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1.  A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients 
Background
Cocaine abuse and dependence continue to be widespread. Currently there are no pharmacotherapies shown to be effective in the treatment of cocaine dependence.
Methods
A 33-week outpatient clinical trial of fluoxetine (60 mg/day, p.o.) for cocaine dependence was conducted that incorporated abstinence-contingent voucher incentives. Participants (n=145) were both cocaine and opioid dependent and treated with methadone. A stratified randomization procedure assigned subjects to one of four conditions: fluoxetine plus voucher incentives (FV), placebo plus voucher incentives (PV), fluoxetine without vouchers (F), and placebo without vouchers (P). Dosing of fluoxetine/placebo was double blind. Primary outcomes were treatment retention and cocaine use based on thrice-weekly urine testing.
Results
The PV group had the longest treatment retention (mean of 165 days) and lowest probability of cocaine use. The adjusted predicted probabilities of cocaine use were: 65% in the P group, 60% in the F group, 56% in the FV group, and 31% in the PV group.
Conclusions
Fluoxetine was not efficacious in reducing cocaine use in patients dually dependent on cocaine and opioids.
doi:10.1016/j.jsat.2010.11.010
PMCID: PMC3078567  PMID: 21266301
Cocaine; Contingency management; Fluoxetine; Methadone
2.  Levodopa Pharmacotherapy for Cocaine Dependence: Choosing the Optimal Behavioral Therapy Platform 
Drug and alcohol dependence  2007;94(1-3):142-150.
Background:
The dopamine precursor levodopa has shown some, albeit relatively weak, promise in treating cocaine dependence. This study sought to identify the most appropriate behavioral therapy platform for levodopa pharmacotherapy by evaluating its effect when administered in combination with behavioral platforms of varying intensities.
Method:
A total of 161 treatment-seeking cocaine dependent subjects received sustained release levodopa/carbidopa (400/100 mg bid, Sinemet) or placebo delivered in combination with Clinical Management (ClinMan); ClinMan+Cognitive Behavioral Therapy (CBT); or ClinMan+CBT+Voucher-Based Reinforcement Therapy (VBRT) in a 12-week randomized, placebo-controlled, double-blind (for medication condition) trial. Medication compliance was monitored with riboflavin (100 mg/capsule) and the Medication Event Monitoring System. Protocol compliance was addressed in weekly, 10-minute nurse-delivered ClinMan sessions. Weekly, 1-hour CBT sessions focused on coping skills training. VBRT (with escalating reinforcer value) provided cash-valued vouchers contingent on cocaine-negative urine toxicology results. Urine benzoylecgonine assays collected thrice-weekly were analyzed by intention-to-treat criteria using generalized linear mixed models.
Results:
Levodopa main effects were found on all outcome measures of cocaine use. Contrasts testing the levodopa-placebo difference within each behavioral platform found reliable effects, favoring levodopa, only in the VBRT platform. Levodopa treatment with vouchers produced higher proportions of cocaine-negative urines and longer periods of consecutive abstinence compared to other treatment combinations.
Conclusion:
This is the first study to find a significant treatment effect for levodopa and, in doing so, to demonstrate that the magnitude of this effect is dependent upon conditions of the behavioral therapy platform. The data support use of levodopa with abstinence-based reinforcement therapy as one efficacious combination in cocaine dependence disorder treatment.
doi:10.1016/j.drugalcdep.2007.11.004
PMCID: PMC2293271  PMID: 18164144
levodopa-carbidopa; cocaine treatment; contingency management; Voucher-Based Reinforcement Therapy; VBRT
3.  Novel pharmacotherapeutic treatments for cocaine addiction 
BMC Medicine  2011;9:119.
