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1.  A Pilot Study of Community-Friendly Manual Guided Drug Counseling 
To facilitate effectiveness testing and dissemination of treatments to community based setting, therapist training manuals that are more “community friendly” are needed. The aim of the current project was to create revised versions of individual drug counseling (IDC) and group drug counseling (GDC) treatment manuals for cocaine dependence and to conduct a preliminary study of their effectiveness. After changing the format and context of existing drug counseling manuals to have greater ease of use in the community, draft manuals were given to 23 community-based counselors for their feedback. Final versions were then used in a pilot randomized clinical trial involving 41 cocaine dependent patients who received 3 months of either IDC + GDC or GDC alone treatment. Counselors implemented the new treatment manuals with acceptable levels of adherence and competence. Outcome results indicated that substantial change in drug use was evident, but the amount of abstinence obtained was limited.
doi:10.1016/j.jsat.2008.09.004
PMCID: PMC2744318  PMID: 19038525
Cocaine dependence; drug counseling; randomized trial
2.  A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence 
Drug and alcohol dependence  2013;133(1):94-99.
BACKGROUND
Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs.
METHODS
The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings.
RESULTS
Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate.
DISCUSSION
Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.
doi:10.1016/j.drugalcdep.2013.05.026
PMCID: PMC3786029  PMID: 23810644
topiramate; cocaine; alcohol; clinical trial; placebo
3.  An Adaptive Approach for Identifying Cocaine Dependent Patients Who Benefit from Extended Continuing Care 
Objective
Study tested whether cocaine dependent patients using cocaine or alcohol at intake or in the first few weeks of intensive outpatient treatment would benefit more from extended continuing care than patients abstinent during this period. The effect of incentives for continuing care attendance was also examined.
Methods
Participants (N=321) were randomized to: treatment as usual (TAU), TAU and Telephone Monitoring and Counseling (TMC), or TAU and TMC plus incentives (TMC+). The primary outcomes were: (1) abstinence from all drugs and heavy alcohol use, and (2) cocaine urine toxicology. Follow-ups were at 3, 6, 9, 12, 18, and 24 months.
Results
Cocaine and alcohol use at intake or early in treatment predicted worse outcomes on both measures (ps≤ .0002). Significant effects favoring TMC over TAU on the abstinence composite were obtained in participants who used cocaine (OR=1.95 [1.02, 3.73]) or alcohol (OR=2.47 [1.28, 4.78]) at intake or early in treatment. A significant effect favoring TMC+ over TAU on cocaine urine toxicology was obtained in those using cocaine during that period (OR= 0.55 [0.31, 0.95]). Conversely, there were no treatment effects in participants abstinent at baseline, and no overall treatment main effects. Incentives almost doubled the number of continuing care sessions received, but did not further improve outcomes.
Conclusion
An adaptive approach for cocaine dependence in which extended continuing care is provided only to patients who are using cocaine or alcohol at intake or early in treatment improves outcomes in this group while reducing burden and costs in lower risk patients.
doi:10.1037/a0034265
PMCID: PMC3938091  PMID: 24041231
cocaine dependence; continuing care; adaptive treatment; incentives; moderators
4.  Predictors of Treatment Outcome in Outpatient Cocaine and Alcohol Dependence Treatment 
We examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine- and alcohol-dependent and were selected for a randomized, double-blind, placebo-controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self-reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self-reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine-dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials.
doi:10.1080/10550490802545174
PMCID: PMC3777818  PMID: 19219669
5.  Achieving smoking abstinence is associated with decreased cocaine use in cocaine-dependent patients receiving smoking-cessation treatment 
Drug and alcohol dependence  2013;134:391-395.
Background
Past research suggests that a significant relationship exists between cigarette smoking and illicit-stimulant abuse. The present study evaluated the association between achieving smoking abstinence in response to smoking-cessation treatment (SCT) and illicit-stimulant abstinence in cocaine- and/or methamphetamine-dependent participants.
Methods
Secondary analysis of a randomized, 10-week trial conducted at 12 substance use disorder (SUD) treatment programs. Two hundred and sixty seven adults, meeting DSM-IV-TR criteria for cocaine and/or methamphetamine-dependence and interested in quitting smoking were randomized to SUD treatment as usual plus SCT consisting of weekly individual smoking cessation counseling, extended-release (XL) bupropion (300 mg/day), nicotine inhaler, and contingency management for smoking abstinence. Illicit-stimulant-abstinence was measured by self-report and urine drug screens. Smoking abstinence was assessed via self-report and carbon monoxide levels.
Results
A significant effect was found for the cocaine-dependent subsample (N=147) in which participants who stopped smoking were abstinent for illicit stimulants an average of 78.2% of the post-smoking-quit weeks (weeks 4-10) relative to 63.6% in participants who continued smoking (X2(1)=8.55, p<.01, d=0.36). No significant effects were found for the sample as a whole (N=249) or for the methamphetamine-dependent subsample (N=102).
Conclusions
The present results suggest that cocaine-dependent patients achieving smoking abstinence in response to SCT might evidence not only improved smoking outcomes but improved cocaine-use outcomes as well. Future research to replicate this finding appears warranted.
doi:10.1016/j.drugalcdep.2013.09.019
PMCID: PMC3889710  PMID: 24128381
cocaine; smoking cessation; methamphetamine
6.  Randomized Trial of Continuing Care Enhancements for Cocaine Dependent Patients Following Initial Engagement 
Objective
The effects of cognitive-behavioral relapse prevention (RP), contingency management (CM), and their combination (CM+RP) were evaluated in a randomized trial with 100 cocaine dependent patients (58% female, 89% African American) who were engaged in treatment for at least two weeks and had an average of 44 days of abstinence at baseline.
Method
The participants were from intensive outpatient programs (IOPs), which provide 10 hours per week of group counseling. The CM protocol provided gift certificates (maximum value of $1,150; mean received= $740) for cocaine-free urines over 12 weeks using an escalating reinforcement schedule, and weekly individual RP sessions were offered for up to 20 weeks. Average number of RP sessions attended was 3 in RP and 13 in CM+RP.
Results
GEE analyses over 18 months post-randomization showed significant effects for CM (but not RP) on urine toxicology and self-reported cocaine use (p=.05), with no significant CM × RP interactions. Secondary analyses indicated CM+RP produced better cocaine urine toxicology outcomes at 6 months than TAU [OR=3.96 (1.33,11.80), p< .01] and RP [OR=4.89 (1.51,15.86), p< .01), and better cocaine urine toxicology outcomes at 9 months than TAU [OR=4.21 (1.37,12.88), p< .01] and RP [OR=4.24 (1.32,13.65), p< .01). Trends also favored CM+RP over CM at 6 [OR=2.93 (0.94,9.07), p= .06] and 9 [OR=2.93 (0.94,9.10), p= .06) months. Differences between the conditions were not significant after 9 months.
