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Director's Report to the National Advisory Council on Drug Abuse - February, 2009

Research Findings - Research on Pharmacotherapies for Drug Abuse

Racemic Gamma Vinyl-GABA (R,S-GVG) Blocks Methamphetamine-triggered Reinstatement of Conditioned Place Preference

This article reports that conditioned place preference to methamphetamine can be blocked in rats using a 2.5 hour pretreatment dose of 300 mg/kg i.p. racemic GVG. Reinstatement is blocked regardless of training dose of priming dose of methamphetamine ranging from 1.0 to 10 mg/kg. These findings suggest that GVG may be an effective treatment to block methamphetamine reinstatement in human methamphetamine users. Demarco, A., Dalal, R.M., Pai, J., Aquilina, S.D., Mullapudi, U., Hammel, C., Kothari, S.K., Leibling, C.N., Patel, V., Schiffer, W.K., Brodie, J.K., and Dewey, S.L. Racemic Gamma Vinyl-GABA (R,S-GVG) Blocks Methamphetamine-triggered Reinstatement of Conditioned Place Preference Synapse 63(2), pp. 87-94, 2008.

Subchronic Racemic Gamma Vinyl-GABA Produces Weight Loss in Sprague Dawley and Zucker Fatty Rats

This paper reports that GVG was tested for its effects on body weight in adolescent Sprague-Dawley rats and in adolescent and adult genetically obese Zucker rats. GVG in doses ranging from 75-300 mg/kg ip dose dependently reduced body weight in all groups following a treatment period of 14 days, suggesting that GVG may be effective as a weight loss tool or obesity treatment. DeMarco, A., Dalal, R.M., Kahanda, M., Mullapudi, U., Pai, J., Hammel, C.., Liebling, C.N., Patel, V., Brodie, J.D., Schiffer, W.K., Dewey, S.L,, and Aquilina, S.D. Subchronic Racemic Gamma Vinyl-GABA Produces Weight Loss in Sprague Dawley and Zucker Fatty Rats. Synapse 63(11), pp. 870-872, 2008.

Opioid and Cocaine Combined Effect on Cocaine-induced Changes in HPA and HPG Axes Hormones in Men

This paper reports on effects of cocaine or the combination of cocaine and nalbuphine (a kappa/mu agonist) in human subjects. Cocaine stimulated ACTH, cortisol, and LH, whereas the combination of nalbuphine and cocaine produced smaller increases in ACTH, and decreased cortisol and LH. These data are consistent with previous studies suggesting that nalbuphine modestly attenuated subjective effects of cocaine, and that subjective and cardiovascular effects of cocaine and nalbuphine were not additive. Goletiani, N., Mendelson, J.H., Sholar, M.B., Sigel, A.J., and Mello, N.K. Opioid and Cocaine Combined Effect on Cocaine-induced Changes in HPA and HPG Axes Hormones in Men. Pharmacology, Biochemistry and Behavior, 2008 (online).

Data Mining in a Behavioral Test Detects Early Symptoms in a Model of Amyotrophic Lateral Sclerosis

This paper described a methodology called pattern array which involved analysis of genetically modified mice that exemplify an animal model of ALS. The technique was able to identify a unique motor pattern that differentiated the mutants from the wild-type mice two months before disease onset, at a stage whey there were no other measures that differentiated these animals. The early discovered symptom may enable the testing of potential therapeutics using these subtle behavioral effects. Kafkafi, N., Yekutieli, D., Yarowsky, P., and Elmer, G. Data Mining in a Behavioral Test Detects Early Symptoms in a Model of Amyotrophic Lateral Sclerosis. Behavioral Neuroscience 122(4), pp. 777-787, 2008.