Cocaine is a stimulant that leads to the rapid accumulation of catecholamines and serotonin in the brain due to prevention of their re-uptake into the neuron that released the neurotransmitter. Cocaine dependence is a public health concern and cause of significant morbidity and mortality worldwide. At present, there are no approved medications for the treatment of this devastating illness, and behavioral interventions have proven to be of limited use. However, there have been a number of recent trials testing promising agents including dopamine agonists, GABAergic medications and the cocaine vaccine. Here we discuss the most recent human clinical trials of potential medications for treatment of cocaine dependence, as well as pre-clinical studies for another promising agent, levo tetrahydropalmatine. Examination of these recent findings shows promise for GABAergic medications and the cocaine vaccine, as well as unique medications such as disulfiram, whose mechanism remains to be determined. Future work may also confirm specific subgroups of patients for treatment response based on clinical characteristics, biomarkers and pharmacogenetics. This review highlights the need for further, bigger studies in order to determine optimal clinical usage.
doi:10.1186/1741-7015-9-119
PMCID: PMC3216852  PMID: 22047090
4.  Pharmacologic approaches to the treatment of cocaine dependence. 
Western Journal of Medicine  1990;152(5):573-577.
When pharmacologic agents are considered in the treatment of cocaine addiction, the objective of such treatment--sustained abstinence--must be considered. Medication and medical approaches have been disappointing in the treatment of cocaine overdose. The central neurobiologic mechanism(s) involved in cocaine toxicity are poorly understood. Without a cocaine antagonist, pharmacologic approaches have been less than promising in preventing relapse. Various psychoactive medications have been tried in early cocaine abstinence, with some success.
PMCID: PMC1002413  PMID: 1971975
5.  Brain mu-opioid receptor binding predicts treatment outcome in cocaine-abusing outpatients 
Biological psychiatry  2010;68(8):697-703.
Background
Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown.
Methods
We determined whether regional brain mOR binding before treatment correlates with outcome and compared it to standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine-abstinence reinforcement whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography (PET) with [11C] carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment, 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology.
Results
Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sub-lobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use.
Conclusions
Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction.
doi:10.1016/j.biopsych.2010.05.003
PMCID: PMC2949457  PMID: 20579973
cocaine; mu-opioid receptor; PET; treatment; addiction; dependence
6.  Pharmacotherapy of Methamphetamine Addiction: An Update 
Methamphetamine dependence is a serious public health problem worldwide for which there are no approved pharmacological treatments. Psychotherapy is still the mainstay of treatment; however, relapse rates are high. The search for effective pharmacological treatment has intensified in the last decade. This review will highlight progress in pharmacological interventions to treat methamphetamine dependence as well as explore new pharmacological targets. Published data from clinical trials for stimulant addiction were searched using PubMed and summarized, as well as highlights from a recent symposium on methamphetamine pharmacotherapy presented at the ISAM 2006 meeting, including interim analysis data from an ongoing D-amphetamine study in Australia. Early pilot data are encouraging for administering D-amphetamine and methylphenidate as treatment for heavy amphetamine users. Abilify at 15 mg/day dose increased amphetamine use in an outpatient pilot study. Sertraline, ondansetron, baclofen, tyrosine, and imipramine were ineffective in proof-of-concept studies. Development of pharmacotherapy for methamphetamine dependence is still in an early stage. Data suggesting D-amphetamine and methylphenidate as effective pharmacotherapy for methamphetamine addiction will need to be confirmed by larger trials. Preclinical data suggest that use of GVG, CB1 antagonist, and lobeline are also promising therapeutic strategies.
doi:10.1080/08897070802218554
PMCID: PMC2597382  PMID: 19042205
Methamphetamine; pharmacotherapy; bupropion; aripiprazole; methylphenidate; D-amphetamine
7.  Psychological treatments for stimulant misuse, comparing and contrasting those for amphetamine dependence and those for cocaine dependence 
Current opinion in psychiatry  2009;22(3):263-268.
Purpose of review
The aim is to compare and contrast psychological treatments for amphetamine and cocaine dependence.
