Journal of Addictive Behaviors,Therapy & RehabilitationISSN: 2324-9005

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Research Article, J Addict Behav Ther Rehabil Vol: 2 Issue: 2

Quetiapine and Topiramate Combination Therapy in Cocaine Addiction: Preliminary Results of Treatment of the Craving

Vincenzo Barretta1*, Fabio Curcio2, Emma Asturaro3 and Francesco Auriemma4
1Noesis-Associazione per la lotta al disagio psicologico ed alla malattia mentale – ONLUS, Italy
2M.D. Hygiene and Preventive medicine – Scientific Consultant Noesis-Associazione per la lotta al disagio psicologico ed alla malattia mentale–ONLUS, Italy
3Psychologist, Cognitive Behavioral Therapist - Scientific Consultant Noesis-Associazione per la lotta al disagio psicologico ed alla malattia mentale–ONLUS, Italy
4M.D. Psychiatrist - Scientific Consultant Noesis-Associazione per la lotta al disagio psicologico ed alla malattia mentale – ONLUS, Italy
Corresponding author : Vincenzo Barretta
Psychiatrist, President – Noesis- Associazione per la lotta al disagio psicologico ed alla malattia mentale – ONLUS, Viale Augusto, 62 – 80125 Napoli, Italy
Tel: +39 3473613986
E-mail: [email protected]
Received: March 23, 2013 Accepted: June 25, 2013 Published: June 27, 2013
Citation: Barretta V, Curcio F, Asturaro E, Auriemma F (2013) Quetiapine and Topiramate Combination Therapy in Cocaine Addiction: Preliminary Results of Treatment of the Craving. J Addict Behav Ther Rehabil 2:2. doi:10.4172/2324-9005.1000107

Abstract

Quetiapine and Topiramate Combination Therapy in Cocaine Addiction: Preliminary Results of Treatment of the Craving

Cocaine addiction represents an important health problem for the whole western society. Despite widespread consumption of such substance and relevant medical, psychological and social problems related thereto, until now no therapy has been approved to treat this condition, although research is actively involved in this domain. The aim of this work was to test a pharmacological treatment (quetiapinetopiramate) owning the potential ability to reduce the craving in subjects addicted to cocaine. We chose to use a pharmacological combination made up of two drugs, that is Quetiapine (mean dose 242.9 +/- 58.3 mg) and Topiramate (mean dose 323.8 +/- 61.0). 21 people with cocaine addiction that fulfilled the inclusion criteria identified by the study, were treated within the population of users relating to a Service for addictions in Naples, from April, 2009 to January, 2012. In order to measure the intensity of craving for the substance we used the Visual Analogue Scale (V.A.S.). Each of them has been administered with Topiramate in combination with Quetiapine at defined dosages. Clinical and toxicological tests took place in order to assess and monitor abstinence from consumption of the substance, intensity of craving and overall physical and mental health status in patients. The evaluation lasted for a period of 6 months. The study group was flanked by a control group consisting of 20 subjects, who were previously treated only by means of psychological interventions. The results of this study showed a significant reduction in craving and consumption of cocaine, as well as a good tolerability of treatment, as proof of a need for further studies on larger samples.

