A multicenter trial of bupropion for cocaine dependence in methadone-maintained patients.

We conducted a multi-site, placebo-controlled, randomized double-blind clinical trial comparing bupropion HCL (300 mg/day) to placebo for the treatment of cocaine dependence in methadone-maintained subjects. A total of 149 subjects at three sites participated in a 12-week study. Outcome measures included cocaine use, level of depression, and psychosocial functioning. Results showed no significant differences between placebo and bupropion. Exploratory analyses suggested a medication effect for the subset of subjects depressed at study entry. The need to target subgroups of cocaine abusers in future pharmacotherapy trials and the possible role of treatment readiness are discussed.

Desipramine treatment for cocaine dependence. Role of antisocial personality disorder.

As a test of the efficacy of desipramine (DMI) in the treatment of cocaine dependence, 59 cocaine-dependent males, maintained on methadone for the treatment of opiate dependence, completed a 12-week, random-assignment, placebo-controlled trial of this medication. At the end of treatment, there were no overall differences between the placebo and DMI groups on a range of outcome measures, including urine toxicology tests. However, an interaction between psychiatric diagnosis and outcome was seen when the sample was divided into those with (51%) and those without (49%) antisocial personality disorder (ASP). Patients with ASP made few gains with either DMI or placebo. Those without ASP made a number of gains with DMI but not placebo, particularly in the areas of psychiatric symptoms, legal status, and family problems. DMI had a significant effect on the psychiatric symptoms and personal adjustment problems, but not the cocaine use, of non-antisocial cocaine abusers. The negative influence of ASP that has been seen in studies of psychosocial therapies for substance-use disorders may also apply to pharmacological therapies.

The effects of psychosocial services in substance abuse treatment.

OBJECTIVE: To examine whether the addition of counseling, medical care, and psychosocial services improves the efficacy of methadone hydrochloride therapy in the rehabilitation of opiate-dependent patients. DESIGN: Random assignment to one of three treatment groups for a 6-month clinical trial: (1) minimum methadone services (MMS)--methadone alone (a minimum of 60 mg/d) with no other services; (2) standard methadone services (SMS)--same dose of methadone plus counseling; or (3) enhanced methadone services (EMS)--same dose of methadone plus counseling and on-site medical/psychiatric, employment, and family therapy. SETTING: The methadone maintenance program of the Philadelphia (Pa) Veterans Affairs Medical Center. SUBJECTS: Ninety-two male intravenous opiate users in methadone maintenance treatment. RESULTS: While methadone treatment alone (MMS) was associated with reductions in opiate use, 69% of these subjects had to be "protectively transferred" from the trial because of unremitting use of opiates or cocaine, or medical/psychiatric emergencies. This was significantly different from the 41% of SMS subjects and 19% of EMS subjects who met the criteria. End-of-treatment data (at 24 weeks) showed minimal improvements among the 10 MMS patients who completed the trial. The SMS group showed significantly more and larger improvements than did the MMS group; and the EMS group showed significantly better outcomes than did the SMS group. Minimum methadone services subjects who had been "protectively transferred" to standard care showed significant reductions in opiate and cocaine use within 4 weeks. CONCLUSIONS: Methadone alone (even in substantial doses) may only be effective for a minority of eligible patients. The addition of basic counseling was associated with major increases in efficacy; and the addition of on-site professional services was even more effective.

Desipramine treatment of cocaine dependence in methadone-maintained patients.

We performed a double-blind, placebo-controlled, randomized 12-week trial of desipramine hydrochloride treatment of cocaine dependence among methadone-maintained patients. Fifty-nine patients completed the 12-week medication trial (36 received desipramine and 23 received placebo), and 94% were recontacted 1, 3, and 6 months after treatment. There were significantly more dropouts in the desipramine than in the placebo group. Baseline to 12-week comparisons of Addiction Severity Index interview data indicated that both groups showed improvements. At 12 weeks, the desipramine group showed significantly better psychiatric status than the placebo group but did not differ from the placebo group on any of 21 other outcome measures, including cocaine use. During the 12-week medication phase and at the 1-month follow-up evaluation, urine toxicology screenings showed no significant difference between groups, but the placebo group had significantly less cocaine use at both the 3- and 6-month follow-up points. We conclude that desipramine has few benefits with regard to control of cocaine use in this population.