Recent findings
Stimulant dependence, in the form of cocaine or amphetamine/methamphetamine dependence, is prevalent worldwide, and their ratio may vary across different countries and regions of countries. The treatment of stimulant disorders has greatly advanced in recent years, and scientific evaluation of behavioral therapies, using randomized clinical trials designs and a stage-wise approach, have demonstrated the safety and efficacy of interventions. Psychological interventions such as cognitive behavioral therapy and contingency management for cocaine and methamphetamines use disorders are well tolerated and moderately effective in achieving drug abstinence. There is evidence that contingency management interventions can help to improve retention in treatment and, in turn, other treatment outcomes. Although there are important differences in the neuropsychiatric and medical consequences of cocaine and amphetamine use disorders, there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of these disorders.
Summary
As there are no Food and Drug Administration-approved medications for the treatment of these disorders, psychological interventions form the basis of their treatment. More research is needed to address the specific psychosocial needs of cocaine and amphetamine-dependent individuals in order to improve their treatment outcomes.
doi:10.1097/YCO.0b013e32832a3b44
PMCID: PMC2825894  PMID: 19307968
amphetamine; behavioral; cocaine; methamphetamine; treatment
8.  Computerized Behavior Therapy for Opioid-Dependent Outpatients: A Randomized Controlled Trial 
We evaluated the efficacy of an interactive, computer-based behavioral therapy intervention, grounded in the community reinforcement approach (CRA) plus voucher-based contingency management model of behavior therapy. Our randomized, controlled trial was conducted at a university-based research clinic. Participants comprised 135 volunteer adult outpatients who met DSM-IV criteria for opioid dependence. All participants received maintenance treatment with buprenorphine and were randomly assigned to one of three treatments: (1) therapist-delivered CRA treatment with vouchers, (2) computer-assisted CRA treatment with vouchers, or (3) standard treatment. The therapist-delivered and computer-assisted CRA plus vouchers interventions produced comparable weeks of continuous opioid and cocaine abstinence (mean = 7.98 and 7.78, respectively) and significantly greater weeks of abstinence than the standard intervention (mean = 4.69; p<.05), yet participants in the computer-assisted CRA condition had over 80% of their intervention delivered by an interactive computer program. The comparable efficacy obtained with computer-assisted and therapist-delivered therapy may enable more widespread dissemination of the evidence-based CRA plus vouchers intervention in a manner that is cost-effective and ensures treatment fidelity.
doi:10.1037/1064-1297.16.2.132
PMCID: PMC2746734  PMID: 18489017
Computerized treatment; opioid dependence; buprenorphine; cognitive-behavior therapy; controlled trial
9.  Anti-relapse medications: Preclinical models for drug addiction treatment 
Pharmacology & therapeutics  2009;124(2):235-247.
Addiction is a chronic relapsing brain disease and treatment of relapse to drug-seeking is considered the most challenging part of treating addictive disorders. Relapse can be modeled in laboratory animals using reinstatement paradigms, whereby behavioral responding for a drug is extinguished and then reinstated by different trigger factors, such as environmental cues or stress. In this review, we first describe currently used animal models of relapse, different relapse triggering factors, and the validity of this model to assess relapse in humans. We further summarize the growing body of pharmacological interventions that have shown some promise in treating relapse to psychostimulant addiction. Moreover, we present an overview on the drugs tested in cocaine or methamphetamine addicts and examine the overlap of existing preclinical and clinical data. Finally, based on recent advances in our understanding of the neurobiology of relapse and published preclinical data, we highlight the most promising areas for future anti-relapse medication development.
doi:10.1016/j.pharmthera.2009.06.014
PMCID: PMC2889132  PMID: 19683019
cocaine; drug screening; methamphetamine; reinstatement; relapse; self-administration
10.  Voucher incentives increase treatment participation in telephone-based continuing care for cocaine dependence 
Drug and alcohol dependence  2010;114(2-3):225-228.
Background
Telephone-based monitoring is a promising approach to continuing care of substance use disorders, but patients often do not engage or participate enough to benefit. Voucher incentives can increase retention in outpatient treatment and continuing care, but may be less effective when reinforcement is delayed, as in telephone-based care. We compared treatment utilization rates among cocaine-dependent patients enrolled in telephone continuing care with and without voucher incentives to determine whether incentives increase participation in telephone-based care.
