Reversal of diminished inhibitory sensory gating in cocaine addicts by a nicotinic cholinergic mechanism.

Cocaine addiction, as with other stimulant abuse, produces psychotic symptoms. Although often moderate to mild in severity, these symptoms are, nevertheless, associated with poorer over-all outcome. Recent studies suggest diminished nicotinic cholinergic neurotransmission as a mechanism of a physiological deficit found in schizophrenia, failure of auditory sensory inhibition. Diminished inhibitory sensory gating also occurs in cocaine addicts, probably because of their increased catecholaminergic neurotransmission, which blocks the inhibition. In the present study, 11 cocaine addicts in the first week of detoxification were recorded electrophysiologically, after which the effects of 6 mg of nicotine gum, were assessed in a double-blind placebo-controlled crossover design. The test was repeated 10 days later. Treatment with nicotine, but not placebo, briefly reversed the inhibitory abnormality on both test days. Although nicotine itself may not be a desirable therapeutic agent, because desensitization of nicotinic receptors limits the time course of its effect, the study identifies a previously unexploited therapeutic target for new drug development for the neuropsychiatric sequelae of cocaine addiction.

Thrice-weekly supervised dosing with the combination buprenorphine-naloxone tablet is preferred to daily supervised dosing by opioid-dependent humans.

A sublingual tablet formulation of buprenorphine combining 8 mg of buprenorphine with 2 mg of naloxone is being targeted for use in settings where less than daily dosing strategies and/or prescription-based dispensing will likely be employed. This study determined patient preferences for, and clinical outcomes during, daily and 3-day per week supervised dosing schedules using the combination tablet. Twenty-four opioid-dependent subjects completing a 16-day baseline entered an outpatient triple crossover trial. Twenty-one days of daily dosing were compared to two different 21-day periods of 3-day per week supervised dosing: a 3-day per week clinic schedule and a 3-day per week take-home schedule in which tablets were provided to subjects to take at home on days between clinic visits. Thirteen patients completed the study. Significantly more doses were ingested under the 3-day per week schedules. Illicit drug use did not differ across conditions and 45% of urine samples tested positive for illicit opioids. Subjects 'liked' both 3-day per week schedules more than the daily schedule, and ratings of feeling 'good' were higher for the 3-day take-home as opposed to 3-day clinic condition. Almost all subjects (91%) rated 3-day take-home as the most preferred schedule. Overall, reducing clinic attendance improved medication compliance and increased client satisfaction without impacting illicit drug use.

Efficacy of daily and alternate-day dosing regimens with the combination buprenorphine-naloxone tablet.

This study evaluated the efficacy of a combination tablet formulation of buprenorphine containing 8 mg of buprenorphine and 2 mg of naloxone for every other day treatment and whether increasing the daily maintenance dose was essential for maintaining an efficacious alternate-day treatment. Twenty-six opioid-dependent outpatients completing a 16-day baseline entered a double-blind, placebo-controlled, triple crossover trial. Twenty-one days of daily combination tablet administration were compared to two different 21-day periods of alternate-day buprenorphine administration where subjects received either 8 or 16 mg of the combination tablet every other day with placebo on the interposed day. Fifty-four percent (14/26) of subjects completed the study, but only two subjects dropped out during the 16-mg alternate-day condition. Rates of medication compliance, illicit opioid use and subject- and observer-rated measures of opioid effects did not distinguish daily from alternate-day treatments in subjects completing the study. However, pupillary diameter was significantly increased during 8-mg alternate-day compared to the 8-mg daily or 16-mg alternate-day treatment. These data replicate earlier findings describing the acceptability of alternate-day buprenorphine treatment using multiples of the daily maintenance dose and extend these findings by establishing the clinical efficacy of daily and alternate-day dosing regimens with the combination buprenorphine naloxone tablet. This study also suggests slightly improved outcomes during alternate-day treatment using multiples of the daily dose.

Buprenorphine dosing every 1, 2, or 3 days in opioid-dependent patients.

RATIONALE: Administration of double the maintenance dose of buprenorphine has been shown to permit every-other-day dosing. Whether longer periods between dosing can be achieved is unknown. OBJECTIVES: To examine whether triple the maintenance dose can be administered every 72 h without opioid withdrawal or intoxication. METHODS: Sixteen opioid-dependent outpatients each received three conditions (1) the maintenance dose of buprenorphine every 24 h, (2) double the maintenance dose every 48 h, and (3) triple the maintenance dose every 72 h under double-blind placebo-controlled conditions. Each conditions was imposed in a random sequence for 21-22 days. Self report and observer measures were taken at 24-h intervals. RESULTS: No significant differences were observed on measures of opioid agonist and withdrawal effects between the dosing conditions. However, averaging effects across conditions may obscure important within-condition effects. When conditions were analyzed by individual days within a condition, several significant effects were observed. For example, 24 h after administration of triple the maintenance dose, significant effects were observed in eight opioid agonist measures. Also, 72 h after administration of triple the maintenance dose, significant effects were observed on four measures of withdrawal. Neither adverse medical reactions nor excessive opioid intoxication were observed. CONCLUSIONS: These results suggest that buprenorphine may be administered safely every 72 h by tripling the maintenance dose, with only minimal withdrawal complaints. Importantly, this 72-h dosing may permit patients to attend clinic thrice weekly without the use of take-home doses.

Behavioral and emotional problems among children of cocaine- and opiate-dependent parents.

OBJECTIVE: To test associations between parental drug abuse and children's problems, children of cocaine- and opiate-dependent parents were compared with demographically matched referred and nonreferred children. METHOD: Cocaine- and opiate-dependent parents in treatment completed the Child Behavior Checklist for 410 children (218 boys, 192 girls) from ages 2 through 18 years (mean = 7.9 years). Children of drug abusers (CDAs) were demographically matched to referred (RCs) and nonreferred children (NRCs). RESULTS: RCs scored lower than CDAs and NRCs on most competence scales, and higher than CDAs and NRCs on all problem scales. CDAs scored lower than NRCs on most competence scales, and higher than NRCs on Withdrawn, Thought Problems, Delinquent Behavior, Aggressive Behavior, Internalizing, Externalizing, and Total Problems. Group status also predicted clinical range scores on most competence and all problem scales. CONCLUSIONS: CDAs showed more internalizing and externalizing psychopathology relative to matched NRCs, but they showed significantly less psychopathology than shown by matched RCs. CDAs are an important group to target for preventive interventions.

Marijuana use and treatment outcome among opioid-dependent patients.

AIMS: Information concerning the association between marijuana use and opioid dependence and its treatment is needed to determine effective clinical guidelines for addressing marijuana use among opioid abusers. SETTING AND PARTICIPANTS: Marijuana use was assessed in 107 people enrolled in treatment for opioid dependence. DESIGN AND MEASUREMENT: Univariate comparisons of marijuana users and non-users and multivariate regression analyses were performed to examine associations between marijuana use and socio-demographic, psychosocial, medical and substance-use variables. The relationship between marijuana use and treatment outcome was also explored in a subset of this sample who received treatment that included buprenorphine detoxification and behavior therapy (N = 79). FINDINGS: Sixty-six per cent of participants were current marijuana users and almost all (94%) continued to use during treatment. Users were less likely to be married than non-users, and more likely to report financial difficulties, be involved in drug dealing and engage in sharing of needles (p < 0.05). A unique effect of marijuana use on drug dealing and sharing needles was retained after statistically controlling for the influence of heroin and alcohol use and other socio-demographic variables. No significant adverse relations were observed between marijuana use and treatment outcome. CONCLUSION: Pending a more comprehensive understanding of the function and consequences of marijuana use on psychosocial functioning, it appears that progress in treatment for opioid dependence can be made without mandating that patients abstain from marijuana use.

Alternate-day buprenorphine dosing is preferred to daily dosing by opioid-dependent humans.