Keywords: cocaine addiction; quetiapine; topiramate; craving; adherence

Keywords

Cocaine addiction; Quetiapine; Topiramate; Craving; Adherence

Introduction

Cocaine addiction is one of public health emergencies throughout Western society. Data from the “National Survey on Drug Use and Health” indicate that in the USA cocaine is used by 2.3 million people, 5 times more than those who take heroin; the use of cocaine among young adults aged 18 to 25 decreased from 2002 to 2010 (from 2.0% to 1.5%) [1]. According to the Report 2012 of the European Monitoring Centre on Drugs and Drug Addiction (EMCDDA) almost 15.5 million European adults between 15 and 64 years have tried cocaine in their lifetime and about 4 million have consumed it during the last year. In 2010/2011, consumption related to the last 12 months, among young adults (15-34 years) ranges from 2.9% (Italy) to 4.2% (United Kingdom) [2]. In Italy the consumption of cocaine in women has doubled for the years from 2001-2005; even for males we witnessed an increase in cocaine consumers from a rate of 2.6% in 2001 to 4.3% in 2005. The 2005 data show a decrease in starting age (between 11 and 17 years). In the same report, the increase in cocaine-related deaths has been highlighted. In the United Kingdom the number of certificates of cocaine-related deaths doubled between 2003 (161) and 2008 (325) [2]. In Italy, requests for treatment at Drug Addiction Centres due to cocaine use increased from 7,700 in 2000 to 21,090 in 2005; on the other hand, the prevalence of the consumption, in the general population (%), from 2010 to 2012 has decreased (-0,14%) [3].
The craving plays an important role in cocaine addiction as it represents the key element of this clinical condition [4,5]; in fact, most relapses depend on it as well as it represents the keyelement to determine the breakdown or extinction of addictionrelated behaviour. It can be defined as an intense desire, associated with impulsive-compulsive features related to assumption of a psychoactive drug, food or any other rewarding object-behaviour. The craving symptoms consist of an association of altered emotional, behavioural and physical states. Fundamental aspects of craving can be summarized as follows: a) attraction toward situations that can ease drug assumption, b) presence of physical, psychological and behavioural symptoms, c) implementation, through compulsive modalities, of behaviours, even criminal, focused on drug search and d) avoidance of any situation involving a drug abstinence condition. It is well known that both the rewarding effects of cocaine and the raising of craving involve dopaminergic transmission [6-8]. It has been found an important relationship between cocaine craving and dopamine receptors occupancy (DAR) in cocaine abusers [9].
Treatments for cocaine consumers. In Europe one can find the highest male-female ratio among all patients in outpatient treatment for drug addiction (5 men for every woman) and an average age of about 32 years. In Italy, the man/woman ratio treated in drug addiction centres is equal to 8:1 and the average age is about 35 years. Despite the wide substance spreading, no therapy has been approved for treating this condition.
Several studies indicate that there is still no evidence of the effectiveness of antipsychotics in cocaine addiction [10], but few studies have been carried out on the effectiveness of Quetiapine, an atypical antipsychotic present on the market for over 10 years. The rationale for the use of Quetiapine is the antagonist action to serotoninergic 5HT1A and 5HT2 receptors, to D1 and D2 type dopaminergic receptors, to H1 type histaminergic receptors and to alpha 1 and alpha 2 adrenergic receptors. Some studies report the results in the treatment of substance use disorders in patients diagnosed with schizophrenia and bipolar disorders [11-13]. Experiments were performed on rats that were trained to produce operant responses to receive rewarding stimulations to the medial forebrain bundle. Quetiapine produced a weak (20%) attenuation of reward. Its actions on dopamine and non-dopamine neurotransmission are likely to account for its effectiveness at blocking the enhancement of reward by cocaine [14]. In 2010 a study was designed to determine the magnitude of the reward attenuation induced by Quetiapine and its effectiveness at reducing the effect of cocaine [15]. The Quetiapine acts on abstinence symptoms related to opioid assumption discontinuation [16]. In 2004 there were case reports in which misuse of the molecule was obvious, although it happened mainly in carceral context [17]. In 2008 a study highlights the ability of Quetiapine to favourably influence craving and abstinence symptoms related to cocaine consumptions [18].
Topiramate is a monosaccharide derivative showing a structure similar to acetazolamide, a carbonic anhydrase inhibitor. In Italy it has been approved for use in 1999 and finds therapeutic indication as adjunctive therapy in treatment-resistant partial seizures in adults and children (Lennox-Gastaut syndrome and infantile spasms) but it is also effective in the treatment of generalized forms of epilepsy. Mechanisms of action are: block of voltage-gated sodium channels; enhanced GABAergic effects through a site different from the one on which benzodiazepines act; antagonism on AMPA/kainate subtype of glutamate receptors; inhibition of erythrocyte carbonic anhydrase; reducing calcium currents of L-type. Topiramate is also used in the prophylaxis of some forms of cephalalgy, in dietological domain and in some metabolic disorders where its hyporexia ability is reported. A study of “Topiramate for Alcoholism Study Group” undertook the task of evaluating the effectiveness of the drug on alcoholism, concluding that it has a promising action on craving [19]. Kampman et al. in 2004 highlights the anti-craving action on a group of 40 African-American individuals addicted to crack [20]. Johnson et al. studied topiramate’s effects on cocaine craving, showing that topiramate pre-treatment reduced cocaine related craving [21]. Other studies report significant reduction in craving intensity in a group of cocaine abusers [22,23]. It has been hypothesized that anti-craving effect is mediated by the GABAergic agonism and by the glutamatergic antagonism These same mechanisms are the basis of its ability to act even on impulse dyscontrol [24,25].
The rationale of the present study was to evaluate the efficacy of the combination therapy using Quetiapine for blocking the enhancement of reward and Topiramate for anti-craving effect and action on impulse dyscontrol. Moreover both drugs have been used separately in cocaine addiction, but no studies have been done using the combination of drugs.
On the other hand, if systematic review and meta-analysis [26,27] put in evidence no significant differences for any of the efficacy measures comparing anticonvulsants with the placebo, available clinical trials indicate that there is insufficient evidence to justify the use of anticonvulsant drugs in treating cocaine dependence, resulting the need of further studies [28].
The aim of our work is to evaluate the ability of quetiapinetopiramate pharmacological combination to limit the craving in subjects addicted to cocaine.

