Faculty Bibliography

OBJECTIVE:Computer-delivered interventions have the potential to improve access to quality addiction treatment care. The objective of this study was to evaluate the effectiveness of the Therapeutic Education System (TES), an Internet-delivered behavioral intervention that includes motivational incentives, as a clinician-extender in the treatment of substance use disorders. METHOD/METHODS:Adult men and women (N=507) entering 10 outpatient addiction treatment programs were randomly assigned to receive 12 weeks of either treatment as usual (N=252) or treatment as usual plus TES, with the intervention substituting for about 2 hours of standard care per week (N=255). TES consists of 62 computerized interactive modules covering skills for achieving and maintaining abstinence, plus prize-based motivational incentives contingent on abstinence and treatment adherence. Treatment as usual consisted of individual and group counseling at the participating programs. The primary outcome measures were abstinence from drugs and heavy drinking (measured by twice-weekly urine drug screens and self-report) and time to dropout from treatment. RESULTS:Compared with patients in the treatment-as-usual group, those in the TES group had a lower dropout rate (hazard ratio=0.72, 95% CI=0.57, 0.92) and a greater abstinence rate (odds ratio=1.62, 95% CI=1.12, 2.35). This effect was more pronounced among patients who had a positive urine drug or breath alcohol screen at study entry (N=228) (odds ratio=2.18, 95% CI=1.30, 3.68). CONCLUSIONS:Internet-delivered interventions such as TES have the potential to expand access and improve addiction treatment outcomes. Additional research is needed to assess effectiveness in non-specialty clinical settings and to differentiate the effects of the community reinforcement approach and contingency management components of TES.

There is preclinical support for using NMDA receptor glutamatergic antagonists to aid in naltrexone-based treatment of opioid dependence. We hypothesized that adding memantine will improve efficacy of extended-release (XR) naltrexone to prevent relapse. In this double blind study opioid-dependent participants (N=82) underwent inpatient detoxification and naltrexone induction. During naltrexone initiation participants were randomized to receive memantine 40 mg or placebo and continued treatment for 12-weeks with XR naltrexone and relapse-prevention therapy. Sixty eight percent of participants completed detoxification and received the first dose of XR naltrexone. Rates of trial completion were significantly greater in participants receiving placebo than memantine (70% vs. 43%, p<0.05). Severity of opioid withdrawal symptoms during the first 3 weeks of the trial appeared to be lower in the group receiving memantine (p=0.07). Adding memantine does not appear to increase the effectiveness of injectable XR naltrexone as a relapse prevention strategy in opioid dependence and may lead to an increase in treatment drop-out.

OBJECTIVE:This study tested the hypothesis that the antidepressant venlafaxine would be an effective treatment for cocaine abusers with concurrent depressive disorders. METHODS:This was a randomized, 12-week, double-blind, placebo-controlled trial of outpatients (N = 130) meeting DSM-IIIR criteria for cocaine dependence and major depression or dysthymia (by SCID interview). Participants were treated with venlafaxine, up to 300 mg/day versus placebo. All patients received weekly individual manual-guided relapse prevention therapy. Weekly outcome measures included Clinical Global Impression Scale (CGI), self-reported cocaine use, urine toxicology and the Hamilton Depression Scale (Ham-D). RESULTS:Mood response, defined as a 50% reduction in the Ham-D between randomization and end of study, was 41% (26/64) on venlafaxine, and 33% (22/66) on placebo (p = .39). Measures of depression (Ham-D and CGI) improved more rapidly on venlafaxine than placebo, but these differences disappeared by weeks 6-8. Cocaine outcomes did not differ between treatment groups, and the proportion of patients achieving three or more consecutive weeks of urine-confirmed abstinence was low (venlafaxine: 16%; placebo: 15%). Reduction in cocaine use was associated with mood response. CONCLUSIONS:Overall, venlafaxine was not superior to placebo on either mood or cocaine use outcomes. Mood improvement was associated with improvement in cocaine use. However, placebo mood response was only moderate, and the proportion of patients achieving sustained abstinence was low. This suggests that the subgroup of cocaine-dependent patients with depressive disorders is relatively treatment resistant, and that further research is needed to improve outcomes for these patients.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Hypothesizing that stress dysregulation may worsen cocaine dependence, we investigated the effect of diurnal cortisol secretion profile, suppression of cortisol secretion, and total cortisol secretion on retention, abstinence-based voucher earnings, days of cravings, and mood status of participants at the end of a 2-week medication-free lead-in prior to randomization in a clinical trial of mirtazapine (60 mg vs. placebo) for depressed cocaine-dependent patients. METHODS:We measured saliva cortisol levels at 9 AM, 2 PM, and 5 PM on the first two consecutive days of a 2-week medication-free lead-in period. Results from saliva samples were used to estimate the total daily level of cortisol, the diurnal profile of secretion (typical vs. atypical), and response to dexamethasone suppression (.1 mg). Seventy-seven patients collected saliva samples at baseline, and 65 (85%) were suitable for profile analysis. RESULTS:Patients with typical profiles (52%) collected significantly more abstinence-based voucher earnings during the lead-in (U = 299.50, p = .025). Diurnal secretion profile did not significantly affect mood status, days of craving, or retention. There were no significant effects of suppression of cortisol secretion or of total cortisol levels on any outcome measures. CONCLUSION/CONCLUSIONS:In a subgroup of cocaine-dependent patients, deviation of cortisol secretion away from the homeostatic diurnal pattern was associated with reduced success at achieving early abstinence, an important determinant of treatment success.