Alternate-day buprenorphine dosing was compared to daily dosing in opioid-dependent outpatients and choice of alternate-day versus daily dosing was assessed. Four dosing schedules were presented in random order under blind and open dosing conditions. Subjects received two exposures to each dosing schedule. During daily dosing, subjects received maintenance doses every 24 h. During blind alternate-day dosing, subjects received double maintenance doses every 48 h; placebo was interposed on intervening days. During open alternate-day dosing, subjects received twice their maintenance dose on Monday, Wednesday and Friday and maintenance doses on Sunday. After completing two exposures to each dosing schedule, subjects chose either daily or alternate-day schedules each week for 1 month. Study participation was contingent on daily attendance and opioid abstinence. Ten subjects were exposed to the four conditions once. Seven subjects repeated these conditions and participated in the choice phase. The effects of daily versus alternate-day dosing were not influenced by blind or open dosing conditions. Subjects' ratings of withdrawal, "sick" and sedation were lower during daily than during alternate-day dosing, but the difference between treatments was small. Nonetheless, subjects still chose alternate-day dosing on 96% of occasions, suggesting that the subject-rated differences between dosing schedules were not influential. These results extend prior findings to open-dosing conditions, and replicate the safety and acceptability of alternate-day buprenorphine treatment. Choice of alternate-day buprenorphine administration underscores the procedure's clinical utility and potential use as a positive reinforcer to enhance opioid treatment.

Determination of buprenorphine in human plasma by gas chromatography-positive ion chemical ionization mass spectrometry and liquid chromatography-tandem mass spectrometry.

Buprenorphine is used for the management of pain and has been advocated for the treatment of opioid addiction. Therapeutic doses result in low plasma concentrations of buprenorphine. In order to assess the safety and efficacy of buprenorphine, sensitive analytical methods are needed. Until recently, gas chromatography-positive ion chemical ionization mass spectrometry (GC-PCI-MS) offered the most sensitive method to selectively quantitate buprenorphine. We have developed and validated a sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS-MS) method for buprenorphine. The method is described and compared with a GC-PCI-MS method validated in this laboratory. One-milliliter aliquots of plasma are required for the LC-ESI-MS-MS method and 2-mL aliquots for the GC-PCI-MS method. Buprenorphine-d4 is used as internal standard for both methods. Derivatization with pentafluoropropionic acid anhydride is used for the GC-PCI-MS method, in which the derivatized protonated molecular ions after loss of water are monitored at m/z 596 and 600. For LC-ESI-MS-MS, the parent protonated molecule ions are monitored at m/z 468 and 472. A single-step extraction of basic plasma with n-butyl chloride provided recoveries of 70-87%. Although a limit of quantitation (LOQ) of 0.1 ng/mL could be established for LC-ESI-MS-MS, we could only achieve an LOQ of 0.5 ng/mL with the GC-PCI-MS assay. The GC-PCI-MS method has a linear range of 0.5 to 40 ng/mL (mean r2 = 0.998, n = 7). For quality control samples at 1.0, 2.5, and 12.5 ng/mL, the intra- and interassay coefficients of variation (CV) did not exceed 14%, and percent of targets were within 16%. The LC-ESI-MS-MS method had a linear range of 0.1 to 10 ng/mL (mean r2 = 0.999, n = 7). For quality control samples at 0.25, 2.5 and 7.5 ng/mL, the intra- and interassay CVs did not exceed 4%, and percent of targets were within 12%. Stability studies demonstrated buprenorphine was stable for up to 24 h, 125 days, and 55 days when stored at room temperature, 4 degrees C, and -20 degrees C, respectively. The utility of the lower LOQ was demonstrated in 40 plasma samples collected up to 96 h after a sublingual dose of buprenorphine; 10 were quantitatable using GC-PCI-MS and 38 using LC-ESI-MS-MS.

Effects of adding behavioral treatment to opioid detoxification with buprenorphine.

This trial assessed whether behavioral treatment improves outcome during a 26-week outpatient opioid detoxification. Thirty-nine opioid-dependent adults were assigned randomly to a buprenorphine dose-taper combined with either behavioral or standard treatment. Behavioral treatment included (a) a voucher incentive program for providing opioid-free urine samples and engaging in verifiable therapeutic activities and (b) the community reinforcement approach, a multicomponent behavioral treatment. Standard treatment included lifestyle counseling. Fifty-three percent of the patients receiving behavioral treatment completed treatment, versus 20% receiving standard treatment. The percentage of patients achieving 4, 8, 12, and 16 weeks of continuous opioid abstinence were 68, 47, 26, and 11 for the behavioral group and 55, 15, 5, and 0 for the standard group, respectively. Behavioral treatment improved outcomes during outpatient detoxification.

Preferences for clinic privileges, retail items and social activities in an outpatient buprenorphine treatment program.