Method

In the quasi-experimental study 21 consecutive subjects (19 males and 2 females), with cocaine addiction were selected to constitute a Quetiapine/Topiramate group (QT group), and observed from April 2009 to January 2012. The study group were compared with control group composed of 20 subjects (18 males and 2 females), quite similar to QT group for age, sex, estimated time and intensity (money spent/ week, time dedicated to cocaine use) of cocaine addiction who were treated from January, 2005 to March, 2009.
Inclusion criteria for both groups: cocaine abuse, following DSM IV-TR [29]; use of cocaine as primary substance; continued use of the substance for at least 12 months; use of substance at least 3 times a week; age between 18 and 50 years old.
Exclusion criteria: heroin and other psychoactive substances abuse and/or addiction and alcohol abuse and/or addiction. Presence of psychotic disorders; presence of cyclothymic or bipolar disorder assessed through psychiatric visits and administration of Mini International Neuropsychiatric Interview (M.I.N.I.), version 5.0.0 based on the DSM IV.
Preliminary psychopathology assessment has been performed through M.I.N.I. The study has been performed according to Declaration of Helsinki. All patients recruited were informed of “offlabel” drug use, study execution modalities so that they signed an informed consent document.
The control group was treated only by means of psychological interventions such as cognitive-behavioural psychotherapy or counselling in weekly individual sessions.
The QT group patients were treated by pharmacological therapy and motivational counselling. The QT group treatment: the subjects were administered with Quetiapine per os at initial dosage of 200 mg (after 4 days titration: first day 50 mg, 2nd day 100 mg and 3rd day 150 mg), then gradually increasing the dose to obtain the desired clinical response, up to a maximum dose of 350 mg/day (mean dose: 242.9 +/- SD 58.3 mg/day) in pharmacological combination with initial dose of 100 mg/day Topiramate (after 4 weeks titration: 1st week 25 mg/day; 2nd week 50 mg/day; 3rd week 75 mg/day and 4th week 100 mg/day) per os up to the maximum dose of 450 mg/day (mean dose of 323.8 +/- SD 61.0 mg/day).
The drugs were given in two divided doses per day. On these two groups periodic interviews and toxicological tests were performed in order to assess and monitor abstinence from substance use, intensity of craving and overall physical and mental condition of patients, in the first two months every week and later biweekly. The evaluation lasted for a period of 6 months. In order to measure the intensity of craving for the substance we used the Visual Analogue Scale (V.A.S.). We established the following outcome measures: (1) decrease in intensity of craving versus baseline; (2) retention in treatment; (number of drop-outs). (3) Tolerability of treatment: number and type of sideeffects arising from treatment. Psychiatric or psychological symptoms occurred in the course of the study, diagnosed by psychiatric clinical interviews following DSM-IV-tr criteria; (4) Use of cocaine during the study, reported by the subject and detected by toxicology tests; amount of cocaine assumed (measured in grams or as money spent). Toxicology tests were performed weekly during first 8 weeks and then every fortnight. The toxicological tests were performed by EIA method and considered positive in case of presence of cocaine metabolites higher than cut off value (300 mg/ml).
Statistical analysis was performed through the one tailed Fisher’s exact test. The Fisher’s test is suitable for the analysis of small samples [30]. The confidence interval for the diagnostic odds ratio was calculated in order to evaluate adherence to treatment [31].