BACKGROUND: Cocaine dependence involves problematic neuroadaptations that might be responsive to modulation of glutamatergic circuits. This investigation examined the effects of subanesthetic ketamine infusions on motivation for quitting cocaine and on cue-induced craving in cocaine-dependent participants, 24 hours postinfusion. METHODS: Eight volunteers with active DSM-IV cocaine dependence not seeking treatment or abstinence were entered into this crossover, double-blind trial. Three 52-min intravenous infusions were administered: ketamine (.41 mg/kg or .71 mg/kg) or lorazepam 2 mg, counterbalanced into three orderings in which ketamine .41 mg/kg always preceded the .71 mg/kg dose. Infusions were separated by 48 hours, and assessments occurred at baseline and at 24 hours postinfusion. Outcomes were change between postinfusion and preinfusion values for: 1) motivation to quit cocaine scores with the University of Rhode Island Change Assessment; and 2) sums of visual analogue scale craving ratings administered during cue exposure. RESULTS: Compared with the active control lorazepam, a single ketamine infusion (.41 mg/kg) led to a mean 3.9-point gain in University of Rhode Island Change Assessment (p = .012), which corresponds to an approximately 60% increase over preceding values. There was a reduction of comparable magnitude in cue-induced craving (p = .012). A subsequent ketamine infusion (.71 mg/kg) led to further reductions in cue-induced craving compared with the control. Infusions were well-tolerated. CONCLUSIONS: Subanesthetic ketamine demonstrated promising effects on motivation to quit cocaine and on cue-induced craving, 24 hours postinfusion. Research is needed to expand on these preliminary results and to evaluate the efficacy of this intervention in clinical settings.

BACKGROUND:Noncompliance with medications may have major impacts on outcomes measured in research, potentially distorting the validity of controlled clinical trials. Riboflavin is frequently used in trials as a marker of adherence. It can be combined with study medication and is excreted in urine where it fluoresces under UV light. This study compares qualitative visual inspection of fluorescence to quantitative fluorometric analysis of riboflavin concentration in its ability to detect the presence of riboflavin in urine. METHODS:Twenty-four volunteers received 0mg, 25mg, and 50mg doses of riboflavin under single-blind conditions, with 20 also receiving a 100mg dose. Five serial urine samples were collected over the following 36h. Quantitative measurement of riboflavin by fluorometric analysis and qualitative assessment of each sample using visual inspection were performed. RESULTS:The overall false positive rate for qualitative assessment was 53%. For quantitative assessment, a riboflavin concentration of 900ng/mL was established to classify positive samples. More than 80% of samples were positive 2-24h following ingestion of 25mg and 50mg, and less than 80% were positive at 36h. At least 95% of observations for the 100mg dose were above 900ng/mL at all timepoints. CONCLUSIONS:Quantitative fluorometric assessment is superior to qualitative visual inspection alone in determining medication adherence. The combination of 25-50mg of daily riboflavin and a cut-off level of 900ng/mL allows for the acceptable sensitivity of missing detection of non-compliant participants while preserving a high level of power to detect all cases of medication compliance.

