Anticonvulsants for cocaine dependence
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy and the acceptability of anticonvulsants medications for cocaine dependence
Background
Cocaine is an alkaloid derived from the leaf of coca, being commonly used as powder, for intranasal or intravenous use, or as crack, a free‐base form which is smoked. Cocaine dependence is a major public health problem that is characterized by recidivism and a host of medical and psychosocial complications (EMCDDA 2006).
There is a wide and well documented range of consequences associated to acute and chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure (Higgins 1994). Both injection and non injection cocaine use are thought to increase the risk of HIV infection through high risk injecting and sexual behaviours (Sorensen 1991).
The illicit use of cocaine has become a persistent health problem worldwide. According to recent national population surveys, between 0.5 % and 6 % of the adult population report having tried cocaine at least once (i.e. lifetime prevalence), with Italy (4.6 %), Spain (4.9 %) and the United Kingdom (6.8 %) being at the upper end of this range. Recent cocaine use (last 12 months) is, in general, reported by less than 1 % of adults; in most countries, the range is between 0.3 % and 1 %. In Spain and the United Kingdom, recent prevalence rates are higher than 2 %. Although cocaine prevalence figures are much lower than comparable figures for cannabis, the prevalence of use among younger adults can be higher than the population average. Lifetime experience among 15‐ to 34‐year‐olds ranges from 1 % to 11.6 %, with the highest levels again being found in Spain (7.7 %) and the United Kingdom (11.6 %). Recent use ranges between 0.2 % and 4.6 %, with Denmark, Ireland, Italy and the Netherlands all having rates of about 2 %; Spain and the United Kingdom over 4 %. (EMCDDA 2006). In the USA in 2004, an estimated 2.0 million persons (0.8 percent) were current cocaine users; of these, 467,000 used crack during the same time period (0.2 percent) (NSDUH 2005).
More recently an increase of cocaine use among addicts seeking treatment has been observed in Italy (Davoli in press; Siliquini 2005), Spain (Suelves 2001), Australia (Topp 2003) and USA (Craddok 1997; Karch 2006).
Although effective pharmacotherapy is available for alcohol and heroin dependence (Faggiano 2003; Mattick 2003; Ntais 2005; O'Brian 2001; Policarpou 2005) none exists currently for cocaine dependence despite two decades of clinical trials primarily involving antidepressant, anti convulsivant anticonvulsants and dopaminergic medications.
There has been extensive consideration of optimal pharmacological approaches to the treatment of cocaine dependence with consideration of both dopamine antagonists and agonists (Grabowski 1997; Kosten 1996).
Four Cochrane reviews have been published on the efficacy of antidepressant (Lima 2003), antipsychotic (Amato 2007), carbamazepine (Lima Reisser 2000) and dopamine agonists (Soares 2003) for the treatment of cocaine dependence but none of them found support for the efficacy of these treatments. One review has been published on the efficacy of psychosocial treatments for psychostimulants dependence (Knapp 2007) showing that existing treatments have shown modest outcomes at best, leading to the conclusion there is still a need to develop and test different formats of existing treatment models and new psychosocial interventions.
Cocaine dependence remains a disorder for which no pharmacological treatment of proved efficacy exists, although considerable advances in the neurobiology of this addiction could guide future medication development.
Cocaine effect seems to rely on its ability to increase the availability of monoamines (dopamine, serotonin and noradrenaline) in the brain. The dopamine increase in specific areas of the meso‐limbic system, which is shared by cocaine with other drugs, like heroin, alcohol, cannabis and nicotine, has been involved in rewarding effect of drugs and self‐administration behaviour in animal and human (Di Chiara 1988; Drevets 1999; Drevets 2001; Volkow 2003).
Anticonvulsants have been candidates for the treatment of cocaine addiction based on the hypothesis that seizure kindling‐like mechanisms contribute to addiction (Crosby 1991; Kranzler 1995).
In addiction, anticonvulsants potentiate gamma‐aminobutyric acid (GABA) ‐ mediated inhibitory neurotrasmission by blocking GABA reuptake into presynaptic nerve terminals and glial cells. Moreover, anticonvulsants may be involved in the potentiation of gamma‐aminobutyric acid (GABA) ‐ mediated inhibitory neurotrasmission by blocking GABA reuptake into presynaptic nerve terminals and glial cells (Czapinski 2005; Landmark 2007). GABA neurons are part of the mesolimbic dopamine system and activation of GABA receptors in the ventral tegmental area is known to dampen dopamine neuronal activity in the nucleus accumbens (Koob 1997). The inhibitory effect of GABA may be effective in blocking cocaine‐induced increases in extracellular dopamine in the nucleus accumbens, which may lead to a decrease in cocaine reinforcement and cocaine self‐administration (Campbell 1999; Kushner 1999).
Some of the anticonvulsants more commonly studied for this purpose are carbamazepine, tiagabine, gabapentin, lamotrigine, topiramate, valproate, phenobarbital, phenytoin and vigabatrin.