Method
Participants were 195 cocaine-dependent patients who completed two weeks of community-based intensive outpatient treatment for substance use disorders and were randomly assigned to receive telephone continuing care with or without voucher incentives for participation as part of a larger clinical trial. The 12-month intervention included 2 in-person orientation sessions followed by up to 30 telephone sessions. Incentivized patients could receive up to $400 worth of gift cards.
Results
Patients who received incentives were not more likely to complete their initial orientation to continuing care. Incentivized patients who completed orientation completed 67% of possible continuing care sessions, as compared to 39% among non-incentivized patients who completed orientation. Among all patients randomized to receive incentives, the average number of completed sessions was 15.5, versus 7.2 for patients who did not receive incentives, and average voucher earnings were $200.
Conclusions
Voucher incentives can have a large effect on telephone continuing care participation, even when reinforcement is delayed. Further research will determine whether increased participation leads to better outcome among patients who received incentives.
doi:10.1016/j.drugalcdep.2010.09.007
PMCID: PMC3046319  PMID: 21041041
cocaine dependence; continuing care; voucher incentives; treatment retention
11.  Contingency Management and Levodopa-Carbidopa for Cocaine Treatment: A Comparison of Three Behavioral Targets 
New data support use of levodopa pharmacotherapy with behavioral contingency management (CM) as one efficacious combination in cocaine dependence disorder treatment. A potential mechanism of the combined treatment effects may be related to dopamine-induced enhancement of the saliency of contingently delivered reinforcers. Evidence to support this mechanism was sought by evaluating levodopa-enhancing effects across distinct CM conditions that varied in behavioral targets. A total of 136 treatment-seeking, cocaine dependent subjects participated in this 12-week, randomized, placebo-controlled trial of levodopa (vs. placebo) administered in combination with one of three behavioral CM conditions. In the CM-URINE condition, subjects received cash-valued vouchers contingent on cocaine-negative urine toxicology results. In the CM-ATTEND condition, the same voucher schedule was contingent on attending thrice weekly clinic visits. In the CM-MEDICATION condition, the same voucher schedule was contingent on Medication Event Monitoring Systems- and riboflavin-based evidence of pill-taking behavior. Primary outcomes associated with each CM target behavior were analyzed using generalized linear mixed models for repeated outcomes. CM responding in the CM-ATTENDANCE and CM-MEDICATION conditions showed orderly effects, with each condition producing corresponding changes in targeted behaviors, regardless of medication condition. In contrast, CM responding in the CM-URINE condition was moderated by medication, with levodopa-treated subjects more likely to submit cocaine-negative urines. These findings specify the optimal target behavior for CM when used in combination with levodopa pharmacotherapy.
doi:10.1037/a0019195
PMCID: PMC3164487  PMID: 20545388
contingency management; levodopa; medication compliance; pharmacotherapy; behavior therapy
12.  Maintenance of reinforcement to address the chronic nature of drug addiction 
Preventive medicine  2012;55(Suppl):S46-S53.
Background
Drug addiction can be a chronic problem. Abstinence reinforcement can initiate drug abstinence, but as with other treatments many patients relapse after the intervention ends. Abstinence reinforcement can be maintained to promote long-term drug abstinence, but practical means of implementing long-term abstinence reinforcement are needed.
Methods
We reviewed 8 clinical trials conducted in Baltimore, MD from 1996 through 2010 that evaluated the therapeutic workplace as a vehicle for maintaining reinforcement for the treatment of drug addiction. The therapeutic workplace uses employment-based reinforcement in which employees must provide objective evidence of drug abstinence or medication adherence to work and earn wages.
Results
Employment-based reinforcement can initiate (3 of 4 studies) and maintain (2 studies) cocaine abstinence in methadone patients, although relapse can occur even after long-term exposure to abstinence reinforcement (1 study). Employment-based reinforcement can also promote abstinence from alcohol in homeless alcohol dependent adults (1 study), and maintain adherence to extended-release naltrexone in opioid dependent adults (2 studies).