A Data Mining Approach to In Vivo Classification of Psychopharmacological Drugs

Data mining is a powerful informatics strategy that has been applied to in vitro data. Pattern array is a data mining algorithm used to analyze mouse open field behavior and characterize the psychophamacological effects of three drug classes including stimulants, opioids, and psychomimetics. Pattern array has discovered behavioral predictors in all three drug classes and unknowns. Although still in its early stages, Pattern Array may develop into a tool for psychotherapeutic drug discovery. Kafkafi, N., Yekutieli, D., and Elmer, G. A Data Mining Approach to in vivo Classification of Psychopharmacological Drugs, Neuropsychopharmaco-logy.1-17, 2008 (online).

Disulfiram Enhances Subjective Effects of Dextroamphetamine in Humans

Disulfiram has shown promise in several clinical trials for cocaine addiction, but its potential utility in the treatment of amphetamine addiction has not been examined. The goal of this study was to determine the effects of disulfiram on acute physiological and subjective responses to dextroamphetamine in healthy volunteers. Five male and 5 female subjects participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects were randomly assigned to a sequence of disulfiram (250 mg/day) or placebo treatments each lasting for 4 days. Day four of each treatment period was the experimental session, in which subjects orally ingested a single dose of dextroamphetamine (20 mg/70 kg). Outcome measures included heart rate, blood pressure, plasma cortisol and prolactin, subjective and performance on the Sustained Attention to Response Test (SART). Disulfiram did not affect dextroamphetamine-induced increases in heart rate, blood pressure, cortisol, or prolactin. Disulfiram did enhance some of the subjective effects of dextroamphetamine including ratings of "high," "anxious," "bad drug effects," "want more drug" and "drug liking" and was also associated with decreased performance in the SART test. How these enhanced subjective amphetamine responses affect cocaine use behavior remains to be determined in future clinical trials. Sofuoglu, M., Poling, J., Waters, A., Sewell, A., Hill, K., Kosten, T. Pharmacol. Biochem. Behav., 90(3), pp. 394-398, 2008.

Cocaine Effects During D-amphetamine Maintenance: A Human Laboratory Analysis of Safety, Tolerability and Efficacy

Results of preclinical laboratory studies and clinical trials indicate that agonist replacements like D-amphetamine may be a viable option for managing cocaine dependence. This study determined the physiological and behavioral effects of cocaine during D-amphetamine maintenance in seven cocaine-dependent participants, with the prediction that cocaine would be well tolerated during D-amphetamine maintenance, and that D-amphetamine would attenuate the behavioral effects of cocaine. After 3-5 days of D-amphetamine maintenance (0, 15, and 30 mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60 mg IN) within a single session. Cocaine doses were separated by 90 min. Cocaine produced prototypical physiological (e.g., increased heart rate, blood pressure, and body temperature) and subject-rated (e.g., increased ratings of Good Effects) effects. During maintenance on the highest D-amphetamine dose, the heart rate increasing effects of cocaine were larger than observed during placebo maintenance. These effects were not clinically significant and no unexpected or serious adverse events were observed. D-amphetamine attenuated some of the subject-rated effects of cocaine. These results are concordant with those of previous preclinical studies, human laboratory experiments and clinical trials, further suggesting that agonist replacement therapy may be a viable strategy for managing cocaine abuse. Rush, C.R., Stoops, W.W., and Hays, L.R. Drug and Alcohol Dependence, 2008. (E-publication ahead of print).

The Safety, Tolerability, and Subject-Rated Effects of Acute Intranasal Cocaine Administration During Aripiprazole Maintenance II: Increased Aripiprazole Dose and Maintenance Period

The experiment reported here examined the safety and tolerability of intranasal cocaine during aripiprazole maintenance. Six cocaine-dependent human subjects were maintained on aripiprazole (15 mg) and placebo for 10 days in counterbalanced order prior to assessing the physiological and subject-rated effects of intranasal cocaine. The results showed that intranasal cocaine produced prototypical stimulant-like effects (e.g., increased blood pressure and heart rate, increased subject ratings of Like Drug and Stimulated), and aripiprazole enhanced these effects on several measures. The study conclusions are that aripiprazole (15 mg/day) is safe and tolerable when combined with cocaine; however, the usefulness of aripiprazole as a treatment for cocaine-use disorders remains to be determined. Lile, J.A., Stoops, W.W., Hays, L.R., and Rush, C.R. Am. J. Drug and Alcohol Abuse, 34, pp. 721-729, 2008.