There is a systematic review already published on the efficacy of carbamazepine for the treatment of cocaine dependence (Lima Reisser 2000) but there are not published reviews on the efficacy of the other anticonvulsant medications.
This review will assess the efficacy of anticonvulsants pharmacotherapy, excluding carbamazepine, on the treatment of cocaine dependence.
Objectives
To evaluate the efficacy and the acceptability of anticonvulsants medications for cocaine dependence
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials and controlled clinical trials which focus on the use of anticonvulsants medication other than carbamazepine for cocaine dependence
Types of participants
Cocaine dependents patients as diagnosed by the Diagnostic and Statistical Manual of Mental Disorder (DSM‐IV‐R) or by specialists. Trials including patients with additional diagnoses of substance dependence will be also eligible. People under 18 years of age and pregnant women will be excluded for the substantially different approach to clinical management of these people. People with comorbid mental health conditions will be included and considered in subgroup analysis
Types of interventions
Experimental intervention
-
Any anticonvulsant medications (except carbamazepine) alone or in combination with any psychosocial intervention
Control Intervention
-
Placebo
-
No intervention
-
Other pharmacological interventions
-
Any psychosocial intervention
If we find trials that compare different anticonvulsant medications, we will made separate subgroup analysis.
Furthermore we will consider different factors as confounders and take them into account in the analysis wherever possible:
‐setting (inpatient or outpatient treatment);
‐starting dose/rate and pattern of dose reduction;
‐scheduled duration of treatment;
‐severity of dependence (duration of use, route of administration, frequency of assumption);
‐health status;
‐psychiatric comorbidity;
‐other treatment offered (psychosocial support);
‐social status;
‐number of previous treatment attempts and previous treatment outcomes
Types of outcome measures
Primary outcomes
(1) Dropouts from the treatment as number of participants who did not complete the treatment
(2) Acceptability of the treatment as number and type of side effects experienced during the treatment;
(3) Use of primary substance of abuse as number of participants that reported the use of cocaine during the treatment, and/or number of participants with urine samples positive for cocaine.
(4) Results at follow‐up as number of participants using cocaine at follow‐up
Secondary outcomes
(5) Compliance
(6) Craving as measured by validated scales e.g. Brief Substance Craving Scale (BSCS), Visual Analog Scale (VAS)
(7) Severity of dependence as measured by validated scales e.g. Addiction Severity Index (ASI), Clinical Global Impression scale (CGI‐S), Clinical Global Impression ‐ Observer Scale (CGI‐O,)
(8) Amount of cocaine use (as measured by grams used or money spent)
(9) Psychiatric symptoms/psychological distress diagnosed using standard criteria e.g. Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria or measured by validated scales e.g. Hamilton depression scale, Profile of Mood States Scale (POMSS), Positive and Negative Syndrome Scale (PANSS)
Search methods for identification of studies
Search strategy for identification of studies
Electronic searches:
We will undertake a comprehensive search to identify all relevant studies. Relevant trials will be obtained from the following sources:
1) The Cochrane Central Register of Controlled Trials (CENTRAL‐ The Cochrane Library, most recent) which include the Cochrane Drugs and Alcohol Groups specialised register
2) MEDLINE (from 1966 ‐ to present)
3) EMBASE (from 1988 ‐ to present )
4) CINAHL (1982‐ to present)
We will compile detailed search strategies for each database searched. These will be based on the search strategy developed for MEDLINE but revised appropriately for each database to take account of differences in controlled vocabulary and syntax rules.
Search strategy for MEDLINE database :
1.exp cocaine‐related disorders/
2.(drug or substance) adj2 (abuse$ or misuse$ or addict$ or dependen$).ti,ab
3.((cocaine$) adj2 (abuse$ or addict$ or dependen$)).ti,ab
4.1 or 2 or 3
5.MH cocaine or
6.TX cocaine
7.5 or 6
8.4 or 7
9.MH anticonvulsants or anticonvulsant*
10.MH acetazolamide or TX acetazolamide
11.TX valproate
12.MM Valproic acid
13.MH Glucocorticoids
14.MH Corticotropin+
15.TX ACTH
16.MH clobazam or TX clobazam
17.MH clonazepam or TX clonazepam
18.MH chloridiazepoxide or TX chloridiazepoxide
19.MH diazepam or TX diazepam
20.MH ethosuximide
21.MH ethotoin or ethotoin
22.TX felbamate
23.TX phenacemide
24.MH phenytoin or TX phenytoin
25.MH Phenobarbital or TX Phenobarbital
26.TX gabapentin
27.MH Hydantoins
28.MH lamotrigine or TX lamotrigine
29.TX levetiracetam
30.MH lidocaine or TX lidocaine
31.MH Mephenytoin or TX Mephenytoin
32.MH Mephobarbital or TX Mephobarbital
33.ethosuccimide
34.MH paraldehyde or paraldehyde
35.TX paramethadione
36.pregabalin
37.MH primidone or TX primidone
38.TX stiripentol
39.TX succinimide
40.TX sulthiame
41.TX tiagabine
42.TX topiramate
43.MH trimethadione or TX trimethadione
44.MH vigabatrin or vagabatrin
45.TX zonisamide
46.9/45 OR
47.46 or 9
48.8 and 47
combined with the phases 1 & 2 of the Cochrane Sensitive Search Strategy for the identification of RCTs as published in Appendix 5b2, Cochrane Handbook for Systematic Reviews of Interventions:
49.randomized controlled trial.pt.