This study evaluated preferences for various clinic privileges, retail items, and social activities for use in an outpatient opioid dependence treatment program. Fifty-three opioid-dependent patients who received treatment with buprenorphine for at least 30 days rank ordered 11 clinic privileges, 19 retail items, and 8 social activities from the most desirable (a rank of 1) to the least desirable (a rank equal to the number of items in that category). Additional questions determined preference for counseling frequency and dosing levels. The top three mean rankings for clinic privileges were $50 cash for opioid-negative urines (2.8), take-home doses of buprenorphine (3.6), and voucher points for opioid-negative urines (4.7). The top three mean rankings for retail items were restaurant gift certificates (4.1), movie passes (4.9), and videotape movie and player rentals (6.8). The top three mean rankings for social activities were movies (2.4), barbecues (3.8), and hiking trips (4.3). There was no preference reported for increases or decreases in counseling frequency. Seventy-four percent of subjects preferred to increase their buprenorphine dose by an average of 60.84% independent of their present dose. Consistent with previous findings from methadone treatment, cash payments for opioid-negative urines and take-home medication were the highest ranked clinic privileges. These results suggest that various retail items and social activities may also be useful for reinforcing positive treatment outcomes during outpatient opioid treatment.

A preliminary investigation of outcome following gradual or rapid buprenorphine detoxification.

Eight opioid-dependent individuals were maintained on daily sublingual buprenorphine (8 mg) for 28 days and assigned randomly to one of two outpatient detoxification schedules under double-blind, double-dummy conditions. The two detoxification schedules were buprenorphine gradual (36 days; N = 3) or buprenorphine rapid (12 days; N = 5). Outcome variables were subject- and observer-ratings of opioid withdrawal, treatment retention and illicit-opioid use. Outcome measures were similar for the two groups during buprenorphine maintenance. Increases in subject-rated opioid withdrawal and illicit-opioid use, and a drop in treatment retention occurred during rapid detoxification. Stable subject-rated opioid withdrawal and treatment retention, and less illicit-opioid use occurred during gradual detoxification. These data suggest that gradual reduction in buprenorphine dose is likely to produce superior treatment outcomes than more rapid buprenorphine detoxification.

Alternate-day dosing during buprenorphine treatment of opioid dependence.

Thirteen opioid-dependent outpatients participated in a double-blind, placebo-controlled, crossover trial. Twenty-one days of daily sublingual buprenorphine administration were compared to 21-days of alternate-day buprenorphine administration where patients received twice their daily maintenance dose every other day with placebo on the interposed day. Observer- and subject-rated measures of opioid agonist and withdrawal effects, pupillary diameter, and dose identifications were collected daily. Ten subjects (77%) completed the study (n = 6, 4 mg/70 kg; n = 4, 8 mg/70 kg); 8 subjects (62%) participated in a second crossover. Sixteen of seventeen measures of opioid agonist and withdrawal effects obtained during alternate-day administration did not differ significantly from those obtained during daily dosing in the ten subjects completing the study. The only significant difference observed was in subject-rated agonist effects, which were significantly lower during alternate-day than daily administration. No differences were observed between treatments on any measure for the eight subjects completing a second crossover. These data suggest that buprenorphine can be administered safely every 48 hours by doubling the maintenance dose. This alternate-day schedule permits patients to attend the clinic less frequently without the risk of diversion associated with take-home doses, may be cost-effective for programs, and may be useful in settings in which travel to the clinic is a barrier to treatment.

The taking of free condoms in a drug abuse treatment clinic: the effects of location and posters.

Drug abuse treatment programs can help reduce high-risk sexual behavior in drug users by promoting condom use. This study examined the influence of distribution location and poster prompts on the taking of free condoms in a drug abuse treatment clinic. Over 6 months, condoms were available alternately, with and without poster prompts, in the clinic's private restroom or public waiting area. Overall, 381% more condoms were taken from the restroom. The presence of poster prompts did not affect condom taking. These results suggest that distribution location is a critical factor in promoting condom taking in public clinic.

The relationship of mean daily blood alcohol levels to admission MAST, clinic absenteeism and depression in alcoholic methadone patients.