Conclusions
These results suggest CM can improve outcomes in cocaine dependent IOP patients who have achieved initial engagement, particularly when combined with relapse prevention.
doi:10.1037/a0018139
PMCID: PMC3076098  PMID: 20099956
cocaine dependence; treatment; contingency management; relapse prevention
7.  Comparative Efficacy of Seven Psychotherapeutic Interventions for Patients with Depression: A Network Meta-Analysis 
PLoS Medicine  2013;10(5):e1001454.
Jürgen Barth and colleagues use network meta-analysis - a novel methodological approach - to reexamine the comparative efficacy of seven psychotherapeutic interventions for adults with depression.
Please see later in the article for the Editors' Summary
Background
Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression.
Methods and Findings
We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = −0.62 to d = −0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = −0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = −0.30, 95% credibility interval [CrI] [−0.54 to −0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [−0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [−0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions.
Conclusions
Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression is a very common condition. One in six people will experience depression at some time during their life. People who are depressed have recurrent feelings of sadness and hopelessness and might feel that life is no longer worth living. The condition can last for months and often includes physical symptoms such as headaches, sleeping problems, and weight gain or loss. Treatment of depression can include non-drug treatments (psychotherapy), antidepressant drugs, or a combination of the two. Especially for people with mild or intermediate depression, psychotherapy is often considered the preferred first option. Psychotherapy describes a range of different psychotherapies, and a number of established types of psychotherapies have all shown to work for at least some patients.
Why Was This Study Done?
While it is broadly accepted that psychotherapy can help people with depression, the question of which type of psychotherapy works best for most patients remains controversial. While many scientific studies have compared one psychotherapy with control conditions, there have been few studies that directly compared multiple treatments. Without such direct comparisons, it has been difficult to establish the respective merits of the different types of psychotherapy. Taking advantage of a recently developed method called “network meta-analysis,” the authors re-examine the evidence on seven different types of psychotherapy to see how well they have been shown to work and whether some work better than others.
What Did the Researchers Do and Find?
The researchers looked at seven different types of psychotherapy, which they defined as follows. “Interpersonal psychotherapy” is short and highly structured, using a manual to focus on interpersonal issues in depression. “Behavioral activation” raises the awareness of pleasant activities and seeks to increase positive interactions between the patient and his or her environment. “Cognitive behavioral therapy” focuses on a patient's current negative beliefs, evaluates how they affect current and future behavior, and attempts to restructure the beliefs and change the outlook. “Problem solving therapy” aims to define a patient's problems, propose multiple solutions for each problem, and then select, implement, and evaluate the best solution. “Psychodynamic therapy” focuses on past unresolved conflicts and relationships and the impact they have on a patient's current situation. In “social skills therapy,” patients are taught skills that help to build and maintain healthy relationships based on honesty and respect. “Supportive counseling” is a more general therapy that aims to get patients to talk about their experiences and emotions and to offer empathy without suggesting solutions or teaching new skills.
The researchers started with a systematic search of the medical literature for relevant studies. The search identified 198 articles that reported on such clinical trials. The trials included a total of 15,118 patients and compared one of the seven psychotherapies either with another one or with a common “control intervention”. In most cases, the control (no psychotherapy) was deferral of treatment by “wait-listing” patients or continuing “usual care.” With network meta-analysis they were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of several psychotherapies within the same trial (where those were available) with indirect comparisons across all trials (using no psychotherapy as a control intervention).
Based on the combined trial results, all seven psychotherapies tested were better than wait-listing or usual care, and the differences were moderate to large, meaning that the average person in the group that received therapy was better off than about half of the patients in the control group. When comparing the therapies with each other, the researchers saw small or no differences, meaning that none of them really stood out as much better or much worse than the others. They also found that the treatments worked equally well for different patient groups with depression (younger or older patients, or mothers who had depression after having given birth). Similarly, they saw no big differences when comparing individual with group therapy, or person-to-person with internet-based interactions between therapist and patient.
However, they did find that smaller and less rigorous studies generally found larger benefits of psychotherapies, and most of the studies included in the analysis were small. Only 36 of the studies had at least 50 patients who received the same treatment. When they restricted their analysis to those studies, the researchers still saw clear benefits of cognitive-behavioral therapy, interpersonal therapy, and problem-solving therapy, but not for the other four therapies.
What Do these Findings Mean?
Similar to earlier attempts to summarize and make sense of the many study results, this one finds benefits for all of the seven psychotherapies examined, and none of them stood as being much better than some or all others. The scientific support for being beneficial was stronger for some therapies, mostly because they had been tested more often and in larger studies.
Treatments with proven benefits still do not necessarily work for all patients, and which type of psychotherapy might work best for a particular patient likely depends on that individual. So overall this analysis suggests that patients with depression and their doctors should consider psychotherapies and explore which of the different types might be best suited for a particular patient.
The study also points to the need for further research. Whereas depression affects large numbers of people around the world, all of the trials identified were conducted in rich countries and Western societies. Trials in different settings are essential to inform treatment of patients worldwide. In addition, large high-quality studies should further explore the potential benefits of some of therapies for which less support currently exists. Where possible, future studies should compare psychotherapies with one another, because all of them have benefits, and it would not be ethical to withhold such beneficial treatment from patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001454.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); information on psychotherapy includes information on its most common forms
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
The UK nonprofit Mind provides information on depression, including an explanation of the most common psychotherapies in the UK
MedlinePlus provides links to other resources about depression (in English and Spanish)
The UK nonprofit healthtalkonline.org has a unique database of personal and patient experiences on depression
doi:10.1371/journal.pmed.1001454
PMCID: PMC3665892  PMID: 23723742
8.  The Role of Therapist Characteristics in Training Effects in Cognitive, Supportive-Expressive, and Drug Counseling Therapies for Cocaine Dependence 
The role of therapist characteristics in therapy training was examined for 62 therapists in a multisite psychotherapy outcome study that included cognitive therapy (CT), supportive-expressive (SE) psychodynamic therapy, and individual drug counseling (IDC) for cocaine-dependent patients. Demographic variables and experience and competence ratings prior to training were correlated with measures of change in competence during the training phase. Higher competence ratings before training were associated with greater change in competence for SE and higher average competence for IDC. More years of experience were associated with greater change in competence for CT therapists, but more hours of pre-training supervision in the CT treatment modality were associated with less change.
PMCID: PMC3330597  PMID: 10896736
Psychotherapy Training and Supervision; Therapist Characteristics; Cocaine
9.  Abstinence-Contingent Recovery Housing and Reinforcement Based Treatment Following Opioid Detoxification 
Addiction (Abingdon, England)  2012;107(5):973-982.
Aims
To conduct a randomized, controlled trial of abstinence-contingent recovery housing delivered with or without intensive day treatment among individuals exiting residential opioid detoxification.
Design
Random assignment to one of three conditions: Recovery housing alone (RH), abstinence-contingent recovery housing with RBT (RH+RBT), or usual care (UC). RH and RH+RBT participants received 12 weeks of paid recovery housing contingent upon drug abstinence. RH+RBT participants also received 26 weeks of RBT, initiated concurrently with recovery housing. Assessments were conducted at 1, 3, and 6 months after treatment enrollment.
