Biomedical subjects

T R Kosten

Publications and source records attributed to T R Kosten.

At least 37 records · Page 2Linked to original sources

PubMed2000

Benzodiazepine use in posttraumatic stress disorder among veterans with substance abuse.

Veterans with posttraumatic stress disorder (PTSD) and substance abuse may abuse benzodiazepines and develop violent dyscontrol when using them. A total of 370 veterans were compared by substance abuse diagnosis (50%), benzodiazepine use (36%), and their interaction on 1-year outcomes after inpatient discharge. Substance abusers were less likely to be prescribed benzodiazepines (26% vs. 45%). No outcome showed a differential worsening by substance abuse or benzodiazepines, although some baseline differences were noted. Outpatient health care utilization was lower in benzodiazepine users (47 vs. 33 visits). Among PTSD patients with comorbid substance abuse, benzodiazepine treatment was not associated with adverse effects on outcome, but it may reduce health care utilization.

Ambulatory Care↗

PubMed2000

Neurobiological adaptations to psychostimulants and opiates as a basis of treatment development.

Abuse of illicit substances, in particular psychostimulants and opiates, is a worldwide public health issue. Chronic use of cocaine and amphetamine causes common neurobiological adaptations that may guide new treatment development. These include perturbations in dopamine and serotonin neurotransmission, leading to trials of antidepressants, and serotonin and dopamine augmentation strategies. The detection of cerebral perfusion abnormalities caused by psychostimulants has led to examination of antiplatelet and excitatory amino acid (EAA) antagonist therapies. Further, development of cocaine vaccines allows for testing of peripheral blockade approaches to cocaine addiction. New approaches to behavioral treatments for cocaine dependence are also reviewed. For opiate dependence, understanding of heroin's effects on mu and kappa opiate receptors has led to investigations of the partial mu agonist buprenorphine in opiate maintenance. Evidence for hyper-excitability of locus coeruleus (LC) noradrenergic neurons and EEA inputs to the LC guides trials of new alpha 2-adrenergic agonists and EEA antagonists to alleviate opiate withdrawal. Finally, clinical experience with withdrawal from methadone and LAAM has led to trials of antagonist-accelerated opiate withdrawal. Improved treatment of psychostimulant and opiate addiction is critically needed, and likely to have wide-reaching impact in health care and society.

Adaptation, Physiological↗

PubMed2000

Prediction of dopamine transporter binding availability by genotype: a preliminary report.

OBJECTIVE: Evidence of a relationship between genotype and binding availability was assessed for the dopamine and serotonin transporter genes. METHOD: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT. RESULTS: Subjects homozygous for the 10-repeat allele at the SLC6A3 locus demonstrated significantly lower dopamine transporter binding than carriers of the nine-repeat allele. There was no effect of SLC6A4 genotype upon serotonin transporter binding. CONCLUSIONS: These findings suggest that genetic variation at the SLC6A3 3' VNTR polymorphism may modify dopamine transporter function.

Adult↗

PubMed2000

Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia.

OBJECTIVE: Schizophrenic patients have high rates of cigarette smoking. The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications. METHOD: Forty-five subjects were randomly assigned to 1) the group therapy program of the American Lung Association (N=17) or 2) a specialized group therapy program for smokers with schizophrenia (N=28) that emphasized motivational enhancement, relapse prevention, social skills training, and psychoeducation. All subjects participated in 10 weeks of treatment with the nicotine transdermal patch (21 mg/day) and 10 weekly group therapy sessions and continued to receive their prestudy atypical (N=18) or typical (N=27) antipsychotic medications. Outcome variables included treatment retention, rate of smoking abstinence, and expired-breath carbon monoxide level. RESULTS: Smoking abstinence rates did not differ in the two group therapy programs. However, atypical antipsychotic agents, in combination with the nicotine transdermal patch, significantly enhanced the rate of smoking cessation (55.6% in the atypical agent group versus 22.2% in the typical group), which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels. Risperidone and olanzapine were associated with the highest quit rates. CONCLUSIONS: The results suggest that 1) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia, 2) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation, and 3) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia.

Administration, Cutaneous↗

PubMed2000

Elevated central serotonin transporter binding availability in acutely abstinent cocaine-dependent patients.