Alcoholism is a prevalent problem encountered during the methadone treatment of opioid dependence. The unique feature of examining alcoholism in methadone clinics is the ability to objectively measure alcohol consumption on a frequent basis. The present study examined how blood alcohol level (BAL) relates to clinic absenteeism and whether any paper and pencil tests predict BAL in alcoholic methadone patients. Thirty-eight alcoholic methadone patients receiving outpatient treatment had their BALs assessed over consecutive 5-day periods for a period of 2 months. The relationship of these BALs to several measures, including the Michigan Alcohol Screening Test (MAST), Beck Depression Inventory (BDI), clinic absenteeism and methadone dose was assessed. Significant positive correlations between mean BAL and admission MAST, mean BAL and clinic absenteeism, and MAST and BDI were observed. Methadone dose tended to be inversely correlated with mean BAL. These findings demonstrate that the MAST predicts mean BAL and that mean BAL is an objective predictor of clinic absenteeism in alcoholic methadone patients. Moreover, the results illustrate the usefulness of methadone clinics as a setting to investigate alcohol abuse and dependence.

Marihuana attenuates the rise in plasma ethanol levels in human subjects.

This study was conducted to determine if plasma ethanol levels are altered as a result of smoking marihuana. Fifteen healthy adult male volunteers who used ethanol and marihuana on a casual basis participated in this study. Subjects were randomly assigned to one of three groups: placebo, low-dose, or high-dose marihuana. The marihuana dose was held constant and each subject drank three different doses of ethanol on 3 separate days spaced at least 1 week apart. Subjects drank either placebo or ethanol at doses of 0.35 g/kg (7.60 mmol/kg) or 0.70 g/kg (15.19 mmol/kg). Thirty minutes after drinking they smoked either a placebo marihuana cigarette, or one containing either 1.26% or 2.53% delta 9-tetrahydrocannabinol. Plasma ethanol levels rose sharply after the 0.7 g/kg dose and peaked at 50 minutes after drinking began (78.25 +/- 4.95 mg/dl). When subjects smoked the high-dose marihuana cigarettes after the 0.7 g/kg dose of ethanol, peak plasma ethanols levels were only 54.80 +/- 8.32 mg/dl at 105 minutes after drinking began. These alterations in plasma ethanol levels paralleled a reduction in the duration of ethanol- and marihuana-induced subjective effects after high doses of both drugs. These data suggest that marihuana may alter ethanol bioavailability.

Quantitative magnetic resonance imaging in heroin- and cocaine-dependent men: a preliminary study.

Quantitative magnetic resonance imaging (MRI) of the brain was performed in nine drug-dependent men with a primary diagnosis of opioid and/or cocaine dependence, and 10 age-matched, non-drug-dependent controls. Individuals were screened for the presence of gross cerebral abnormalities before T1 and T2 analyses. Regional T1 and T2 times were calculated on a single 5-mm thick axial slice positioned just below the caudal margin of the lateral ventricles, passing through the caudate and putamen. A voxel of interest (VOI) cursor was placed bilaterally within the putamen, caudate, frontal gray matter, frontal white matter, or posterior white matter. T1 and T2 values were determined for each VOI using an iterative chi 2 minimization program. T1 and T2 relaxation times did not differ significantly between the subject groups in any brain region studied. These results suggest that T1 and T2 relaxation times may not identify microstructural central nervous system changes resulting from chronic opiate and cocaine abuse.

Ethanol-induced alterations in EEG alpha activity and apparent source of the auditory P300 evoked response potential.

The relationship among topographic brain electrical activity mapping, auditory-evoked response potentials (ERPs), plasma ethanol levels and subjective reports of intoxication was examined in 4 male volunteers. The source of the auditory P300 ERP (a measure of selective attention and memory encoding) was estimated using a recently developed computer program. The effect of ethanol on the P300 wave was studied using a standard oddball paradigm both with and without a concomitant divided attention task. Ethanol (0.7 g/kg) administration produced marked increases in EEG alpha activity during the ascending limb of the blood ethanol curve. Acute ethanol administration caused a delay in the latency and a reduction in the amplitude of the auditory P300 ERP. A similar effect on P300 topography was noted in waves that were affected by the tones while the subjects also listened to a story (divided attention). After ethanol, the source of the P300 wave appeared to have shifted to a position posterior and inferior to its original location. P300 ERP's generated during the divided attention task were also disrupted and shifted to positions inferior to their original. However, the variability of the dipole vector was much greater during the divided attention task than after ethanol administration. These data demonstrate that ethanol's effects on cognitive processing skills may be similar to those produced when individuals experience distractions while concentrating on a task.