50.randomized controlled trials/
51.controlled clinical trial.pt.
52.random allocation/
53.double blind method/
54.single blind method/
55.49 or 50 or 51 or 52 or 53 or 54
56.clinical trial.pt.
57.exp clinical trials/
58.(clin$ adj trial$).ab,ti.
59.((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ab,ti
60.exp PLACEBOS/
61.placebo$.ab,ti
62.random$.ab,ti
63.exp Research Design/
64.56 or 57 or 58 or 59 or 60 or 61 or 62 or 63
65.55 or 64
66.48 and 65
67.limit 66 to human
Manual searches
We will also search:
(1) the reference lists of all relevant papers to identify further studies.
(2) some of the main electronic sources of ongoing trials:
"National Research Register
"Current Controlled Trials (http://www.controlled‐trials.com/)
"Clinical Trials.gov
"Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (https://oss‐sper‐clin.agenziafarmaco.it/)
"Trialsjournal.com
(3) conference proceedings likely to contain trials relevant to the review.
We will contact investigators seeking information about unpublished or incomplete trials.
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
(1) Study selection:
One author (Amato) will inspect the search hits by reading titles and abstracts. Each potentially relevant study located in the search will be obtained in full text and assessed for inclusion independently by two authors (Minozzi, Amato). Doubts will be resolved by discussion between all the authors.
(2) Assessment of the methodological quality:
One author (Minozzi) will assess study quality according to the criteria indicated in Cochrane Reviews Handbook 4.2 (Higgins 2007):
Selection bias:
Empirical research has shown that lack of adequate allocation concealment is associated with bias (Chalmers 1993; Moher 1998; Moher 1999; Schulz 1995). Iindeed, concealment has been found to be most important in preventing bias than other components of allocation, such as the generation of the allocation sequence.
Performance bias:
Systematic differences in the care provided to the participants in the comparison groups and the placebo effect could take place in the addiction field. Blinding of providers avoids co intervention and ascertainment bias whereas blinding of participants avoids contamination, systematic differences in compliance, systematic differences in the placebo effect and detection bias.
Attrition bias:
Loss to follow up and drop out from the study is one of the major problem in the field of addiction. Retention in treatment is very often the primary outcome measure in these trials; for this reason the information on people who left the study will not be used as a validity criterion.
Detection bias:
To keep blind the people who will assess outcomes is particularly important when subjective outcome measures are used.
Selection bias, performance bias and detection bias will be assessed and rate as follow:
(1) Selection bias: allocation concealment
A: adequate allocation concealment, central randomizations (e.g. allocation by a central office unaware of subject characteristics), pre‐numbered or coded identical bottles or containers which are administered serially to participants, drug prepared by the pharmacy, serially numbered, opaque, sealed envelopes, on‐site computer system combined with allocations kept in a locked unreadable; computer file that can be accessed only after the characteristics of an enrolled participant have been entered or other description that contained elements convincing of concealment.;
B: unclear allocation concealment: when the authors either did not report an allocation concealment approach at all or report an approach that did not fall in the category A or C.
C: inadequate allocation concealment: alternation or reference to case numbers, dates of birth, day of the week. Any procedure that is entirely transparent before allocation, such as an open list of random numbers or other description that contained elements convincing of not concealment
(2) Performance bias: blinding of those providing and receiving the intervention
A: double blind
B: single blind (blinding of participants)
C: unclear
D: no blinding
(3) Detection bias: blinding of the outcome assessor
A. Blind to treatment allocation at outcome assessment
B: Unclear
C: Not blind to treatment allocation at outcome assessment
The methodological quality will be not a criterion for inclusion; in order to assess the effect of the low quality studies we will perform a sensitivity analysis, either including or excluding the classes C studies.
(3) Data extraction
Data will be extract independently by two authors (Amato, Minozzi). Any disagreement will be discuss between all the authors. Key findings will be summarized narratively in the first instance and then assessed for meta‐analysis where possible.
(4) Data synthesis:
Dichotomous outcomes will be analyse calculating the Relative Risk (RR) for each trial with the uncertainty in each result being expressed by their confidence intervals. Continuous outcomes will be analyse calculating the Weighted Mean Difference (WMD) with 95%CI.
Funnel plot (plot of the effect estimate from each study against the sample size or effect standard error) will be used to assess the potential for bias related to the size of the trials, which could indicate possible publication bias.