Evaluation of the Cardiovascular and Subjective Effects of Rivastigmine in Combination With Methamphetamine in Methamphetamine-Dependent Human Volunteers

Acetylcholine (ACh) has been implicated in the reinforcing and locomotor activating effects produced by methamphetamine. Recent data suggest that acetylcholinesterase (AChE) inhibitors attenuate methamphetamine-seeking behavior in rates. This double-blind, between-subjects, placebo-controlled inpatient study was conducted in 23 non-treatment seeking methamphetamine-dependent subjects to determine the safety (adverse events, mood changes, cardiovascular effects) and preliminary efficacy (subjective effects) of the AChE inhibitor rivastigmine when tested in combination with methamphetamine. Prior to randomization to study drug, infusions of saline (day 4; 0 mg) and methamphetamine (day 5; 30 mg iv) were given to all participants in single-blinded fashion. On day 7 and continuing through day 11, participants were randomized to receive oral placebo (0 mg, N=7) or rivastigmine (1.5 mg, N=7; 3 mg, N=9). On day 11, subjects received saline and methamphetamine infusions again under double-blind conditions. Data analysis revealed that rivastigmine was not associated with increased adverse events or alterations in mood. As expected, acute methamphetamine exposure (30 mg, iv) increased heart rate and blood pressure as well as several positive subjective effects, ARCI ratings, and reported monetary value (p<0.05). The date indicated that rivastigmine, at 3 mg, significantly attenuated methamphetamine-induced increases in diastolic blood pressure, and self-reports of "anxious" and "desire" (p,0.05). These findings suggest that pharmacological manipulations that enhance brain ACh warrant continued investigation as potential treatments for methamphetamine addiction. De La Garza, R., Shoptaw, S., and Newton, T.F. Int. J. Neuropsychopharmacol., 11(6), pp. 729-741, 2008.

Effects of Early and Recent Adverse Experiences on Adrenal Response to Psychosocial Stress in Depressed Adolescents

As observed in depressed adults, there is considerable variability in the degree and direction of hypothalamic pituitary adrenal (HPA) dysfunction in depressed adolescents. The variability in HPA findings may be attributed to experiential factors. In this study, a modified version of a standard psychosocial stressor used in adults, the Trier Social Stress Test (TSST) was administered to 30 adolescents with major depressive disorder and 25 healthy adolescent volunteers. Cortisol concentrations were measured in saliva samples collected before and after the stressor. Information was also gathered on early and recent adverse experiences with standard interviews. The results of this study showed that participants from both groups had increased cortisol secretion in response to TSST. The combination of early-life adversity and high levels of chronic stress during adolescence was the most powerful predictor of enhanced adrenal response to the TSST. These results support previous findings on the role of experiential factors on HPA response to stress and in the development of mood disorders. Dissection of the heterogeneous pathophysiology of adolescent depression will assist in developing more specific interventions for different subgroups of adults. Rao, U., Hammen, C., Ortiz, L.R., Chen, L., and Poland, R.E. Biol. Psychiatry, 64, pp. 521-526, 2008.