Conclusion
Treatments should seek to promote life-long effects in patients. Therapeutic reinforcement may need to be maintained indefinitely to prevent relapse. Workplaces could be effective vehicles for the maintenance of therapeutic reinforcement contingencies for drug abstinence and adherence to addiction medications.
doi:10.1016/j.ypmed.2012.03.013
PMCID: PMC3437006  PMID: 22668883
Reinforcement; Incentives; Contingency Management; Cocaine; Heroin; Drug Addiction; Treatment; Employment; Poverty; Relapse
13.  Effects of Oral Methamphetamine on Cocaine Use: A Randomized, Double-Blind, Placebo-Controlled Trial 
Drug and alcohol dependence  2008;101(1-2):34-41.
Background
No medication is currently approved for the treatment of cocaine dependence, but several preclinical and clinical reports suggest agonist-like medications, e.g. amphetamine analogues, may be a productive strategy for medication development.
Objective
This current proof-of-concept study sought to evaluate the safety, tolerability, and effectiveness of methamphetamine as a candidate treatment for cocaine dependence.
Methods
A randomized, double-blind, placebo-controlled study served to evaluate three treatment conditions in 82 cocaine-dependent individuals: (1) placebo (0 mg, 6×/day; n = 27), (2) immediate release (IR) methamphetamine (5 mg, 6×/day; n = 30), (3) sustained release (SR) methamphetamine (30 mg first pill, 1×/day; 0 mg 5×/day; n = 25). The study employed a sequential, two-phase design (i.e., 4 weeks of medication and counseling followed by 4 weeks of medication/counseling plus a contingency management procedure).
Results
Both preparation forms of methamphetamine were well tolerated, with similar retention to placebo (0 mg, 33%; 30 mg IR, 30%, 30 mg SR, 32%). Methamphetamine SR was associated with decreased sleep and increased weight loss. Medication adherence rates were high for the first dose of the day (95%), while adherence for subsequent capsules was lower. Those in the SR condition exhibited consistently lower rates of cocaine-positive urine samples (0 mg, 60%; 30 mg IR, 66%, 30 mg SR, 29%), p<0.0001, and reported the greatest reduction in craving for cocaine, p<0.05.
Conclusions
SR methamphetamine significantly reduced cocaine use and craving. Additional research is warranted to develop and evaluate agonist-like medications that may effectively treat cocaine dependence.
doi:10.1016/j.drugalcdep.2008.10.016
PMCID: PMC2742691  PMID: 19058926
cocaine; methamphetamine; dextroamphetamine; agonist-like treatment
14.  Methamphetamine Cured my Cocaine Addiction 
Cocaine dependence is an enduring problem and years of research and drug development has yet to produce an efficacious pharmacotherapy. Recent clinical research suggests that chronic treatment with amphetamine-like medications produces tolerance to cocaine’s reinforcing effects and may offer a viable pharmacotherapy. Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously addicted to cocaine are reviewed. Data obtained from initial screen and informal conversation suggested that all participants considered methamphetamine to have helped them stop using cocaine and eliminate cocaine craving. Methamphetamine also significantly decreased their alcohol consumption but did not alter cannabis or nicotine use.
doi:10.4172/2155-6105.1000103
PMCID: PMC3467950  PMID: 23066512
Drug abuse; Stimulants; Tolerance; Pharmacotherapies; Prodrug
15.  Topiramate for the treatment of methamphetamine addiction: a multi-center placebo-controlled trial 
Addiction (Abingdon, England)  2012;107(7):1297-1306.
Aims
Topiramate has shown efficacy at facilitating abstinence from alcohol and cocaine abuse. This double-blind, placebo-controlled outpatient trial tested topiramate for treating methamphetamine addiction.
Design
Participants (N=140) were randomized to receive topiramate or placebo (13 weeks) in escalating doses from 50 mg/day to the target maintenance of 200 mg/day in weeks 6–12 (tapered in week 13). Medication was combined with weekly brief behavioral compliance enhancement treatment.
Setting
The trial was conducted at eight medical centers in the United States.
Participants
One hundred forty methamphetamine-dependent adults took part in the trial.
Measurements
The primary outcome was abstinence from methamphetamine during weeks 6 – 12. Secondary outcomes included use reduction versus baseline, as well as psychosocial variables.
Findings
In the intent-to-treat analysis, topiramate did not increase abstinence from methamphetamine during weeks 6–12. For secondary outcomes, topiramate reduced weekly median urine methamphetamine levels and observer-rated severity of dependence scores significantly. Subjects with negative urine before randomization (N=26) had significantly greater abstinence on topiramate versus placebo during study weeks 6–12. Topiramate was safe and well tolerated.
Conclusions
Topiramate does not appear to promote abstinence in methamphetamine users but can reduce the amount taken and reduce relapse rates in those who are already abstinent.
doi:10.1111/j.1360-0443.2011.03771.x
PMCID: PMC3331916  PMID: 22221594
topiramate; methamphetamine abuse; abstinence facilitation; treatment
16.  Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction 
Addiction (Abingdon, England)  2010;105(1):38-48.
Background
No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenuation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system.
Aim
To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward.
Methods
Preclinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed.
Results and conclusions
Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine (Ach) and norepinephrine (NE) are particularly well-suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market, have a good safety profile, and low abuse potential. These include galantamine, donepezil, and rivastigmine (cholinesterase inhibitors), varenicline (partial nicotine agonist), guanfacine (alpha2-adrenergic agonist), and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction.
doi:10.1111/j.1360-0443.2009.02791.x
PMCID: PMC2808705  PMID: 20078461
Cognition; stimulants; cognitive enhancers; pharmacotherapy
17.  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
18.  Delay Discounting is Associated with Treatment Response among Cocaine-Dependent Outpatients 
Rationale
Delay discounting (DD) describes the rate at which reinforcers lose value as the temporal delay to their receipt increases. Steeper discounting has been positively associated with vulnerability to substance use disorders, including cocaine use disorders.
Objectives
In the present study, we examined whether DD of hypothetical monetary reinforcers is associated with the duration of cocaine abstinence achieved among cocaine-dependent outpatients.
Methods
Participants were 36 adults who were participating in a randomized controlled trial examining the efficacy of voucher-based contingency management (CM) using low-magnitude (N = 18) or high-magnitude (N = 18) voucher monetary values.
Results
DD was associated with the number of continuous weeks of cocaine abstinence achieved, even after adjusting for treatment condition during the initial 12-week (t(33) = 2.48, p = .045) and entire recommended 24-week of treatment (t(33) = 2.40, p = .022). Participants who exhibited steeper discounting functions achieved shorter periods of abstinence in the Low-magnitude voucher condition (12-week: t(16) = 2.48, p = .025; 24-week: t(16) = 2.68, p = .017), but not in the High-magnitude voucher condition (12-week: t(16) = 0.51, p = .618; 24-week: t(16) = 1.08, p = .298), although the interaction between DD and treatment condition was not significant (12-week: t(32) = −1.12, p = .271; 24-week: t(32) = −0.37, p = .712).
Conclusions
These results provide further evidence on associations between DD and treatment response and extend those observations to a new clinical population (i.e., cocaine-dependent outpatients), while also suggesting that a more intensive intervention like the High-magnitude CM condition may diminish this negative relationship between DD and treatment response.
doi:10.1037/a0023617
PMCID: PMC3476946  PMID: 21517195
Temporal discounting; delay discounting; cocaine dependence; contingency management; vouchers; treatment response
19.  The cost effectiveness of prize-based and voucher-based contingency management in a population of cocaine- or opioid-dependent outpatients 
Drug and alcohol dependence  2009;102(1-3):108-115.
Objective
To evaluate the cost-effectiveness of using prize-based and voucher-based contingency management (CM) as additions to standard treatment for cocaine- or heroin-dependent outpatients in community treatment centers.
Methods
This cost-effectiveness analysis is based on a randomized clinical trial conducted at three community-based outpatient psychosocial substance abuse treatment clinics. A total of 142 cocaine- or heroin-dependent outpatients were randomly assigned to one of three treatment conditions: standard treatment (ST), ST with prizes (prize CM), or ST with vouchers (voucher CM) for 12 weeks. The primary patient outcome was the longest duration of confirmed abstinence (LDA) from cocaine, opioids and alcohol during treatment. Unit costs were collected from the three participating clinics. Resource utilizations and patient outcomes were obtained from the clinical trial. Incremental cost-effectiveness ratios (ICERs) and acceptability curves were used to evaluate the relative cost-effectiveness of the interventions.
Results
Based on the ICERs and acceptability curves, ST is likely to be the most cost-effective intervention when the threshold value to decision makers of lengthening the LDA during treatment by 1 week is less than approximately $166, and prize CM is likely to be the most cost-effective intervention when the threshold value is greater than approximately $166.
Conclusions
Prize CM was found likely to be the most cost-effective intervention over a comparatively wide range of threshold values for lengthening the LDA during treatment by 1 week. However, additional studies with alternative incentive parameters are required to determine the generalizability of our results.
doi:10.1016/j.drugalcdep.2009.02.005
PMCID: PMC2679219  PMID: 19324501
acceptability curves; contingency management; cost-effectiveness; prizes; vouchers
20.  Inmunoterapias para las adicciones a las drogas Immunotherapies for Drug Addictions 
Adicciones  2008;20(2):111-115.
Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders.
PMCID: PMC2633931  PMID: 18551223
immunotherapy; vaccine; drug abuse; treatment; cocaine; nicotine
21.  Acamprosate: a new tool in the battle against alcohol dependence 
Acamprosate, a medication that has been used in Europe for years, is the newest drug to be approved by the US Federal Drug Administration for the treatment of alcohol dependence. It has been shown to assist in the maintenance of abstinence in recently detoxified alcohol-dependent individuals. The following review delineates the proposed mechanism of action and pharmacokinetics of the drug. Findings of clinical trials are outlined and topics such as cost effectiveness, comparison with other medications used for the treatment of alcohol dependences as well as combination pharmacotherapy are discussed. In combination with psychosocial treatment, acamprosate is a promising tool for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal. This review also illustrates the continued need to search for more effective treatments, as the overall effectiveness of our currently available pharmacotherapies remains limited in the long-term maintenance of recovery from alcohol dependence.
PMCID: PMC2671951  PMID: 19412493
acamprosate; alcohol; alcohol dependence; abstinence
22.  Extended Release Mixed Amphetamine Salts and Topiramate for Cocaine Dependence: A Randomized Controlled Trial 
Biological psychiatry  2012;72(11):950-956.
Background
Cocaine dependence is a substantial public health problem, yet there are no clearly effective medication treatments. Amphetamine and topiramate have both shown promise for the treatment of cocaine dependence in preclinical and early-stage clinical studies.
Method
Eighty-one cocaine-dependent adults were randomized to receive a combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo for twelve weeks under double-blind conditions. MAS-ER doses were titrated over two weeks to a maximum dose of 60 mg daily and topiramate doses were titrated over six weeks to a maximum dose of 150 mg twice daily. All participants received a supportive behavioral intervention. The primary outcome was the proportion of individuals who achieved three consecutive weeks of abstinence as measured by urine toxicology confirmed self-report.
Results
The overall proportion of participants who achieved three consecutive weeks of abstinence was larger in the extended-release mixed amphetamine salts and topiramate group (33.3%) than in placebo group (16.7%). There was a significant moderating effect of baseline total number of cocaine use days (Wald χ2=3.75, df =1, P=.05) on outcome suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use.
Conclusions
The results of this study supported our hypothesis that the combination of MASER and topiramate would be superior to placebo in achieving three weeks of consecutive abstinence. These findings provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals.
doi:10.1016/j.biopsych.2012.05.032
PMCID: PMC3648884  PMID: 22795453
cocaine dependence; amphetamines; topiramate; treatment; clinical trial; substance dependence
23.  Contingent reinforcement of abstinence with individuals abusing cocaine and marijuana. 
Two males diagnosed with cocaine dependence received a behavioral intervention comprised of contingency management and the community reinforcement approach. During the initial phase of treatment, reinforcement was delivered contingent on submitting cocaine-free urine specimens. The community reinforcement approach involved two behavior therapy sessions each week. Almost complete cocaine abstinence was achieved, but regular marijuana use continued. During a second phase, reinforcement magnitude was reduced, but remained contingent on submitting cocaine-free specimens. Behavior therapy was reduced to once per week. Cocaine abstinence and regular marijuana use continued. Next, reinforcement was delivered contingent on submitting cocaine- and marijuana-free specimens. This modified contingency resulted in an abrupt increase in marijuana abstinence and maintenance of cocaine abstinence. One- and 5-month follow-ups indicated that cocaine abstinence continued, but marijuana smoking resumed. These results indicate that the behavioral intervention was efficacious in achieving abstinence from cocaine and marijuana; maintenance, however, was achieved for cocaine only.
doi:10.1901/jaba.1991.24-657
PMCID: PMC1279622  PMID: 1797769
24.  Monetary Alternative Reinforcers More Effectively Decrease Intranasal Cocaine Choice Than Food Alternative Reinforcers 
Cocaine dependence continues to be a significant public health concern. Contingency management, wherein alternative reinforcers are made available upon cocaine abstinence, has shown promise for decreasing cocaine use. Other research has modeled this effect and demonstrated that alternative reinforcers also reduce cocaine self-administration in the laboratory. Results from both clinical and laboratory studies suggest that the type and value of alternative reinforcers influences their ability to decrease drug choice. The purpose of the present experiment was to determine the effect of money or food alternative reinforcers, valued at $0.01, 0.25, 0.50 and 1.00, on intranasal cocaine (4 [placebo] and 30 mg) choice. Cocaine was chosen to a greater extent than placebo across alternative reinforcer types and values, but the monetary alternative reinforcer suppressed drug choice to a greater degree than the food reinforcer. These results are concordant with previous findings and suggest that money may be a more effective alternative reinforcer for decreasing cocaine use. Future research should determine the sensitivity of this model to specific behavioral aspects of contingency management and whether food could compete with drugs as reinforcers in humans under laboratory conditions.
doi:10.1016/j.pbb.2010.01.003
PMCID: PMC2830279  PMID: 20109483
Cocaine; Alternative Reinforcer; Humans
25.  Evaluation of Subjective Effects of Aripiprazole and Methamphetamine in Methamphetamine-Dependent Volunteers 
A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind inpatient clinical pharmacology study to assess potential interactions between intravenous (IV) methamphetamine (15mg and 30mg) and oral aripiprazole (15mg). In addition, the effects of aripiprazole treatment on abstinence related craving and cue-induced craving were evaluated. Participants included non-treatment seeking, methamphetamine dependent patients (N=16), 18-45 years of age, currently using methamphetamine. Following baseline methamphetamine dosing (15mg and 30mg), participants received 2 weeks of treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and methamphetamine-related cues. Methamphetamine dosing (15mg and 30mg) was then repeated. Aripiprazole treatment had no effect on cue-induced methamphetamine craving, or on daily baseline craving assessed over the course of medication treatment, though aripiprazole treatment was associated with increased craving independent of methamphetamine dosing. Aripiprazole treatment was associated with significantly higher ratings on ARCI subscales reflecting euphoria and amphetamine-like effects following methamphetamine dosing. Aripiprazole was treatment was also associated with significant reductions in ratings of “bad effects” and reductions on the ARCI subscale for sedation effects following methamphetamine dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following methamphetamine dosing, but had no other effects on cardiovascular responses to methamphetamine. Aripiprazole treatment did not alter the pharmacokinetics of methamphetamine. These findings indicate that aripiprazole treatment appears to be safe in volunteers with methamphetamine dependence, though the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute methamphetamine suggests that 15mg aripiprazole is unlikely to be efficacious for the treatment of methamphetamine dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for methamphetamine dependence.
doi:10.1017/S1461145708009097
PMCID: PMC2782728  PMID: 18664303

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