Setting
Outpatient drug-free substance abuse treatment program in Baltimore, Maryland.
Participants
Patients (N = 243) who completed medication-assisted opioid detoxification.
Measurements
Primary outcome was drug abstinence (opioid- and cocaine-negative urine and no self-reported opioid or cocaine use in the previous 30 days). Secondary outcomes included abstinence at all time points (1, 3, and 6 months), days in recovery housing, and employment.
Findings
Overall rates of drug abstinence were 50% for RH+RBT, 37% for RH, and 13% for UC (p < .001). At 6 months, RH+RBT participants remained more likely to meet abstinence criteria than UC participants (37% vs. 20%, p = .016). Length of stay in recovery housing mediated abstinence outcomes and was longer in RH+RBT (49.5 days) than in RH (32.2 days; p < .002).
Conclusions
Abstinence-contingent recovery housing improves abstinence in opioid-dependent adults following medication-assisted detoxification. The addition of intensive ‘reinforcement-based treatment’ behavioural counseling further improves treatment outcomes in part by promoting longer recovery house stays.
doi:10.1111/j.1360-0443.2011.03750.x
PMCID: PMC3421907  PMID: 22151478
10.  Individual psychodynamic psychotherapy and psychoanalysis for schizophrenia and severe mental illness 
Background
People with schizophrenia and severe mental illness may require considerable support from health care professionals, in most cases over a long period of time. Research on the effects of psychotherapy for schizophrenia has shown mixed results. Although pharmacological interventions remain the treatment of choice, the effects of treatments focusing on psychosocial factors affecting schizophrenia are important.
Objectives
To review the effects of psychodynamic psychotherapy, psychoanalysis, or both, for people with schizophrenia or severe mental illness.
Search methods
For the updated review, we searched the Cochrane Schizophrenia Group Trials Register (June 2008) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.
Selection criteria
We sought all randomised trials of individual psychodynamic psychotherapy or psychoanalysis for people with schizophrenia or severe mental illness.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis using a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD) and weighted mean differences (WMD) using a fixed-effect model.
Main results
We included four randomised trials (total 528 participants, 5 comparisons). All used a psychodynamic approach and reported limited data.
For individual psychodynamic therapy versus medication alone we found significantly more participants in the therapy group were unable to be discharged (n=92, RR 8.35 CI 2.0 to 34.3, NNH 3 CI 2 to 6). We found no significant difference between groups in the number of participants who were re-hospitalised (n=24, RR 0.63 CI 0.3 to 1.4) during long-term analyses. At 12 months, fewer participants in the psychotherapy groups needed additional medications compared with those who did receive medication (n=74, RR 0.64 CI 0.5 to 0.8, NNT 3 CI 3 to 6), and also at three years follow up (n=87, RR 0.85 CI 0.8 to 1.0, NNT 7 CI 5 to 26).
For individual psychodynamic therapy plus medication versus medication alone we found no significant difference in suicide (n=92, RR 0.16 CI 0.01 to 2.9) or suitability for discharge (n=92, RR 1.09 CI 0.2 to 7.4). Also, we found re-hospitalisation rates in long-term analyses were equivocal (n=24, RR 1.00 CI 0.4 to 2.6). For insight-orientated psychodynamic psychotherapy versus reality adaptive psychotherapy we found no significant difference in re-hospitalisation rates (n=164, RR 1.20 CI 0.9 to 1.6), but we found study attrition favoured the insight-orientated psychodynamic psychotherapy group at 12 months (n=164, RR 0.46 CI 0.3 to 0.6, NNT 2 CI 2 to 4). For individual psychodynamic psychotherapy versus group psychotherapy we found no significant difference in global state ‘not improved’ (n=100, RR 1.27 CI 1.0 to 1.7). For individual psychodynamic therapy plus medication versus individual psychodynamic therapy we found rates of re-hospitalisation during long-term analyses were equivocal (n=24, RR 1.00 CI 0.4 to 2.6). There is no clear evidence of any positive effect of psychodynamic therapy and the possibility of adverse effects seems never to have been considered. We did not identify any trials using a psychoanalytic approach.
Authors’ conclusions
Current data do not support the use of psychodynamic psychotherapy techniques for hospitalised people with schizophrenia. If psychoanalytic therapy is being used for people with schizophrenia there is an urgent need for trials.
doi:10.1002/14651858.CD001360
PMCID: PMC4171459  PMID: 11686988
*Psychoanalytic Therapy; *Psychotherapy; Hospitalization; Mental Disorders [therapy]; Randomized Controlled Trials as Topic; Schizophrenia [*therapy]; Humans
11.  Modafinil for the treatment of cocaine dependence✩ 
Drug and alcohol dependence  2009;104(1-2):133.
Aim
Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.
Methods
This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200 mg, and 69 to modafinil 400 mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days.
Results
The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p > 0.79). However, two secondary outcomes showed significant effects by modafinil 200 mg: the maximum number of consecutive non-use days for cocaine (p = 0.02), and a reduction in craving (p = 0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p < 0.02).
Conclusions
These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.
doi:10.1016/j.drugalcdep.2009.04.015
PMCID: PMC2818032  PMID: 19560290
Modafinil; Cocaine-related disorders; Alcoholism; Pharmacotherapy; Risk factors
12.  Increased serum brain-derived neurotrophic factor (BDNF) is predictive of cocaine relapse outcomes: A prospective study 
Biological psychiatry  2011;70(8):706-711.
Background
Cocaine dependence is associated with high relapse rates but few biological markers associated with relapse outcomes have been identified. Extending preclinical research showing a role for central Brain Derived Neurotrophic Factor (BDNF) in cocaine seeking, we examined whether serum BDNF is altered in abstinent, early recovering, cocaine-dependent individuals and if it is predictive of subsequent relapse risk.
Methods
Serum samples were collected across three consecutive mornings from 35 treatment-engaged, 3 week abstinent cocaine-dependent inpatients (17M/18F) and 34 demographically matched hospitalized healthy control participants (17M/17F). Cocaine dependent individuals were prospectively followed on days 14, 30 and 90 post-treatment discharge to assess cocaine relapse outcomes. Time to cocaine relapse, number of days of cocaine use (frequency), and amount of cocaine use (quantity) were the main outcome measures.
Results
High correlations in serum BDNF across days indicated reliable and stable serum BDNF measurements. Significantly higher mean serum BDNF levels were observed for the cocaine-dependent patients compared to healthy control participants (p<.001). Higher serum BDNF levels predicted shorter subsequent time to cocaine relapse (hazard ratio: HR: 1.09, p<.05), greater number of days (p<.05) and higher total amounts of cocaine used (p = .05).