Stress-related Factors in Cannabis Use and Misuse: Implications for Prevention and Treatment

A systematic review of published studies on the role of stress as a risk factor and motivation for cannabis use/misuse suggest that cannabis is commonly used as a stress-coping strategy. Negative life events, trauma, and maladaptive coping were all related to consumption. Cannabis use for stress-coping purposes was most evident when examining chronic as compared with experimental use. Although many individuals may be able to use cannabis without consequences, there appears to be a subset of individuals who experience greater life stress and who may be more likely to use for stress-coping purposes and may be at greater risk for addiction. Chronic use may potentiate stress-related motivation to use/abuse cannabis and is associated with decision-making deficits and alterations in brain-stress pathways that may exacerbate compulsive drug seeking and sensitize individuals to stress-related drug use. Overall, stress-coping interventions and harm reduction focused on reducing the amount ingested may facilitate prevention and recovery efforts. Hyman, S.M., and Sinha, R. J. Substance Abuse Treatment, 2008 (E-publication ahead of print).

Chronic Stress, Drug Use, and Vulnerability to Addiction

This review article evaluates the role of stress as a risk factor in the development of addiction and in addiction relapse vulnerability and discusses research gaps in the connection between stress and addiction, with the aim of presenting questions the answers to which could significantly influence new prevention and treatment strategies. Preclinical research of stress exposure and reinstatement models, the underlying pathophysiology associated with stress-related risk of addiction, and a discussion of population-based and epidemiological studies, are all presented. Sinha, R. Ann. N.Y. Acad. Sci. 1141, pp. 105-130, 2008.

Self-administration of Cocaine, Cannabis and Heroin in the Human Laboratory: Benefits and Pitfalls

This review describes self-administration procedures for modeling addiction to cocaine, cannabis and heroin in the human laboratory, the benefits and pitfalls of the approach, and the methodological issues unique to each drug. It also addresses the predictive validity of the model for testing treatment medications. The results show that all three drugs of abuse are reliably and robustly self-administered by non-treatment seeking research volunteers. In terms of pharmacotherapies, cocaine use is extraordinarily difficult to disrupt either in the laboratory or in the clinic. A range of medications has been shown to significantly decrease cocaine's subjective effects and craving without decreasing either cocaine self-administration or cocaine abuse by patients. These negative data combined with recent positive findings with Modafinil suggest that self-administration procedures are an important intermediary step between pre-clinical and clinical studies. In terms of cannabis, a recent study suggests that medications that improve sleep and mood during cannabis withdrawal decrease the resumption of marijuana self-administration in abstinent volunteers. Clinical data on patients seeking treatment for their marijuana use are needed to validate these laboratory findings. Finally, in contrast to cannabis or cocaine dependence, three are three efficacious FDA-approved medications to treat opioid dependence, all of which decrease both heroin self-administration and subjective effects in the human laboratory. In summary, self-administration procedures provide meaningful behavioral data in a small number of individuals. These studies contribute to our understanding of the variables maintaining cocaine, marijuana and heroin intake, and are important in guiding the development of more effective drug treatment programs. Haney, M. Addiction Biology, 14, pp. 9-21, 2008.

Controversies in Translational Research: Drug Self-administration

Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. The purpose of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. Self-administration across species was tested with various medications for heroin and cocaine. The conclusions were that the self-administration model has reliably identified medications to treat opioid dependence, and the recent data with Modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. The study reports that there have been numerous false positives when subjective effects are the primary outcome measures, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect. Haney, M., and Spealman, R. Psychopharm. 199, pp. 403-419, 2008.