OBJECTIVE: Recent work has underscored the role of serotonergic neurotransmission in chronic neural adaptations to cocaine dependence. The authors tested for evidence of serotonergic dysfunction during acute abstinence from cocaine, a period of high risk for relapse in cocaine dependence. METHOD: Binding availability of dopamine transporters and serotonin transporters was measured in 15 cocaine-dependent subjects during acute abstinence and in 37 healthy comparison subjects by using [(123)I]beta-CIT and single photon emission computed tomography. RESULTS: Significant increases in diencephalic and brainstem serotonin transporter binding (16.7% and 31.6%, respectively) were observed in cocaine-dependent subjects. Brainstem serotonin transporter binding was significantly inversely correlated with age across diagnostic groups. CONCLUSIONS: These findings provide further evidence of serotonergic dysfunction during acute abstinence from chronic cocaine use. Age-related decline in brainstem serotonin transporter binding may underlie the poor response to selective serotonin reuptake inhibitor antidepressants seen in some elderly depressed patients.

Adult↗

PubMed1999

The effects of naltrexone maintenance on the response to yohimbine in healthy volunteers.

BACKGROUND: Preclinical research suggests that opiate antagonists may alter stress responsiveness. This study describes the effect of pretreatment with the opioid antagonist naltrexone on the response to a noradrenergic stressor, the alpha-2-receptor-antagonist, yohimbine, in healthy subjects. The current study was designed to compare the change in responses to yohimbine after 2 weeks of treatment with naltrexone to the response after at least 2 weeks of treatment with placebo. METHODS: After a week of placebo naltrexone treatment, ten subjects were randomized into a double-blind cross-over to placebo or active naltrexone (50 mg p.o. daily) on weeks 2 to 4, and the converse condition for weeks 5 to 7. Subjects received challenges in a random, fixed sequence with placebo and active yohimbine (i.v., 0.2 mg/kg) on weeks 1, 4, and 7. The active-active combination generally had the strongest drug effects. RESULTS: There were statistically significant (p < .05) interactions of naltrexone condition X yohimbine condition for subject ratings of "nervous," "not liking the drug effect," "talkative," and "urge to urinate," and a trend (p < .10) for cortisol levels. CONCLUSIONS: The results suggest that clinically used naltrexone doses alter sensitivity to yohimbine.

Adult↗

PubMed1999

Desipramine in opioid-dependent cocaine abusers maintained on buprenorphine vs methadone.

BACKGROUND: Cocaine abuse occurs in 40% to 60% of patients entering opioid maintenance treatment, and effective pharmacotherapies are needed for this combined dependence. METHODS: This 13-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of desipramine hydrochloride (0 or 150 mg/d) plus buprenorphine hydrochloride (12 mg/d) or methadone hydrochloride (65 mg/d) in 180 opioid-dependent cocaine abusers (124 men, 56 women). Supervised urine samples were obtained thrice weekly, and self-reported cocaine and heroin use was reported once weekly. Desipramine plasma levels were determined at weeks 4 and 10. RESULTS: In men, opioid abstinence 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 more rapidly over time than placebo. Self-reported opioid use confirmed these findings. Desipramine plasma levels were higher in women than in men, particularly those on buprenorphine maintenance. Higher desipramine plasma levels were associated with greater opioid, but not cocaine, abstinence. CONCLUSIONS: Desipramine may be a useful adjunctive medication in facilitating opioid and cocaine abstinence in opioid-maintained patients. The efficacy of opioid medications to treat opioid or cocaine dependence may differ by sex. These findings highlight the importance of including sex as a factor when examining treatment outcome in these types of trials.

Adult↗

PubMed1999

Current concepts in pharmacotherapy of substance abuse.

The cost to society of alcohol, tobacco, and illicit drug dependence is enormous. Although the importance of treatment for substance abuse to public health is increasingly acknowledged, pharmacotherapy is generally underutilized. However, the selection of medications for clinical testing is increasingly guided by the rapidly evolving science of addictive drugs and behavior. The benefit of medication for smoking cessation is firmly established, particularly for nicotine replacement and antidepressant therapy. Naltrexone is an important addition to the pharmacopoeia, and acamprosate may soon be approved as well. Although no new medications are approved for cocaine and amphetamine abuse, a variety of candidate treatments have shown promise in ongoing studies. Opiate substitution therapy is highly effective for rehabilitation of heroin addiction, and several alternative forms will soon be available; alternative forms of opiate detoxification have also received attention. Overall, there is increasing recognition that physicians have an obligation to identify and treat all forms of substance dependence, although knowledge of the efficacy of the available treatments is steadily increasing.

Alcoholism↗

PubMed1999

Individual differences in humans responding under a cocaine discrimination procedure: discriminators versus nondiscriminators.