Effects of enzyme induction, renal and cardiac function on ketamine plasma kinetics in patients with ketamine long-term analgosedation.

Steady-state plasma levels of ketamine and its metabolites norketamine and dehydronorketamine were determined in 4 different groups of a total of 27 patients with ketamine long-term analgosedation (1.1 - 1.3 mg/kg/h). In 9 of the patients who had normal liver and kidney function (group 1), steady-state levels after 3 days of continuous infusion were 1.2 +/- 0.3 micrograms/ml ketamine, 1.0 +/- 0.6 micrograms/ml norketamine, and 2.6 +/- 1.0 micrograms/ml dehydronorketamine. The measured ketamine levels in group 1 were in agreement with the expected value, which may be calculated from published pharmacokinetic data after bolus injection. In 8 patients with acute renal failure (group 2), a tendency to about 20% higher ketamine steady-state plasma levels compared to group 1 was observed, but this difference was not significant. However, dehydronorketamine plasma levels were significantly higher in this group. Only a minor fraction of the ketamine dose (10% and 4%) was eliminated during hemodialysis or hemofiltration treatment, respectively. Steady-state plasma levels in 5 patients with cardiogenic shock (group 3) did not differ significantly from those of group 1. In 5 patients with long-term use of barbiturates (group 4), steady-state plasma levels of ketamine were significantly lower compared to groups 1 and 3, most likely due to barbiturate-induced enzyme induction. Hyperdynamic circulatory reactions were not observed in any of the patients. Psychomimetic effects could be excluded in 16 of the patients and were unlikely in 6 patients. In 5 further patients, psychomimetic effects could not definitely be excluded due to difficulties in non-verbal communication.

Increase in desipramine serum levels associated with methadone treatment.

Five men in a methadone treatment program who were also receiving desipramine had significantly higher desipramine serum levels when taking both drugs than when taking the antidepressant alone. Monitoring of desipramine serum levels may be useful with such patients.

Metabolic disposition of ajmaline.

Urine was collected from six patients receiving a continuous infusion of 20 mg/h ajmaline. Pooled urine was extracted with and without enzymatic conjugate cleavage or hydrolysis with concentrated hydrochloric acid. The extracts were analyzed by gas chromatography/mass spectrometry. Ajmaline and its metabolites in urine were identified in the form of their acetylated derivatives. Twenty two different acetylated derivatives of ajmaline and its metabolites could be detected. Three of these derivatives were artifacts generated by acetylation and/or thermal decomposition. The major metabolic pathways were mono- and di-hydroxylation of the benzene ring with subsequent O-methylation, reduction of the C-21, oxidation of the C-17 and C-21-hydroxyl function, N-oxidation, and a combination of these metabolic steps. Ajmaline and its metabolites were mainly excreted in the form of their conjugates. Furthermore, the interference of sparteine, debrisoquine, quinidine, and nifedipine with ajmaline metabolism was studied with semiquantitative thin-layer chromatography. Ajmaline metabolism was inhibited by co-administration of sparteine or quinidine, but not by debrisoquine or nifedipine. Sparteine most likely competed with ajmaline metabolism. Quinidine probably bound competitively to ajmaline-metabolizing enzymes without being metabolized itself. Additionally, the metabolic ratio of hydroxyajmaline/ajmaline in urine was determined in 9 extensive metabolizers and one poor metabolizer of dextromethorphan. The poor metabolizer had a significantly reduced metabolic ratio of hydroxyajmaline/ajmaline, which indicates that ajmaline metabolism probably co-segregates with polymorphic sparteine/debrisoquine/dextromethorphan metabolism.