Substance Abuse Vaccines

Conventional substance-abuse treatments have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and phencyclidine (PCP). This review article reports on the utility of vaccination to block the effects of these drugs on the brain and what factors influence the effects of antibodies on drug pharmacodynamics. The review also presents the current status of vaccine development for nicotine, cocaine, methamphetamine, phencyclidine and morphine. There are currently three nicotine conjugate vaccines (NicVAX, NicQb, and TA-NIC) which were well tolerated in Phase I trials and have advanced to Phase IIb or Phase III. Both Phase I and Phase II trials have been completed using a cholera toxin B conjugated cocaine preparation (TA-CD) for cocaine dependence. Animal studies with conjugate vaccines have shown that substantial quantities of antibodies can reduce the accumulation of PCP in the brain; similar results have been found with passive immunization using anti-PCP monoclonal antibodies. Animal studies of methamphetamine vaccines are in the early stages, although passive administration of monoclonal antibodies has been shown to reduce methamphetamine self-administration in rats and to reduce locomotor activity in rats given high-dose methamphetamine. Although there are FDA-approved medications for opioid dependence, the spread of HIV/AIDS has sparked renewed interest in vaccines against heroin and morphine, as the economics of pharmacological and behavioral treatments make current substance-abuse programs less feasible in third-world countries. Early preclinical experiments with morphine conjugate vaccines showed some positive results which would justify continued research in this area. Orson, F.M., Kinsey, B.M., Singh, R.A.K., Wu, Y., Gardner, T., and Kosten, T.R. Ann. N.Y. Acad. Sci. 1142, pp. 257-269, 2008.

Sex and Opioid Maintenance Dose Influence Response to Naloxone in Opioid-dependent Humans: a Retrospective Analysis

Pooled self-report and physiological data from 32 male and 15 female methadone or levo-alpha-acetyl methadol (LAAM) maintained volunteers were retrospectively analyzed for individual differences in response to naloxone (0.15 mg/70 kg, IM) and placebo at 20 and 40 min post-injection. Males and females were each divided by the median split methadone maintenance dose (MMD, in mg/kg body weight) into high and low MMD groups and MMD was used as a factor in the analyses, along with sex, drug, and time post-drug. Females in the low but not high, MMD group showed naloxone-induced increases in ratings on the Antagonist and Mixed-Action sub-scales of the Adjective Rating Scale, and the Lysergic acid diethyl amine (LSD) sub-scale of the Addiction Research Center Inventory at 20 min post-injection. Males in the high MMD group showed significant naloxone-induced increases in scores of these measures at both post-injection time-points. In addition, low MMD subjects showed more short-lived naloxone-induced increases on Visual Analogue Scale (VAS) Bad and Any drug effects ratings than high MMD subjects. These results suggest that those on a lower MMD, especially women, experience a more intense, but short-lived, response to naloxone, whereas those on a higher MMD experience a more modest, but longer-lasting effect. Chopra, M.P., Feldman, Z., Mancino, M.J., and Oliveto, A. Sex and Opioid Maintenance Dose Influence Response to Naloxone in Opioid-dependent Humans: A Retrospective Analysis. Pharmacol. Biochem. Behav., 90(4), pp. 787-796, 2008.

A Phase 3 Placebo-controlled, Double-blind, Multi-site

Trial of the Alpha-2-Adrenergic Agonist, Lofexidine, for Opioid Withdrawal Lofexidine is an alpha-2-adrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. The objective of this study was to demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. The study design was an inpatient, Phase 3, placebo-controlled, double-blind, randomized multi-site trial with three phases: (1) opioid agonist stabilization phase (days 1-3), (2) detoxification/medication or placebo phase (days 4-8), and (3) post detoxification/medication phase (days 9-11). Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. The main outcome measure was a Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (second opioid detoxification treatment day). Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (least squares means 19.5+/-2.1 versus 30.9+/-2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). The authors concluded that lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification. Yu, E., Miotto, K., Akerele, E., Montgomery, A., Elkashef, A., Walsh, R., Montoya, I., Fischman, M.W., Collins, J., McSherry, F., Boardman, K., Davies, D.K., O'Brien, C.P., Ling, W., Kleber, H., and Herman, B.H. Drug Alcohol Depend., 97(1-2), pp. 158-168, 2008.