Twenty-six cocaine-abusing volunteers were trained to discriminate cocaine (80 mg/70 kg, p.o.) from placebo. On the basis of a discrimination acquisition criterion (i.e., >80% drug-appropriate responding for 4 consecutive sessions within 8-10 sessions), 18 participants were classified as discriminators (Ds) and 8 as nondiscriminators (NDs). Relative to Ds, NDs reported a greater amount of cocaine use per time. During the training phase, NDs showed significantly lower ratings than Ds on a stimulant ratings scale, regardless of the training drug condition. During the test-of-acquisition phase, cocaine-induced increases in scores on ratings of drug strength, anxious-nervous and cocaine high, as well as on a euphoria ratings scale, were significantly greater in Ds than NDs, relative to placebo. These results suggest that drug use history, general arousal level, and drug sensitivity may be important variables influencing the acquisition of cocaine versus placebo discrimination in cocaine abusers.

Adult↗

PubMed1999

Interactions of cocaine with nimodipine: a brief report.

This double blind, placebo controlled study of acute calcium channel antagonist use during cocaine administration in five patients found that 60 mg of nimodipine treatment attenuated the systolic, but not diastolic, blood pressure effects of cocaine. In three subjects, a 90 mg dose of nimodipine showed a greater attenuation than that of 60 mg. Subjective effects of cocaine were not altered by either dose of nimodipine.

Adult↗

PubMed1999

Day treatment versus enhanced standard methadone services for opioid-dependent patients: a comparison of clinical efficacy and cost.

OBJECTIVE: This study examined the differential efficacy and relative costs of two intensities of adjunctive psychosocial services--a day treatment program and enhanced standard care--for the treatment of opioid-dependent patients maintained on methadone hydrochloride. METHOD: A 12-week randomized clinical trial with 6-month follow-up was conducted in a community-based methadone maintenance program. Of the 308 patients who met inclusion criteria, 291 began treatment (day treatment program: N=145; enhanced standard care: N=146), and 237 completed treatment (82% of those assigned to the day treatment program and 81% of those receiving enhanced standard care). Two hundred twenty of the patients participated in the 6-month follow-up (75% of those in the day treatment program and 73% of those in enhanced standard care provided a follow-up urine sample for screening). Both interventions were 12 weeks in duration, manual-guided, and provided by master's-level clinicians. 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 on- and off-site services. Outcome measures included twice weekly urine toxicology screens, severity of addiction-related problems, prevalence of HIV risk behaviors, and program costs. RESULTS: Although the cost of the day treatment program was significantly higher, there was no significant difference in the two groups' use of either opiates or cocaine. Over the course of treatment, drug use, drug-related problems, and HIV risk behaviors decreased significantly for patients assigned to both treatment intensities. Improvements were maintained at follow-up. CONCLUSIONS: Providing an intensive day treatment program to unemployed, inner-city methadone patients was not cost-effective relative to a program of enhanced methadone maintenance services, which produced comparable outcomes at less than half the cost.

Adult↗

PubMed1998

The effect of lamotrigine on naloxone-precipitated opiate withdrawal.

We hypothesized that lamotrigine, a putative glutamate release antagonist, would attenuate glutamate-mediated signs of opiate withdrawal. Seven heroin-dependent subjects were hospitalized, stabilized on oral levorphanol 6 mg three times daily, and thrice underwent withdrawal precipitated by naloxone 0.4 mg intravenously. Lamotrigine (placebo, 250 mg, and 500 mg) was randomly given as a pretreatment 6 h before naloxone. Lamotrigine did not significantly attenuate any measure of opiate withdrawal. Lamotrigine was well-tolerated in subjects, although one did develop an allergic rash.

Adult↗

PubMed1998

Disulfiram effects on acute cocaine administration.

Disulfiram (Antabuse) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence. This inpatient randomized, double-blind, placebo-controlled, within-subjects study was conducted to determine whether disulfiram (placebo, 250 or 500 mg/day) alters responses to acute intranasal cocaine (placebo, 1 or 2 mg/kg) administration. Effects of disulfiram on cocaine pharmacokinetics, physiological, and behavioral responses were determined. Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses, but did not significantly alter behavioral responses to cocaine. These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients.

Acute Disease↗

PubMed1998

Concurrent use of cocaine and alcohol is more potent and potentially more toxic than use of either alone--a multiple-dose study.

BACKGROUND: Simultaneous abuse of cocaine and alcohol is widespread and increasingly detected in patients seeking emergent care. This double-blind, randomized, within-subjects study used a paradigm more closely approximating practices of drug abusers to better understand the pathogenesis of cocaine-alcohol abuse. METHODS: Subjects meeting DSM-IV criteria for cocaine dependence and alcohol abuse participated in three drug administration sessions: four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg) administered following the initial cocaine dose and a second dose (120 mg/kg) at 60 min calculated to maintain plasma alcohol concentration at approximately 100 mg/dL during cocaine administration; four doses of cocaine/placebo alcohol; four doses of cocaine placebo/alcohol. Pharmacokinetic, physiological, and behavioral effects were followed over 8 hours. RESULTS: Cocaine-alcohol produced greater euphoria and increased perception of well-being relative to cocaine. Heart rate significantly increased following cocaine-alcohol administration relative to either drug alone. Cocaine concentrations were greater following cocaine-alcohol administration. Cocaethylene had a longer halflife with increasing concentrations relative to cocaine at later time points. CONCLUSIONS: Enhanced psychological effects during cocaine-alcohol abuse may encourage ingestion of larger amounts of these substances over time placing users at heightened risk for greater toxicity than with either drug alone.

Adult↗

PubMed1998

Regional cerebral blood flow during acute and chronic abstinence from combined cocaine-alcohol abuse.

Regional cerebral blood flow (rCBF) was assessed using SPECT and HMPAO in ten cocaine abusers within 72 h of last cocaine use and then after 21 days of abstinence. In comparison to normals the cocaine abusers had significantly reduced rCBF in 11 of 14 brain regions with the largest reductions in the frontal and parietal cortex and greater rCBF in the brain stem. These perfusion defects appeared to be primarily due to combined alcohol and cocaine abuse and frontal but not parietal defects appeared to resolve partially during 21 days of abstinence.

Adult↗

PubMed1998

Chronic disulfiram treatment effects on intranasal cocaine administration: initial results.

BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inability to modulate cocaine effects with alcohol may decrease cocaine use. METHODS: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high" with increased anxiety in the context of inability to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disulfiram.

Administration, Intranasal↗

PubMed1998

Plasma homovanillic acid and the dopamine transporter during cocaine withdrawal.

BACKGROUND: Plasma homovanillic acid (HVA) has been used as a measure of central dopaminergic activity but the validity of this method continues to be investigated. We used single photon emission tomography (SPECT) assessment of the dopamine (DA) transporter for comparison with plasma HVA in subjects at varying stages of abstinence from cocaine. METHODS: Nineteen subjects were studied in two separate treatment sites. Plasma HVA and methoxyhydroxyphenethyleneglycol (MHPG) were measured by gas chromatography-mass spectroscopy (GC-MS). The DA transporter was quantified using the SPECT ligand [123I]B-CIT. RESULTS: At 2 weeks of abstinence and beyond there was an increasing positive correlation between plasma HVA and the SPECT measurement of the DA transporter (V3"). CONCLUSIONS: Plasma HVA may be more likely to reflect DA transporter density in the striatum when there is not a major drug-related change in the DA system.

Adult↗

PubMed1998

Rapid and ultrarapid opioid detoxification techniques.

OBJECTIVE: To review the scientific literature on the effectiveness of rapid opioid detoxification (RD) (opioid withdrawal precipitated by naloxone hydrochloride or naltrexone) and ultrarapid opioid detoxification (URD) (opioid withdrawal precipitated by naloxone or naltrexone under anesthesia or heavy sedation) techniques. DATA SOURCES: The MEDLINE database was searched from 1966 through 1997 using the indexing terms naloxone, naltrexone, substance dependence, and substance withdrawal syndrome. Additional data sources included bibliographies of papers identified on MEDLINE and bibliographies in textbooks on substance abuse. STUDY SELECTION: Inclusion criteria were studies of RD or URD, pharmacologic protocols specified, and clinical outcomes specified and reported. Exclusion criteria were unpublished data, data not in peer-reviewed journals, abstract-only publications, and review articles. DATA EXTRACTION: The methodologic characteristics of studies were extracted by the authors and summarized according to key components of research design concerning subject characteristics, therapy allocation, and outcomes assessed. DATA SYNTHESIS: A qualitative analysis was performed on the 12 studies of RD and the 9 studies of URD identified in our search. The RD studies enrolled 641 subjects (range for individual studies, 1-162): 7 were inpatient studies, and the protocols varied considerably, as did the outcomes assessed. Three RD studies included a control group, 2 used a randomized design, and 3 reported outcomes beyond 12 days. The URD studies enrolled 424 subjects (range for individual studies, 6-300): all were inpatient studies, the detoxification and anesthesia protocols varied, 3 included a control group, 2 used a randomized design, and 2 reported outcomes for URD beyond 7 days. CONCLUSIONS: The existing literature on RD and URD is limited in terms of the number of subjects evaluated, the variation in protocols studied, lack of randomized design and use of control groups, and the short-term nature of the outcomes reported. Further research is needed using more rigorous research methods, longer-term outcomes, and comparisons with other methods of treatment for opioid dependence.

Clinical Trials as Topic↗