Pharmacological and behavioral treatments of cocaine dependence: controlled studies.

The cocaine epidemic has stimulated novel treatments aimed at reducing relapse to this extremely addicting drug. After detoxification and standard treatment, former cocaine users continue to exhibit strong cocaine craving and physiological changes when presented with cocaine-related stimuli. Because these conditioned responses may increase the risk of relapse, a new treatment has been developed to extinguish such responses. The extinction process, consisting of repeated presentations of cocaine-related stimuli until the stimuli gradually lose their ability to evoke conditioned responses, is integrated into a comprehensive rehabilitation program. Cocaine dependence is often combined with opiate dependence. Desipramine has been added to methadone maintenance in an attempt to reduce dependence on both substances. Methadone impedes catabolism of desipramine so that relatively low doses of desipramine may produce antidepressant effects and possibly reduce the desire to use cocaine. Preliminary evidence from a placebo-controlled study of desipramine in combination with methadone suggests that desipramine produces significant improvements in psychological functioning, but its effects on reduction of cocaine use are less dramatic.

Urinary metabolism of chlorphenoxamine in man.

After an oral dose of 40 mg of 4-chlorophenyl-methylbenzyloxy-N,N-dimethyl-ethylamine(chlorphe noxamine, Systral) urinary metabolism was studied by gas chromatography/mass spectrometry. Besides the unchanged drug, 8 metabolites and 7 artifacts and derivates could be identified. Metabolism is similar to that of the structurally related antihistaminic drugs diphenhydramine and doxylamine. The main metabolic pathways are: 1. N-demethylation, 2. oxidative desamination and formation of an alcohol and a carbonic acid derivative, 3. cleavage of the ether bond, and 4. hydroxylation of the phenyl ring. For determination of chlorphenoxamine in plasma an assay using gas chromatography was developed. Chlorphenoxamine plasma levels were beyond the limit of detection (10 ng/ml) 30, 60, 120, 240, 480, and 1200 min after oral intake.

Acute tetrachloroethylene poisoning--blood elimination kinetics during hyperventilation therapy.

After ingestion of 12-16 g tetrachloroethylene, a 6-year-old boy was admitted to the clinic in coma. In view of the high initial tetrachloroethylene blood level, hyperventilation therapy was performed. Under this therapeutic regimen, the clinical condition of the patient improved considerably. The tetrachloroethylene blood level profile which was determined under hyperventilation therapy could be computer-fitted to a two-compartment model. Elimination of tetrachloroethylene from the blood compartment occurred via a rapid and a slow process with half-lives of 30 min and 36 hours, respectively. These values compared favourably with the half-lives of 160 min and 33 hours under normal respiratory conditions. During hyperventilation therapy, the relative contribution to the fast elimination process increased from 70% for physiological minute volume to 99.9%. A minor fraction of the ingested dose was excreted with the urine (integral of 1% during the first 3 days). In contrast to previous results, trace amounts of unchanged tetrachloroethylene were detected in the urine besides trichloroacetic acid and trichloroethanol.

Naltrexone: a clinical perspective.

The narcotic antagonist naltrexone was studied in over 300 opiate addicts. Patient selection was a major factor in determining retention and treatment outcome. Treatment time ranged from 1 week to over a year (mean = 2 months). A quarter of the study patients had multiple treatment episodes. Stabilized patients had few side effects, except for occasional nausea and abdominal cramps. Almost half the subjects tested naltrexone by using opiates at least once; all reported satisfactory narcotic blockade. Very few subjects switched to nonopiates to get high, although several did increase their alcohol consumption during the first weeks of therapy. One-third of subjects contacted in a follow-up study were opiate-free 6 months after stopping naltrexone, indicating a successful short-term treatment modality.