Conclusions
High serum BDNF levels in recovering cocaine-dependent individuals are predictive of future cocaine relapse outcomes and may represent a clinically relevant marker of relapse risk. These data suggest that serum BDNF levels may provide an indication of relapse risk during early recovery from cocaine dependence.
doi:10.1016/j.biopsych.2011.05.013
PMCID: PMC3186871  PMID: 21741029
BDNF; cocaine dependence; cocaine relapse; treatment outcome
13.  Process Predictors of the Outcome of Group Drug Counseling 
Objective
This study examined the relation of process variables to the outcome of group drug counseling, a commonly used community treatment, for cocaine dependence.
Method
Videotaped group drug counseling sessions from 440 adult patients (23% female, 41% minority) were rated for member alliance, group cohesion, participation, self-disclosure, positive and non-positive feedback and advice, during the 6-month treatment of cocaine dependence. Average, session-level, and slopes of process scores were evaluated. Primary outcomes were monthly cocaine use (days using out of 30), next session cocaine use, and duration of sustained abstinence from cocaine. Secondary outcomes were endorsement of 12-step philosophy and beliefs about substance abuse.
Results
More positive alliances (with counselor) were associated with reductions in days using cocaine per month and next-session cocaine use, and increases in endorsement of 12-step philosophy. Patient self-disclosure about the past and degree of participation in the group were generally not predictive of group drug counseling outcomes. More advice from counselor and other group members were consistently associated with poorer outcomes in all categories. Individual differences in changes in process variables over time (linear slopes) were generally not predictive of treatment outcomes.
Conclusions
Some group behaviors widely believed to be associated with outcome, such as self-disclosure and participation, were not generally predictive of outcomes of group drug counseling, but alliance with the group counselor was positively associated, and advice giving negatively associated, with the outcome of treatments for cocaine dependence.
doi:10.1037/a0030101
PMCID: PMC3565014  PMID: 23106760
group drug counseling; cocaine dependence; predictors; process ratings
14.  Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence 
Background
Buprenorphine is a partial μ-opiate agonist and κ-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence.
Methods
Two hundred outpatients currently dependent on both cocaine and opiates were randomly assigned to double-blind groups receiving a sublingual solution of buprenorphine (2, 8, or 16 mg daily, or 16 mg on alternate days, or placebo), plus weekly individual drug abuse counseling, for 13 weeks. The chief outcome measures were urine concentrations of opiate and cocaine metabolites (quantitative) and proportion of urine samples positive for opiates or cocaine (qualitative). Group differences were assessed by use of mixed regression modeling.
Results
The target dose of buprenorphine was achieved in 179 subjects. Subjects receiving 8 or 16 mg buprenorphine daily showed statistically significant decreases in urine morphine levels (P = .0135 for 8 mg and P < .001 for 16 mg) or benzoylecgonine concentrations (P = .0277 for 8 mg and P = .006 for 16 mg) during the maintenance phase of the study. For the 16-mg group, mean benzoylecgonine concentrations fell from 3715 ng/mL during baseline to 186 ng/mL during the withdrawal phase; mean morphine concentrations fell from 3311 ng/mL during baseline to 263 ng/mL during withdrawal. For the 8-mg group, mean benzoylecgonine concentrations fell from 6761 ng/mL during baseline to 676 ng/mL during withdrawal; mean morphine concentrations fell from 3890 ng/mL during baseline to 661 ng/mL during withdrawal. Qualitative urinalysis showed a similar pattern of results. Subjects receiving the highest dose showed concomitant decreases in both urine morphine and benzoylecgonine concentrations. There were no significant group differences in treatment retention or adverse events.
Conclusions
A sublingual buprenorphine solution at 16 mg daily is well tolerated and effective in reducing concomitant opiate and cocaine use. The therapeutic effect on cocaine use appears independent of that on opiate use.
doi:10.1016/j.clpt.2003.09.004
PMCID: PMC2633656  PMID: 14749690
15.  A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine 
PLoS Medicine  2008;5(6):e117.
Background
Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.
Methods and Findings
Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.
Conclusions
Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.
Investigating the mechanism of cocaine's effect on fetal brain development, Chun-Ting Lee and colleagues find that down-regulation of cyclin A by a cocaine metabolite inhibits neural proliferation.
Editors' Summary
Background.
Every year, cocaine abuse by mothers during pregnancy exposes thousands of unborn infants (fetuses) to this powerful and addictive stimulant. Maternal cocaine abuse during early pregnancy increases the risk of miscarriage; its use during late pregnancy slows the baby's growth and can trigger premature labor. Babies exposed to cocaine shortly before birth are often irritable and have disturbed sleep patterns. They can also be very sensitive to sound and touch and consequently hard to comfort. These problems usually resolve spontaneously within the first few weeks of life but some permanent birth defects are also associated with frequent cocaine abuse during pregnancy. In particular, babies exposed to cocaine before birth sometimes have small heads—an abnormality that generally indicates a small brain—and, although they usually have normal intelligence, the development of their thinking skills and language is often delayed, and they can have behavioral problems.
Why Was This Study Done?
Exposure to cocaine before birth clearly interferes with some aspects of brain development. More specifically, it reduces the number and position of neurons (the cells that transmit information in the form of electrical impulses around the body) within the brain. All neurons develop from neural progenitor cells, and previous research suggests that cocaine exposure before birth inhibits the proliferation of these cells in the developing brain. It would be useful to understand exactly how cocaine affects neural progenitor cells, because it might then be possible to prevent the drug's adverse effects on brain development. In this study, therefore, the researchers investigate the molecular mechanism that underlies cocaine's effect on neural progenitor cells.
What Did the Researchers Do and Find?
When the researchers investigated the effects of cocaine on AF5 cells (rat neural progenitor cells that grow indefinitely in the laboratory), they found that concentrations of cocaine similar to those measured in fetal brains after maternal drug exposure inhibited the proliferation of AF5 cells by blocking the “G1-to-S transition.” This is a stage that cells have to pass through between each round of cell division (the production of two daughter cells from one parent cell). Next, the researchers showed that cocaine-treated AF5 cells made much less cyclin A2, a protein that controls the G1-to-S transition, than untreated cells. Cocaine also decreased cyclin A2 levels in neural progenitor cells freshly isolated from human fetal brains and in fetal rat brains exposed to the drug while in their mother's womb. Treatment of AF5 cells with a cyclin A2 expression vector (a piece of DNA that directs the production of cyclin A2) counteracted the down-regulation of cyclin A2 and restored AF5 proliferation in the presence of cocaine. Other experiments indicate that the reduction of cyclin A2 by cocaine in AF5 cells involves the accumulation of “reactive oxygen species,” by-products of the breakdown of cocaine by a protein that is a member of a family of proteins called cytochrome P450. Finally, treatment of pregnant rats with cimetidine (which inhibits the action of cytochrome P450) counteracted both the inhibition of neural progenitor cell proliferation and the cyclin A2 down-regulation that cocaine exposure induced in the brains of their unborn pups.
What Do These Findings Mean?
These findings show that the cocaine-induced inhibition of neural progenitor cell proliferation involves, at least in part, interfering with the production (that is, causing down-regulation) of cyclin A2. They also show that this down-regulation is induced by the breakdown of cocaine by cytochrome P450, and that in both a rat cell line and in fetal rats, the cytochrome P450 inhibitor cimetidine (a drug that is already used clinically for stomach problems) can block the adverse effects of cocaine on the proliferation of neural progenitor cells. These findings need to be confirmed in animals more closely related to people than rats, and the long-term effects of cimetidine need to be investigated, in particular its effects on cocaine toxicity. Nevertheless these results raise the possibility that giving cimetidine or other drugs with similar effects to pregnant women who are addicted to cocaine might prevent some of the harm that their drug habit does to their unborn children, although it is not clear whether there is a dosage of cimetidine that might be both safe and adequate for this purpose.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050117.
A PLoS Medicine Perspective article by Steven Hyman further discusses this study
The US National Institute on Drug Abuse provides a fact sheet on cocaine (in English and Spanish)
The UK charity Release provides information and advice to the public and professionals about the law and drugs, including information about cocaine
MedlinePlus also provides a list of links to information about cocaine (in English and Spanish)
The March of Dimes Foundation, a US nonprofit organization for the improvement of child health, provides information about illicit drug use during pregnancy (in English and Spanish)
The Organization of Teratology Information Specialists also provides a fact sheet on cocaine and pregnancy (in English, Spanish, and French)
doi:10.1371/journal.pmed.0050117
PMCID: PMC2504032  PMID: 18593214
16.  Measuring adherence and competence of dynamic therapists in the treatment of cocaine dependence 
This article presents the development of a new 82-item rating scale of therapist adherence and competence for supportive-expressive (SE) dynamic psychotherapy for the treatment of cocaine dependence. Sixty- four items are rated for adherence, appropriateness, and quality of prescribed interventions. As part of the pilot/training phase of the National Institute on Drug Abuse Collaborative Cocaine Treatment Study, two independent expert judges rated 32 audiotapes of SE therapy sessions with cocaine-dependent patients, 10 tapes of cognitive therapy (CT) sessions, and 10 tapes of individual drug counseling (IDC) sessions. Reliability was acceptable for adherence but poor for quality and appropriateness. SE therapists used more expressive (interpretative) techniques than did either CT therapists or IDC counselors, and they used more supportive techniques than did IDC counselors.
PMCID: PMC3330446  PMID: 9058557
17.  Employment-Based Abstinence Reinforcement as a Maintenance Intervention for the Treatment of Cocaine Dependence: A Randomized Controlled Trial 
Addiction (Abingdon, England)  2009;104(9):1530-1538.
Context:
Due to the chronic nature of cocaine dependence, long-term maintenance treatments may be required to sustain abstinence. Abstinence reinforcement is among the most effective means of initiating cocaine abstinence. Practical and effective means of maintaining abstinence reinforcement programs over time are needed.
Objective:
Determine whether employment-based abstinence reinforcement can be an effective long-term maintenance intervention for cocaine dependence.
Design:
Participants (N=128) were enrolled in a 6-month job skills training and abstinence initiation program. Participants who initiated abstinence, attended regularly, and developed needed job skills during the first six months were hired as operators in a data entry business and randomly assigned to an employment only (Control, n = 24) or abstinence-contingent employment (n = 27) group.
Setting:
A nonprofit data entry business.
Participants:
Unemployed welfare recipients who persistently used cocaine while enrolled in methadone treatment in Baltimore.
Intervention:
Abstinence-contingent employment participants received one year of employment-based contingency management, in which access to employment was contingent on provision drug-free urine samples under routine and then random drug testing. If a participant provided drug-positive urine or failed to provide a mandatory sample, then that participant received a temporary reduction in pay and could not work until urinalysis confirmed recent abstinence.
Main Outcome Measure:
Cocaine-negative urine samples at monthly assessments across one year of employment.
Results:
During the one-year of employment, abstinence-contingent employment participants provided significantly more cocaine-negative urine samples than employment only participants (79.3% and 50.7%, respectively; p = 0.004, OR = 3.73, 95% CI = 1.60 – 8.69).
Conclusions:
Employment-based abstinence reinforcement that includes random drug testing is effective as a long-term maintenance intervention, and is among the most promising treatments for drug dependence. Workplaces could serve as therapeutic agents in the treatment of drug dependence by arranging long-term employment-based contingency management programs.
Trial Registration:
clinicaltrials.gov. Identifier: NCT00249496
doi:10.1111/j.1360-0443.2009.02657.x
PMCID: PMC2729763  PMID: 19686522
Cocaine; Methadone; Employment; Contingency management; Abstinence reinforcement
18.  Examining Differential Effects of Psychosocial Treatments for Cocaine Dependence: An Application of Latent Trajectory Analyses 
Drug and alcohol dependence  2009;106(2-3):164.
Background
The NIDA Collaborative Cocaine Treatment Study yielded different efficacies for different psychosocial treatments for cocaine dependence. However, substantial heterogeneity of patient outcomes was evident. Longitudinal data analysis techniques can be helpful in examining differential effects of psychosocial interventions on specific subpopulations of patients.
Methods
Overall drug and cocaine use of 346 patients diagnosed with DSM-IV cocaine dependence and treated with one of four psychosocial interventions were assessed monthly during 6-month treatment. Growth mixture models were used to identify patient subgroups based on typical patterns of change in substance use during treatment and to evaluate differential treatment effects within these subgroups.
Results
Three patient subgroups following different change patterns in cocaine and overall drug use were identified irrespective of the treatment type: (a) those with moderate baseline severity of drug use and very rapid reduction of drug use during treatment, (b) those with moderate baseline severity of drug use and moderate reduction of drug use during treatment, and (c) those with severe levels of baseline drug use with moderate reduction of drug use during treatment. Patient baseline characteristics enabled discrimination between these subgroups. Individual drug counseling was most efficacious among those patients with moderate baseline severity and moderate treatment response. There were no differential treatment effects in the two other patient subgroups.
Conclusions
The population of treatment-seeking cocaine dependent individuals is heterogeneous. Research on patient subgroups with different change patterns revealed its potential to enable classifications of patients that indicate which treatment is most effective for which type of patient.
doi:10.1016/j.drugalcdep.2009.08.009
PMCID: PMC2814930  PMID: 19782480
Cocaine Dependence; Psychosocial Treatment; Differential Treatment Effects; Patterns of Change; Growth Mixture Modeling
19.  A PLACEBO CONTROLLED TRIAL OF MEMANTINE FOR COCAINE DEPENDENCE WITH HIGH-VALUE VOUCHER INCENTIVES DURING A PRE-RANDOMIZATION LEAD-IN PERIOD 
Drug and alcohol dependence  2010;111(1-2):97-104.
Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of cocaine dependence. We hypothesized that memantine, a low potency, uncompetitive NMDA receptor antagonist, would be safe and effective in the treatment of cocaine dependence, particularly in preventing relapse to cocaine use in abstinent individuals.
Cocaine dependent patients (N =112) were enrolled. The trial began with a 2-week placebo lead-in period during which patients received high-value voucher contingency management to induce abstinence. Participants were then randomized to receive either memantine 20 mg bid (N=39) or placebo (N=42) for 12-weeks in combination with individual relapse-prevention therapy. The randomization was stratified by abstinence status during the lead-in period. The primary outcome was the weekly proportion of days of cocaine use.
There were no significant differences in cocaine use outcome between the groups treated with memantine versus placebo. Thus, the efficacy of memantine 40 mg/d for the treatment of cocaine dependence was not supported. Urine-confirmed abstinence during the lead-in period was achieved by 44% of participants, and was a strong predictor of subsequent cocaine abstinence during the trial. This suggests that this clinical trial design, an intensive behavioral intervention during a lead-in period, resolves cocaine dependent patients into two subgroups, one that rapidly achieves sustained abstinence and may not need a medication, and another that displays persistent cocaine use and would most likely benefit from a medication to help induce abstinence. Targeting the latter subgroup may advance medication development efforts.
doi:10.1016/j.drugalcdep.2010.04.006
PMCID: PMC2930076  PMID: 20537812
Cocaine dependence; Pharmacotherapy trials; NMDA receptors; Placebo lead-in; High value contingency reinforcement
20.  Sertraline Delays Relapse in Recently Abstinent Cocaine-Dependent Patients with Depressive Symptoms1 
Addiction (Abingdon, England)  2011;107(1):131-141.
Aims
Whether the selective serotonin reuptake inhibitor sertraline at 200 mg/day delays relapse in recently abstinent cocaine dependent individuals
Design
12-week, double blind, placebo-controlled clinical trial with 2-week residential stay followed by 10-wk outpatient participation
Setting
Veterans Affairs residential unit and outpatient treatment research program
Participants
Cocaine-dependent volunteers (N=86) with depressive symptoms (Hamilton score > 15), but otherwise no major psychiatric or medical disorder or contraindication to sertraline.
Measurements
Participants were housed on a drug-free residential unit (wks 1–2) and randomized to receive sertraline or placebo. Participants then participated on an outpatient basis during weeks 3–12 while continuing to receive study medication. Patients participated in a day substance abuse day treatment program during weeks 1–3 and underwent weekly cognitive behavioral therapy during weeks 4–12. The primary outcome measure was thrice-weekly urine results and secondary measure was Hamilton Depression scores.
Findings
Pre hoc analyses were performed on those who participated beyond week 2. Generally no group differences in retention or baseline characteristics occurred. Sertraline patients showed a trend toward longer time before their first cocaine-positive urine (“lapse,” χ2=3.67, p=0.056), went significantly longer before having two consecutive urine samples positive for cocaine (“relapse,” χ2=4.03, p=0.04) and showed significantly more days to lapse (26.1±3.2±10.5; z = 2.89, p=0.004) and relapse (21.3±10.8 vs 32.3±14.9; z=2.25, p=0.02). Depression scores decreased over time (F=43.43, p<0.0001), but did not differ between groups (F =0.09, p = 0.77).
Conclusions
Sertraline delays time to relapse relative to placebo in cocaine dependent patients who initially achieve at least two weeks of abstinence.
doi:10.1111/j.1360-0443.2011.03552.x
PMCID: PMC3237722  PMID: 21707811
cocaine dependence; randomized clinical trial; placebo control; sertraline; relapse prevention; cognitive behavioral therapy
21.  Employment-based abstinence reinforcement as a maintenance intervention for the treatment of cocaine dependence: post-intervention outcomes 
Addiction (Abingdon, England)  2011;106(5):960-967.
Aims
Due to the chronicity of cocaine dependence, practical and effective maintenance interventions are needed to sustain long-term abstinence. We sought to assess the effects of long-term employment-based reinforcement of cocaine abstinence after discontinuation of the intervention.
Design
Participants who initiated sustained opiate and cocaine abstinence during a 6-month abstinence reinforcement and training program worked as data entry operators and were randomly assigned to a group that could work independent of drug use (Control, n = 24), or an abstinence-contingent employment (n = 27) group that was required to provide cocaine- and opiate-negative urine samples to work and maintain maximum rate of pay.
Setting
A nonprofit data entry business.
Participants
Unemployed welfare recipients who persistently used cocaine while in methadone treatment.
Measurements
Urine samples and self-reports were collected every six months for 30 months.
Findings
During the employment year, abstinence-contingent employment participants provided significantly more cocaine-negative samples than controls (82.7% and 54.2%; P = .01, OR = 4.61). During the follow-up year, the groups had similar rates of cocaine-negative samples (44.2% and 50.0%; P = .93), and HIV-risk behaviors. Participants’ social, employment, economic, and legal conditions were similar in the two groups across all phases of the study.
Conclusions
Employment-based reinforcement effectively maintains long-term cocaine abstinence, but many patients relapse to use when the abstinence contingency is discontinued, even after a year of abstinence-contingent employment. Relapse could be prevented in many patients by leaving employment-based abstinence reinforcement in place indefinitely, which could be facilitated by integrating it into typical workplaces.
doi:10.1111/j.1360-0443.2011.03364.x
PMCID: PMC3074032  PMID: 21226886
Cocaine; Methadone; Employment; Contingency management; Abstinence reinforcement
22.  Reactivity to Laboratory Stress Provocation Predicts Relapse to Cocaine 
Drug and alcohol dependence  2009;106(1):21.
Background
Cocaine dependence is a chronic relapsing disorder characterized by periods of abstinence and high rates of return to drug using behavior. Elevated levels of stress have been associated with relapse to cocaine; however, the nature of this association is not well understood.
Methods
The relationship between reactivity to three human laboratory provocations and relapse to cocaine was investigated. Participants were 53 cocaine-dependent individuals who were admitted for a 2-day inpatient stay during which a psychosocial provocation (i.e., the Trier Social Stress Task), a pharmacological provocation (i.e., administration of 1ųg/kg corticotrophin releasing hormone; CRH), and a drug cue exposure paradigm were completed. Adrenocorticotrophic hormone (ACTH), cortisol, heart rate, and subjective cocaine craving and stress were assessed at baseline and at multiple time points post-task. Participants’ cocaine use was monitored for approximately one month following testing.
Results
The majority (72.3%) of participants relapsed to cocaine during the follow-up period. In response to the CRH and drug cue exposure, elevated subjective craving and stress were significant predictors of cocaine use during follow-up. In response to the Trier, attenuated neuroendocrine responses were significant predictors of cocaine use.
Conclusions
The findings provide further evidence of the ability of laboratory paradigms to predict relapse. The observed associations between stress reactivity and subsequent cocaine use highlight the clinical importance of the findings. Predictors of relapse may vary based on the type of provocation utilized. Interventions aimed at normalizing stress response, as measured using laboratory paradigms, may prove useful in relapse prevention.
doi:10.1016/j.drugalcdep.2009.07.016
PMCID: PMC2815094  PMID: 19726138
stress; craving; cocaine; ACTH; cortisol; stress reactivity
23.  Alpha Synuclein Protein Levels are Increased in Serum from Recently Abstinent Cocaine Abusers 
Drug and alcohol dependence  2007;94(1-3):246-250.
Alpha synuclein is increased in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. Recent studies have shown increased alpha-synuclein protein expression in serum of alcoholic patients that is linked with severity of alcohol craving. The aim of this study was to analyze the serum levels of alpha synuclein in healthy subjects and in recently abstinent cocaine abusers. Alpha synuclein protein expression was measured by enzyme-linked immunosorbent assay in serum specimens obtained from 38 recently abstinent cocaine dependent patients and 14 control subjects. The presence of cocaine dependence disorder was based on the Structured Clinical Interview (DSM-IV). Drug severity was assessed by the Addiction Severity Index ratings and composite measures. Scores of the intensity and frequency of cocaine craving episodes were obtained from the Minnesota Cocaine Craving Questionnaire. The serum concentrations of alpha synuclein in cocaine dependent patients were significantly higher as compared with age-matched drug-free controls (p < 0.001). Alpha synuclein levels in blood were significantly correlated with the intensity (r = 0.60, p < 0.001) and frequency (r = 0.64. p < 0.001) of cocaine craving and with thirty days of cocaine use in the prior month before entry to treatment (r = 0.56, p < 0.005). However, there was no correlation between the serum protein levels of alpha synuclein and age in either group. This report is the first demonstration of altered alpha synuclein levels in peripheral blood from cocaine abusers. These data agree with previous reports in postmortem brain of cocaine abusers and provide support for an association between alpha synuclein and cocaine dependence.
doi:10.1016/j.drugalcdep.2007.09.020
PMCID: PMC2366137  PMID: 18055133
Cocaine; serum; dopamine; craving; synuclein
24.  Optimum Methadone Compliance Testing 
Executive Summary
Objective
The objective of this analysis was to determine the diagnostic utility of oral fluid testing collected with the Intercept oral fluid collection device.
Clinical Need: Target Population and Condition
Opioids (opiates or narcotics) are a class of drugs derived from the opium poppy plant that typically relieve pain and produce a euphoric feeling. Methadone is a long-acting synthetic opioid used to treat opioid dependence and chronic pain. It prevents symptoms of opioid withdrawal, reduces opioid cravings and blocks the euphoric effects of short-acting opioids such as heroin and morphine. Opioid dependence is associated with harms including an increased risk of exposure to Human Immunodeficiency Virus and Hepatitis C as well as other health, social and psychological crises. The goal of methadone treatment is harm reduction. Treatment with methadone for opioid dependence is often a long-term therapy. The Ontario College of Physicians and Surgeons estimates that there are currently 250 physicians qualified to prescribe methadone, and 15,500 people in methadone maintenance programs across Ontario.
Drug testing is a clinical tool whose purpose is to provide objective meaningful information, which will reinforce positive behavioral changes in patients and guide further treatment needs. Such information includes knowledge of whether the patient is taking their methadone as prescribed and reducing or abstaining from using opioid and other drugs of abuse use. The results of drug testing can be used with behavior modification techniques (contingency management techniques) where positive reinforcements such as increased methadone take-home privileges, sustained employment or parole are granted for drug screens negative for opioid use, and negative reinforcement including loss of these privileges for drug screens positive for opioid used.
Body fluids including blood, oral fluid, often referred to as saliva, and urine may contain metabolites and the parent drug of both methadone and drugs of abuse and provide a means for drug testing. Compared with blood which has a widow of detection of several hours, urine has a wider window of detection, approximately 1 to 3 days, and is therefore considered more useful than blood for drug testing. Because of this, and the fact that obtaining a urine specimen is relatively easy, urine drug screening is considered the criterion measure (gold standard) for methadone maintenance monitoring. However, 2 main concerns exist with urine specimens: the possibility of sample tampering by the patient and the necessity for observed urine collection. Urine specimens may be tampered with in 3 ways: dilution, adulteration (contamination) with chemicals, and substitution (patient submits another persons urine specimen). To circumvent sample tampering the supervised collection of urine specimens is a common and recommended practice. However, it has been suggested that this practice may have negative effects including humiliation experienced by patient and staff, and may discourage patients from staying in treatment. Supervised urine specimen collection may also present an operational problem as staff must be available to provide same-sex supervision. Oral fluid testing has been proposed as a replacement for urine because it can be collected easily under direct supervision without infringement of privacy and reduces the likelihood of sample tampering. Generally, the results of oral fluid drug testing are similar to urine drug testing but there are some differences, such as lower concentrations of substances in oral fluid than urine, and some drugs remain detectable for longer periods of time in urine than oral fluid.
The Technology Being Reviewed
The Intercept Oral Specimen Collection Device (Ora-Sure Technologies, Bethlehem, PA) consists of an absorbent pad mounted on a plastic stick. The pad is coated with common salts. The absorbent pad is inserted into the mouth and placed between the cheek and gums for 3 minutes on average. The pad absorbs the oral fluid. After 3 minutes (range 2min-5 min) the collection device is removed from the mouth and the absorbent pad is placed in a small vial which contains 0.8mL of pH-balanced preservative, for transportation to a laboratory for analysis. It is recommended that the person undergoing oral fluid drug testing have nothing to eat or drink for a 10- minute period before the oral fluid specimen is collected. This will remove opportunity for adulteration. Likewise, it is recommended that the person be observed for the duration of the collection period to prevent adulteration of the specimen. An average of 0.4 mL of saliva can be collected. The specimen may be stored at 4C to 37C and tested within 21 days of collection (or within 6 weeks if frozen).
The oral fluid specimen must be analyzed in a laboratory setting. There is no point-of-care (POC) oral fluid test kit for drugs of abuse (other than for alcohol). In the laboratory the oral fluid is extracted from the vial after centrifugation and a screening test is completed to eliminate negative specimens. Similar to urinalysis, oral fluid specimens are analyzed first by enzyme immunoassay with positive specimens sent for confirmatory testing. Comparable cut-off values to urinalysis by enzyme immunoassay have been developed for oral fluids
Review Strategy
 
Research Question
What is the diagnostic utility of the Intercept oral specimen device?
Inclusion criteria:
Studies evaluating paired urine and oral fluid specimens from the same individual with the Intercept oral fluid collection device.
The population studied includes drug users.
Exclusion criteria:
Studies testing for marijuana (THC) only.
Outcomes:
Sensitivity and Specificity of oral fluid testing compared to urinalysis for methadone (methadone metabolite), opiates, cocaine, benzodiazepines, and alcohol.
Quality of the Body of Evidence
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A description of the GRADE system is reported in Appendix 1.