Safety and Feasibility of Sublingual Buprenorphine for the Treatment of Neonatal Abstinence Syndrome

In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial mu-opioid agonist used for treatment of adult detoxification and maintenance. The primary objective of this study was to demonstrate the feasibility and the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered. The methodology was to conduct a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 g/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system. Results indicated that sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to approximately 0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated. In conclusion, buprenorphine administered via the sublingual route is feasible and apparently safe (small N) and may represent a novel treatment for neonatal abstinence syndrome. Kraft, W.K., Gibson, E., Dysart, K., Damle, V.S., Larusso, J.L., Greenspan, J.S., Moody, D.E., Kaltenbach, K., and Ehrlich, M.E. Sublingual Buprenorphine for Treatment of Neonatal Abstinence Syndrome: a Randomized Trial. Pediatrics 122(3), pp. 601-607, September 2008.

Treating Pregnant Women Dependent on Opioids Is Not the Same as Treating Pregnancy and Opioid Dependence

The aim of this review is to articulate a set of evidence-based recommendations for consideration as guidance in the management of opioid-dependent pregnant women and infants. Methods included PubMed literature searches carried out to identify recent key publications in the areas of pregnancy and opioid dependence, neonatal abstinence syndrome (NAS) prevention and treatment, multiple substance abuse and psychiatric comorbidity. Results indicated that pregnant women dependent on opioids, require careful treatment to minimize harm to the fetus and neonate and to improve maternal health. Applying multi-disciplinary treatment as early as possible, while allowing medication maintenance and regular monitoring, benefits mother and child both in the short and the long term. However, there is a need for randomized clinical trials with sufficient sample sizes. Opioid maintenance therapy is the recommended treatment approach during pregnancy. Treatment decisions must encompass the full clinical picture, with respect to frequent complications arising from psychiatric comorbidities and the concomitant consumption of other drugs. In addition to standardized approaches to pregnancy, equivalent attention must be given to the treatment of NAS, which occurs frequently following opioid prescriptions. Unfortunately, methodological flaws and inconsistencies confound interpretation of today's literature. Winklbaur, B., Kopf, N., Ebner, N., Jung, E., Thau, K., and Fischer, G., Treating Pregnant Women Dependent on Opioids Is Not the Same as Treating Pregnancy and Opioid Dependence: A Knowledge Synthesis For Better Treatment For Women and Neonates. Addiction 103(9) pp. 1429-1440, Sepember 2008.

Clinical and Research Issues in the Treatment of Opioid-dependent Pregnant Women

This is an important methodological publication which addresses common questions that clinicians face when treating pregnant women with opioid dependence. Guidance, based on both research evidence and the collective clinical experience of the authors, is provided to aid clinical decision making. The authors are from the Maternal Opioid Treatment, Human Experimental Research (MOTHER) project. The MOTHER project is a double-blind, double-dummy, flexible-dosing, parallel-group clinical trial examining the comparative safety and efficacy of methadone and buprenorphine for the treatment of opioid dependence in pregnant women and their neonates. The article discusses appropriate assessment during pregnancy and addresses clinical management stages including maintenance medication selection, induction, and stabilization; as well as opioid agonist medication management before, during, and after delivery. In addition, methods of pain management; breast-feeding; and transfer to aftercare are reviewed. Lastly, other important clinical issues including managing co-occurring psychiatric disorders and medication interactions are explained. Jones, H.E., Martin, P.R., Heil, S.H., Kaltenbach, K., Selby, P., Coyle, M.G., Stine, S.M., O'Grady, K.E., Arria, A.M., and Fischer, G. Treatment of Opioid-dependent Pregnant Women: Clinical and Research Issues. J. Subst. Abuse Treat. 35(3) pp. 245-259, October 2008.

Neonatal Outcomes Correlated With Maternal Buprenorphine Dose and Metabolite Concentrations in Meconium

Relationships among maternal buprenorphine dose, meconium buprenorphine and metabolite concentrations, and neonatal outcomes are reported. Free and total buprenorphine and norbuprenorphine, nicotine, opiates, cocaine, benzodiazepines, and metabolites were quantified in meconium from 10 infants born to women who had received buprenorphine during pregnancy. Neither cumulative nor total third-trimester maternal buprenorphine dose predicted meconium concentrations or neonatal outcomes. Total buprenorphine meconium concentrations and buprenorphine/norbuprenorphine ratios were significantly related to neonatal abstinence syndrome (NAS) scores >4. As free buprenorphine concentration and percentage free buprenorphine increased, head circumference decreased. Thrice-weekly urine tests for opiates, cocaine, and benzodiazepines and self-reported smoking data from the mother were compared with data from analysis of the meconium to estimate in utero exposure. Time of last drug use and frequency of use during the third trimester were important factors associated with drug-positive meconium specimens. The results suggest that buprenorphine and metabolite concentrations in the meconium may predict the onset and frequency of NAS. Kacinko, S.L., Jones, H.E., Johnson, R.E., Choo, R.E., and Huestis, M.A. Correlations of Maternal Buprenorphine Dose, Buprenorphine, and Metabolite Concentrations in Meconium With Neonatal Outcomes. Clin. Pharmacol. Ther. 84(5), pp. 604-612, November 2008.

Buprenorphine is Useful in the Treatment of Prescription Opioid Addiction

Dependence on and abuse of prescription opioid drugs is now a major health problem, with initiation of prescription opioid abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opioids, there has been an increased emphasis on the treatment of pain. Pain is now seen as the "5th vital sign" and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are caught between the imperative to treat pain with opioids and the fear of producing addiction in some patients. The emerging epidemic of prescription opioid abuse is discussed in conjunction with the utility of buprenorphine in the treatment of this addiction. Case histories of successful treatment with buprenorphine are used to illustrate it's effectiveness. Mendelson, J., Flower, K., Pletcher, M.J., and Galloway, G.P. Addiction to Prescription Opioids; Characteristics of the Emerging Epidemic and Treatment With Buprenorphine. Exp. Clin. Psychopharmacol, 16(5), pp. 435-441, October 2008.

Nicotine Gum for Pregnant Smokers: a Randomized Controlled Trial

The purpose of this study was to estimate the safety and efficacy of treatment with 2-mg nicotine gum for smoking cessation during pregnancy. Pregnant women who smoked daily received individualized behavioral counseling and random assignment to a 6-week treatment with 2-mg nicotine gum or placebo followed by a 6-week taper period. Women who did not quit smoking were instructed to reduce the number of cigarettes smoked by substituting with gum. Measures of tobacco exposure were obtained throughout the study. Participants in the nicotine (n = 100) and placebo (n = 94) groups were comparable in age, race/ethnicity, and smoking history. Biochemically validated smoking-cessation rates were not significantly higher with nicotine gum compared with placebo (after 6 weeks of treatment: 13% compared with 9.6%, P=.45; at 32-34 weeks of gestation: 18% compared with 14.9%, P=.56). Using a completer analysis, nicotine gum significantly reduced the number of cigarettes smoked per day (nicotine gum: -5.7 [standard deviation (SD)=6.0]; placebo: -3.5 [SD=5.7], P=.035), and cotinine concentration (nicotine gum: -249 ng/mL [SD=397]; placebo: -112 ng/mL [SD=333]; P=.04). Birth weights were significantly greater with nicotine gum compared with placebo (3,287 g [SD=566] and 2,950 g [SD=653], respectively, P<.001). Gestational age was also greater with nicotine-replacement therapy than with placebo (38.9 weeks [SD=1.7] and 38.0 weeks [SD=3.3], respectively; P=.014). Although nicotine gum did not increase quit rates, use of nicotine gum increased birth weight and gestational age, two key parameters in predicting neonatal wellbeing. Oncken, C., Dornelas, E., Greene, J., Sankey, H., Glasmann, A., Feinn, R., and Kranzler, H.R. Obstet. Gynecol. 112(4), pp. 859-867, 2008.


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