (28% of the original sample) or "no" (50% of the original sample) to in utero tobacco exposure were included in the analyses. Telescoping was calculated as the difference between the age respondents smoked their "first full cigarette" and the age when they started smoking daily. Females who reported being exposed in utero transitioned from initial to daily cigarette use more rapidly than females not exposed. The opposite effect was found for males, which may be related to our finding that in utero exposure lowered the age of cigarette experimentation in exposed compared with unexposed males. Measures of current cigarette use and dependence (i.e., Fagerstrom Test for Nicotine Dependence, prior withdrawal, number of past year quit attempts) were significantly associated with reported in utero exposure, gender, or interactions of exposure and gender. In utero tobacco exposure may accelerate the progression from experimentation to daily use in girls, result in early tobacco experimentation among boys, and produce higher levels of nicotine dependence among adult smokers. Oncken, C., McKee, S., Krishnan-Sarin, S., O'Malley, S. and Mazure, C. Gender Effects of Reported In Utero Tobacco Exposure on Smoking Initiation, Progression and Nicotine Dependence in Adult Offspring. Nicotine Tob. Res. 6(5), pp. 829-833, October 2004.

Naltrexone for the Treatment of Cocaine-alcohol Dependence

This study evaluates whether patients with cocaine-alcohol dependence might benefit from naltrexone (NTX) pharmacotherapy when delivered in conjunction with psychotherapy. Eighty outpatients meeting DSM-IV criteria for alcohol and cocaine dependence were randomly assigned to receive NTX (placebo or 50 mg/d) combined with psychotherapy (Relapse Prevention [RP] or Drug Counseling [DC]) for twelve weeks. It was hypothesized that the skills training focus of RP therapy, in combination with NTX 50 mg/d, would produce greater reductions in cocaine and alcohol use. Outcome measures included self- and objective reports of substance use, treatment retention, medication compliance, and adverse effects. During the first four weeks of treatment, the percentage of cocaine-positive urine screens was significantly lower for those receiving RP therapy (22%) than those receiving DC (47%); however, this difference subsequently diminished. No medication effects were found. All groups reported less alcohol use at the end of treatment. Treatment retention was the same among the groups, with about 33% of the subjects completing all twelve weeks of treatment. The active medication group showed better medication compliance, while the number of adverse events was low overall and not significantly different by group. In conclusion, NTX at 50 mg/d did not reduce cocaine or alcohol use. These findings stand in contrast to previously reported positive findings for NTX and RP in patients with a single diagnosis of cocaine dependence. Schmitz, J.M., Stotts, A.L., Sayre, S.L., DeLaune, K.A. and Grabowski, J. Treatment of Cocaine-alcohol Dependence with Naltrexone and Relapse Prevention Therapy. Am J Addict.13(4), pp. 333-341, July-September 2004.

Relative Efficacy of Daily, Twice and Thrice Weekly Buprenorphine Dosing

This randomized clinical trial evaluated the relative efficacy of three buprenorphine dosing schedules. Opioid-dependent adults were randomly assigned to receive buprenorphine seven, 3 or 2 days per week for 24 weeks. Daily maintenance doses were 4, 8, 10, or 12 mg of the sublingual buprenorphine solution. Participants who attended the clinic daily received a maintenance dose of buprenorphine daily. Participants who attended the clinic thrice weekly received double their maintenance dose on Monday and Wednesday, followed by a triple dose on Friday. Participants who attended the clinic twice weekly received quadruple their maintenance dose of buprenorphine on Monday and triple their maintenance dose on Friday. Results demonstrated that all dosing regimens were of comparable efficacy in promoting treatment retention, opioid and cocaine abstinence, and reductions in HIV risk behavior (especially as related to drug use) and severity of life problems. Predictor analyses identified sub-populations of opioid-dependent individuals that may have a more positive treatment outcome under each buprenorphine dosing condition. Less-than-daily dosing schedules may provide the opportunity for treatment programs to serve a greater number of opioid-dependent patients and reduce the risk of medication diversion, which may, in turn, have a positive impact on community support of science-based treatment for opioid-dependence. Marsch, L.A., Bickel, W.K., Badger, G.J. and Jacobs, E.A. Buprenorphine Treatment for Opioid Dependence: The Relative Efficacy of Daily, Twice and Thrice Weekly Dosing. Drug Alcohol Depend. 77(2), pp. 195-204, February 14, 2005.

Effects of Acute Opiate Withdrawal and Drug Reinforcement Opportunity on Opioid Craving and Seeking Behaviors

The author used a 3 x 2 within-subject randomized crossover design to assess craving and operant behavioral effects of 3 pretreatments (naloxone 0.1 mg/70 kg, fentanyl 0.75 mg/70 kg, or saline iv) and drug or money reinforcement opportunity in 8 methadone-maintained volunteers. Each pretreatment was paired with response-contingent (15 x fixed-ratio 100) delivery of drug (fentanyl 1.5 mg/70 kg iv) and money (rated equivalent of fentanyl) in different sessions. Naloxone significantly increased opioid craving, withdrawal signs, and symptoms, but not operant behavior, relative to saline and fentanyl pretreatment. However, drug versus money reinforcement opportunity did not significantly increase opioid craving or seeking behavior. Greenwald, M.K. Opioid Craving and Seeking Behavior in Physically Dependent Volunteers: Effects of Acute Withdrawal and Drug Reinforcement Opportunity. Exp Clin Psychopharmacol. 13(1), pp. 3-14, February 2005.

Progesterone Treatment and Cocaine Responses

The investigators examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. Sofuoglu, M., Mitchell, E. and Kosten, T.R. Effects of Progesterone Treatment on Cocaine Responses in Male and Female Cocaine Users. Pharmacol Biochem Behav. 78(4), pp. 699-705, August 2004.


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