Summary of Findings
A total of 854 potential citations were retrieved. After reviewing titles and abstracts, 2 met the inclusion and exclusion criteria. Two other relevant studies were found after corresponding with the author of the 2 studies retrieved from the literature search. Therefore a total of 4 published studies are included in this analysis. All 4 studies carried out by the same investigator meet the definition of Medical Advisory Secretariat level III (not a-randomized controlled trial with contemporaneous controls) study design. In each of the studies, paired urine and oral fluid specimens where obtained from drug users. Urine collection was not observed in the studies however, laboratory tests for pH and creatinine were used to determine the reliability of the specimen. Urine specimens thought to be diluted and unreliable were removed from the evaluation. Urinalysis was used as the criterion measurement for which to determine the sensitivity and specificity of oral fluid testing by the Intercept oral fluid device for opiates, benzodiazepines, cocaine and marijuana. Alcohol was not tested in any of the 4 studies. From these 4 studies, the following conclusions were drawn:
The evidence indicates that oral fluid testing with the Intercept oral fluid device has better specificity than sensitivity for opiates, benzodiazepines, cocaine and marijuana.
The sensitivity of oral fluids testing with the Intercept oral fluid device seems to be from best to worst: cocaine > benzodiazepines >opiates> marijuana.
The sensitivity and specificity for opiates of the Intercept oral fluid device ranges from 75 to 90% and 97- 100% respectively.
The consequences of opiate false-negatives by oral fluid testing with the Intercept oral fluid device need to be weighed against the disadvantages of urine testing, including invasion of privacy issues and adulteration and substitution of the urine specimen.
The window of detection is narrower for oral fluid drug testing than urinalysis and because of this oral fluid testing may best be applied in situations where there is suspected frequent drug use. When drug use is thought to be less frequent or remote, urinalysis may offer a wider (24-48 hours more than oral fluids) window of detection.
The narrow window of detection for oral fluid testing may mean more frequent testing is needed compared to urinalysis. This may increase the expense for drug testing in general.
POC oral fluid testing is not yet available and may limit the practical utility of this drug testing methodology. POC urinalysis by immunoassay is available.
The possible applications of oral fluid testing may include:
Because of its narrow window of detection compared to urinalysis oral fluid testing may best be used during periods of suspected frequent or recent drug use (within 24 hours of drug testing). This is not to say that oral fluid testing is superior to urinalysis during these time periods.
In situations where an observed urine specimen is difficult to obtain. This may include persons with “shy bladder syndrome” or with other urinary conditions limiting their ability to provide an observed urine specimen.
When the health of the patient would make urine testing unreliable (e,g., renal disease)
As an alternative drug testing method when urine specimen tampering practices are suspected to be affecting the reliability of the urinalysis test.
Possible limiting Factors to Diffusion of Oral Fluid Technology
No oral fluid POC test equivalent to onsite urine dips or POC analyzer reducing immediacy of results for patient care.
Currently, physicians get reimbursed directly for POC urinalysis. Oral fluid must be analyzed in a lab setting removing physician reimbursement, which is a source of program funding for many methadone clinics.
Small amount of oral fluid specimen obtained; repeat testing on same sample will be difficult.
Reliability of positive oral fluid methadone (parent drug) results may decrease because of possible contamination of oral cavity after ingestion of dose. Therefore high methadone levels may not be indicative of compliance with treatment. Oral fluid does not as yet test for methadone metabolite.
There currently is no licensed provincial laboratory that analyses oral fluid specimens.
Abbreviations
2-ethylidene- 1,5-dimethyl-3,3-diphenylpyrrolidine
enzyme immunoassay
Enzyme Linked Immunosorbent Assay (ELISA),
Enzyme Multiplied Immunoassay Test (EMIT)
Gas chromatography
gas chromatography/mass spectrometry
High-performance liquid chromatography
Limit of Detection
Mass spectrometry
Methadone Maintenance Treatment
Oral fluid testing
Phencyclidine
Point of Care Testing
tetrahydrocannabinol
11-nor-delta-9-tetrhydrocannabinol-9-carboxylic acid
urine drug testing
PMCID: PMC3379523  PMID: 23074492
25.  Post-traumatic stress disorder 
Clinical Evidence  2010;2010:1005.
Introduction
Post-traumatic stress disorder (PTSD) may affect 10% of women and 5% of men at some stage, and symptoms may persist for several years. Risk factors include major trauma, lack of social support, peritraumatic dissociation, and previous psychiatric history or personality factors.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent PTSD? What are the effects of interventions to treat PTSD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 46 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: affect management; antiepileptic drugs; antihypertensive drugs; benzodiazepines; brofaromine; CBT; drama therapy; eye movement desensitisation and reprocessing; fluoxetine; group therapy; hydrocortisone; hypnotherapy; inpatient treatment programmes; Internet-based psychotherapy; mirtazapine; multiple-session CBT; multiple-session collaborative trauma support; multiple-session education; nefazodone; olanzapine; paroxetine; phenelzine; psychodynamic psychotherapy; risperidone; SSRIs (versus other antidepressants); sertraline; single-session group debriefing; single-session individual debriefing; supportive psychotherapy; supportive counselling; temazepam; tricyclic antidepressants; and venlafaxine.
Key Points
Post-traumatic stress disorder (PTSD) is characterised by disabling symptoms of re-experiencing a traumatic event, avoidance behaviour, and hyperarousal (e.g., irritability or hypervigilance), lasting at least 1 month. PTSD may affect 10% of women and 5% of men at some stage, and symptoms may persist for several years.Risk factors include major trauma, lack of social support, peritraumatic dissociation, and previous psychiatric or personality factors.
Multiple-session trauma-focused CBT may be effective at preventing development of PTSD in people with psychological distress after a traumatic event. However, we don't know whether multiple-session trauma-focused CBT is beneficial for people who have experienced a traumatic event but have not been diagnosed with psychological distress.
We don't know whether antiepileptic drugs, antihypertensive drugs, hydrocortisone, multiple-session collaborative trauma support, multiple-session education, single-session group debriefing, or temazepam are beneficial in preventing PTSD. Single-session individual debriefing may increase the rate of PTSD after a traumatic event compared with no debriefing, and supportive counselling may be less effective than multiple-session CBT at preventing onset of PTSD.
In people with PTSD, trauma-focused CBT improves PTSD symptoms compared with no treatment or with other psychological interventions, including stress management and present-centred therapy. Eye movement desensitisation and reprocessing seems as effective as trauma-focused CBT in the treatment of chronic PTSD. We don't know whether other psychological treatments (affect management, drama therapy, group therapy, hypnotherapy, inpatient treatment regimens, Internet-based psychotherapy, psychodynamic psychotherapy, or supportive psychotherapy) are beneficial in people with PTSD.
Paroxetine may improve symptoms in people with PTSD. However, venlafaxine does not seem effective at improving symptoms, and the benefits of fluoxetine are unclear. We found insufficient good evidence to assess the effects of sertraline, tricyclic antidepressants, or benzodiazepines.We found limited evidence that sertraline and nefazodone may be equally effective at improving symptoms of PTSD, but we don't know how other antidepressants compare with each other in the treatment of PTSD.We don't know whether antiepileptic drugs, antihypertensive drugs, brofaromine, nefazodone, olanzapine, phenelzine, mirtazapine, or risperidone are beneficial in people with PTSD.
PMCID: PMC2907597  PMID: 21718580

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