OBJECTIVE:To determine whether treatment of attention-deficit/hyperactivity disorder (ADHD) with osmotic-release oral system (OROS) methylphenidate promotes abstinence from smoking among smokers with ADHD who have greater severity of ADHD symptoms at baseline or greater improvement in ADHD during treatment. METHOD/METHODS:This is a secondary analysis of data from a randomized, double-blind, 11-week trial conducted between December 2005 and January 2008 at 6 clinical sites; the original trial was sponsored by the National Drug Abuse Clinical Trials Network. Adult cigarette smokers (aged 18-55 years) who met DSM-IV criteria for ADHD were randomly assigned to OROS methylphenidate (72 mg/d) (n = 127) or matching placebo (n = 128). All participants received nicotine patches (21 mg/d) and weekly individual smoking cessation counseling. Logistic regression was used to model prolonged abstinence from smoking (ascertained by self-report and breath carbon monoxide testing) as a function of treatment, baseline ADHD Rating Scale-IV (ADHD-RS) score, change in ADHD-RS score during treatment, and their interactions. RESULTS:Treatment interacted with both ADHD-RS score at baseline (P = .01) and change in ADHD-RS score during treatment (P = .008). Among patients with higher ADHD-RS scores (> 36) at baseline and the most improvement in ADHD during treatment (ADHD-RS change score ≥ 24), 70.0% of those who took OROS methylphenidate achieved abstinence from smoking compared to 36.8% of those who took placebo (P = .02). In contrast, among patients with the lowest ADHD-RS baseline scores (≤ 30), 30.3% of those who took OROS methylphenidate achieved abstinence from smoking compared to 60.7% of those who took placebo (P = .02). CONCLUSIONS:OROS methylphenidate, in combination with nicotine patch, may be an effective treatment for nicotine dependence among smokers with more severe ADHD and more robust response of ADHD symptoms to medication. OROS methylphenidate may be counterproductive among smokers with lower severity of ADHD. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier: NCT00253747.

OBJECTIVE:This study examines sociodemographic and clinical characteristics, as a function of primary substance of abuse, among clients approached, screened, and assessed for eligibility in a 10-site effectiveness trial of a Web-based psychosocial intervention for substance use disorders. Consistent with the design of effectiveness trials, eligibility criteria were broad and exclusion criteria minimal; thus, the recruited sample may be viewed as relatively representative of patients seeking treatment throughout the United States. METHODS:χ tests for categorical variables and F tests for continuous variables were used to analyze demographic, substance use, physical and mental health, and sexual risk data collected at screening and baseline; pairwise comparisons between primary substance subgroups for baseline data were conducted if the test statistic P value was 0.01 or less. RESULTS:Few participants expressed disinterest in the study at screening because of the computer-assisted intervention. A diverse sample of substance users completed baseline and were enrolled: 22.9% marijuana; 21.7% opiates; 20.9% alcohol; 20.5% cocaine; and 13.9% stimulants users. Marijuana users demonstrated the greatest differences across primary substances: they were younger, less likely to be married or attend 12-step meetings, and more likely to be in treatment as a result of criminal justice involvement. All patients, even marijuana users, reported comparable rates of co-occurring mental health disorders and sexual risk and substantial rates of polysubstance use disorders. CONCLUSIONS:Primary substance of abuse may be a less important indicator of overall severity compared with co-occurring disorders and other factors common across treatment seekers, further demonstrating the need for integrated treatment services and care and comprehensive pretreatment assessment.

BACKGROUND:FDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use ("testing the blockade") fail to produce reinforcement. We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups. METHODS:An 8-week, double-blind, placebo-controlled trial (N=57), compared the efficacy of low (192 mg) and high (384 mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment. RESULTS:Interaction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo. CONCLUSIONS:Findings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems.