Efficacy of Psychostimulant Drugs for Cocaine Dependence

Xavier Castells; Miguel Casas; Rosa Bosch; Josep Antoni Ramos‐Quiroga; Carlos Roncero; Xavier Vidal; Dolors Capellà

doi:10.1002/14651858.CD007380

Efficacy of Psychostimulant Drugs for Cocaine Dependence

Authors' declarations of interest

Version published: 08 October 2008 Version history

https://doi.org/10.1002/14651858.CD007380

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the efficacy and safety of CNS stimulants for cocaine abuse with and without coexisting co morbidities by means of a meta‐analysis in the context of a systematic review.

Background

Cocaine use disorders, including cocaine abuse and cocaine dependence (DSM IV), prevalence is growing and cocaine use related disorders have become a worldwide public health problem. It is estimated that, approximately 2.3 million Americans were currently using cocaine in 2003, with approximately one third of that group smoking crack cocaine (SAMSHA 2004). In addition, 1.1 million people used cocaine for the first time during that year, representing an slight increase over the previous 3 years. In the European Union (EU) cocaine use has been uninterruptedly increasing since mid 1990. 3.7% of the EU adult population has used cocaine in their life, being more than 5 % in Spain, Italy and the United Kingdom. Use over the past year prevalence is 1.3 % on average, but above 2% again in Spain, Italy and the United Kingdom (EMCDDA 2007a).

The prevalence of cocaine use and cocaine related disorders is specially high in vulnerable populations such as patients with Attention Deficit/Hyperactivity Disorder (ADHD) or opioid dependence. Thirty five percent of patients with ADHD have a comorbid cocaine abuse (Levin 1998). Besides, cocaine is found as a secondary drug in 23 % of opioid dependents seeking treatment in the EU (EMCDDA 2007b) and up to 50% in the United States (Kosten 1987;Kidorf 1993).

Description of the condition

Cocaine use disorders comprise two clinical entities: cocaine abuse and cocaine dependence. Both disorders are characterized by ongoing cocaine use despite recurring significant physical, psychical and social problems associated with such use (DSM IV). In addition to that, cocaine dependence is characterized by tolerance, withdrawal, and a pattern of compulsive administration (DSM IV).

From biologic point of view, cocaine addiction is characterized by a dopaminergic and glutamates dis‐regulation. Cocaine is a dopamine (DA) and norepinephrine (NE) reuptake inhibitor and thus, it increases DA in the nucleus accumbens. DA release in the nucleus accumbens has been associated with drug reinforcing properties (Koob 1988; Volkow 1997a). With repeated cocaine use a down‐regulation of both DA release and DA₂ receptors in striatum (Volkow 1990; Volkow 1996; Volkow 1997b; Volkow 2004) occurs. The DAergic dysfunction explains two core features of cocaine dependence: tolerance and withdrawal. Together with a DA dysfunction a glutamate hyperactivity, mainly at the prefrontal cortex and amygdala, characterize from a biological point of view the two remaining cocaine dependence characteristics: a compulsive pattern of cocaine use and relapse to cocaine use after a cocaine‐free period (Kalivas 2005).

Description of the intervention

Replacement therapy involves the substitution of abused drug, which is often illegal, used parenterally several times a day, by a legal, orally administered one with long half life. A substitutive drug has a similar mechanism of action and behavioral effects to the abused one, but with a lower addictive potential, being able to block drug craving and withdrawal, and leading to drug abstinence and involving patients to follow medical and psychological assistance (Gorelick 2004). This strategy has proved to be efficacious for heroin (Dole 1969; Mattick 2003) and nicotine (Silagy 2004) dependence.

How the intervention might work

Why it is important to do this review

Around 50 drugs have been assessed for the treatment of cocaine dependence, but none of them has clearly shown to be efficacious (Kleber 2007), consequently no drug has yet been approved by the FDA or the EMEA for the treatment of cocaine dependence. However, since promising results have been shown with CNS stimulants (Castells 2007), several clinical trials are currently being carried out with these drugs (clinicaltrial.gov).

Objectives

To assess the efficacy and safety of CNS stimulants for cocaine abuse with and without coexisting co morbidities by means of a meta‐analysis in the context of a systematic review.

Methods

Criteria for considering studies for this review

Types of studies

Only randomised parallel groups placebo controlled clinical trials will be included.

Types of participants

Participants will be adults meeting criteria for cocaine abuse or cocaine dependence. In both disorders, cocaine is chronically misused leading to impairment in functioning, in cocaine abuse. Cocaine dependence is defined by a compulsive cocaine use despite related problems. This repeated cocaine use can result in tolerance or withdrawal.

Types of interventions

Experimental intervention: will be CNS stimulants for cocaine abuse. Because “psychostimulant” or “CNS stimulant” are not terms describing a pharmacological group but a pharmacological effect, there is not a single list of drugs with this effect. For this reason CNS stimulants are classified into several groups, according to their main indication, in drug classification systems such as the Anatomical Therapeutic Chemical (ATC) Classification and the American Hospital Formulary Service Pharmacologic‐Therapeutic Classification System. Consequently, a drug search was performed to obtain a complete list of drugs with psychostimulant effect. For this purpose, all drugs belonging to groups or subgroups suspected of containing potential psychomotor stimulant drugs were extracted. These pharmacological groups were the N06BA (Centrally acting sympathomimetics), A08AA (Centrally acting anti obesity products), N06BC (Xanthine derived), N06BX (Other psychostimulants and nootropics), N07BA (Drugs used in nicotine dependence) and R03DA (Xanthines) from the ATC Classification; and 12:92 (Miscellaneous autonomic drugs), 28:16.04.92 (Antidepressants, miscellaneous), 28:20.04 (Amphetamines), 28:20.92 (Anorexigenic agents and respiratory and cerebral stimulants, miscellaneous) and 86:16 (Respiratory smooth muscle relaxants) from the AHFS Classification. Furthermore, drugs metabolised to a known psychostimulant such as selegiline will be included. The World Anti‐Doping Agency (WADA) list and other sources of information in pharmacology and psychopharmacology will be reviewed too. From this list of potential CNS stimulants, only those drugs having at least one published study showing a CNS stimulant effect will be included in the definitive list of psychostimulants. CNS stimulant effect was defined as an increased CNS activity resulting in fatigue relief, improved performance in simple tasks, increased locomotor activity and anorexia in healthy subjects.

Control intervention: placebo.

Types of outcome measures

Primary outcomes

Efficacy on cocaine use assessed by means of the mean number of positive urine across the study.
Sustained cocaine abstinence (at least 2 weeks of continuous abstinence).
Retention rate.

Secondary outcomes

Safety outcomes:

Number of patients who dropped out the study due to any adverse events.
Number of patients who abused study medication.

2. Secondary efficacy outcomes:

Self‐reported cocaine use.
Cocaine craving (assessed by a quantitative scale).
Survival.
Clinical severity assessed by the Clinical Global Impression.
Global Activity Functioning
Anxiety symptoms assessed by a standardised instrument
Depressive symptoms assessed by a standardised instrument

Only for studies including dual opioid‐cocaine abusers:

Heroin use assessed by means of urine screens.
Sustained heroin abstinence.
Self‐reported heroin use.

Only for studies including dual ADHD‐cocaine abusers:

ADHD symptoms severity assessed by a standardised instrument

Search methods for identification of studies

Electronic searches

We well search the following database:

Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, issue 3 )
MEDLINE (January 1966 to July 2008)
EMBASE (January 1988 to July 2008)
PsycINFO (1985 to July 2008)
CINAHL ‐ Cumulative Index to Nursing & Allied Health Literature (1982 to July 2008)

We will search MEDLINE using MeSH headings and text words shown in Appendix 1. We will combine the search with the Cochrane highly sensitive search strategy as contained in the Cochrane Handbook for Reviews of Interventions (Higgins 2008)

We will adapt each database to take account of differences in controlled vocabulary and syntax rules.

We will search for ongoing clinical trials and unpublished studies via Internet searches on the following sites:

http://www.controlled‐trials.com;
http://clinicalstudyresults.org;
http://centralwatch.com

Searching other resources

Personal Contact

The contact author of all included studies, and experts in the field and pharmaceutical companies will be contacted and asked to identify other published, unpublished or ongoing trials.

Citations

The reference lists of retrieved studies and relevant review articles will be inspected to identify any further studies
For each included study, a citation search will be performed in ISI Web of Knowledge to identify any later studies that may have cited it.

All searches will include non‐English language literature and studies with English abstracts will be assessed for inclusion. When considered likely to meet inclusion criteria, studies will be translated.

Data collection and analysis

Selection of studies

Abstracts of potentially relevant studies will be inspected by two reviewers (XC, RB) and the full article of those studies deemed to be relevant will be requested. Where unpublished trials are identified, the coordinators will be contacted to request data.

Data extraction and management

Full papers will be inspected by at least two reviewers (XC, RB and TR) using a piloted data extraction sheet. Any disagreement will be resolved by consensus or appeal to a third author (DC). In case of missing information, authors will be emailed and missing data will be requested. A second approach will be made if no answer is obtained after one month from the first email.

The following data will be extracted:

Study description and funding:

Author
Year of publication
Country
Authors ascription affiliation: Pharmaceutical industry (Yes/No)
Study funding: Pharmaceutical industry (Yes/No)

Methods:

Sequence generation
Allocation concealment
Blinding of patients/clinicians/therapists/assessors
Design: single site/multiple site
Study length (from randomisation to treatment completion)
Number of participants
Handling of drop‐outs (ITT vs. PP)
Instruments administered to assess study outcomes.

Participants:

Inclusion/Exclusion criteria
Gender
Age (Mean, SD)
Race (% Caucasian, % Afro‐American, % other)
Employment status (% unemployed)
Comorbid disorders (% with comorbid psychiatric disorders)

Intervention:

Type of CNS stimulant
Dose
Pharmaceutical presentation
Assessment of compliance (method used to assess treatment compliance)
Adjunctive psychological interventions (description of the adjunctive psychological interventions)

Outcomes:

Cocaine use by means of urine screen (mean (SD) positive urine screens across the study)
Sustained cocaine abstinence (% patients achieving sustained cocaine abstinence)
Self‐reported cocaine use (mean (SD) days of cocaine use across the study)
Heroin use by means of urine screen (mean (SD) positive urine screens across the study)
Self‐reported heroin use (mean (SD) days of heroin use across the study)
Cocaine craving (mean (SD) cocaine craving score at study conclusion)
ADHD severity (mean ADHD (SD) cocaine craving score at study conclusion and % of patients achieving a 30% decrease in the ADHD severity score)
Clinical impression (% patients achieving an ICG score of 1 or 2 at study conclusion)
Anxiety symptoms severity (mean (SD) cocaine anxiety score at study conclusion)
Depressive symptoms severity (mean (SD) cocaine depression score at study conclusion)
Patients withdrawn due to adverse events (% patients withdrawn due to any adverse event, % patients withdrawn due to CV adverse events)
Number of patients who abused study medication
Number of patients who finished the study

Assessment of risk of bias in included studies

Each reviewer will independently assign included studies to quality categories in accordance with the dimensions mentioned below. Reviewers will seek to resolve any differences, but where this is not possible DC will adjudicate.

Sequence generation

Description: the method used to generate the allocation sequence will be described in detail so as to assess whether it should have produced comparable groups; review authors' judgment: was the allocation concealment sequence adequately generated?