Results

Craving was assessed in patients remaining in the study
The QT group showed a decrease in substance craving: a) at the basal detection the average VAS was equal to 9.6 as proof of a very high average level of cocaine craving (15 subjects showed a score of 10; 3 subjects showed a score of 9 and 3 other subjects showed a score of 8.5). b) At the fourth week, with doses of 100 mg of Topiramate and 200 mg of Quetiapine, there was a decrease in intensity of craving (mean decrease for all patients: 67.1%); 6 subjects showed a decline of 70%, 5 subjects showed a decrease equal to 80%, 4 subjects showed a decrease of 50%, 3 subjects showed a decrease of 90% and 3 other subjects showed a decrease of 40% versus baseline. c) At the twelfth week 11 subjects of QT group showed an increase in intensity of craving which, in some cases, reached average values equal to 8.5 while 6 subjects showed episodes of resumption of the substance use which, however, represented “punctiform events” that lasted up to a maximum of 24/48 hours. Small increases in dosage of medicines allowed a gradual decrease in craving. d) At the 18th treatment week the average values of decrease in craving reached 79.5%. e) At the 24th week the average decrease in craving attained 81.5%, the subjects revealed a raise of the substance desire in relation to events, places or people that were able to solicit memory of the substance, but that it was possible to resist and the desire extinguished almost always only after a few short minutes (Figure 1).
Figure 1: QT group craving mean value (VAS scale).
In the control group: a) the baseline average value of the craving measured through V.A.S was equal to 8.4; b) at the sixth month there were still 7 abstinent subjects who showed an average measured value of 4.4, reduced by 52.3% (two subjects showed a craving equal to 3, two other patients revealed a craving of 5 and three subjects showed a craving equal to 4) (Figure 2). c) Analysis of craving at the sixth month of treatment highlights the fact that the QT Group showed an anti-craving action significantly greater than the control group action.
Figure 2: QT group vs. Control group craving mean value.
In the control group: a) the baseline average value of the craving measured through V.A.S was equal to 8.4; b) at the sixth month there were still 7 abstinent subjects who showed an average measured value of 4.4, reduced by 52.3% (two subjects showed a craving equal to 3, two other patients revealed a craving of 5 and three subjects showed a craving equal to 4) (Figure 2). c) Analysis of craving at the sixth month of treatment highlights the fact that the QT Group showed an anti-craving action significantly greater than the control group action.
Retention and drop out
QT group: 71.4% (15/21) of the subjects showed high adherence, after completing the study and showing negative toxicology tests for a period of six months. 28.6% (6/21) of the subjects showed relapses into cocaine use, which were then successfully treated by increasing the therapy doses. As already reported above, the maximum doses achieved during the duration of the study were 350 mg/day for Topiramate and 450 mg/day for Quetiapine. The six drop-outs who did not complete the observational period were interviewed later and reported the intolerability of side effects. Three patients discontinued the treatment during the first month and three patients between the eighth and the ninth week; the use of cocaine, resulted less frequent and intense.
In QT group 15 subjects who have continued the therapy until the sixth month showed a negative urine drug test during the observation period. As for the craving, abstinence has been achieved and maintained by 71.4% (15/21) over the observation period that lasted 6 months.
Control group: The retention in treatment at the sixth month was 45% (9/20). The statistical analysis carried out by the one-tailed Fisher’s exact test shows a p = 0.08.
Adverse events, tolerability and psychic conditions
QT group: 14 subjects reported the occurrence of adverse events such as sedation, dizziness and difficulty concentrating. These symptoms occurred, however, in mild and gradually declining form after the first few days. Only 2 subjects reported extrapyramidal type diseases requiring additional treatment with anti-cholinergics, 11 subjects reported improved night sleep and 15 subjects reported an apparent decrease in impulsiveness and irritability, evaluated by clinical interview. Therapy interruption was not necessary in any of the case-studies. During the whole duration of the study there were no relevant pathological type failures, while it was possible to report, however, some episodes of dysphoria, feeling of inner tension and restlessness or apathetic-anhedonic type symptoms.
Use of cocaine during the study
QT group: These data show that 71.4% of the assessed sample discontinued the use of cocaine for a period of 6 months.
In the control group: 35% of subjects discontinued the use of cocaine for the duration of the study.
Analysis of adherence of QT group compared to the control group showed an Odds Ratio (OR) of 4.643; 95% Confidence Interval (CI) from 1.241 to 17.369.

Conclusion

This study offers preliminary evidences of action of Quetiapine in combination with Topiramate on cocaine craving. First of all, GABAergic activity of Topiramate, decreasing impulsivity could promote resistance to substance use desire, the antagonism of Quetiapine dopaminergic action in combination with glutamate receptors by Topiramate could intervene as to push towards further consumption decrease.
This work, however, highlights the good treatment tolerability, as regards dosages used that are to be considered as average dosages in relation to those used for diseases for which these drugs are officially indicated, as reported by the respective technical. On a number of subjects, the treatment shows ability to make improvements on psychopathological dimensions, observed by clinical interview, such as outcome measures (mainly, irritability/impulsivity size) that have to be considered as beneficial effects to decrease abstinence symptoms otherwise observable. Retention in treatment was generally good, it was enough to reassure and make counselling interventions on goodness and temporariness of effects (if any) and carry out slight alterations of medicine dosage to get new collaboration and to strengthen the therapeutic alliance.
Scientific literature report few clinical trials in which two molecules have been used in combination for the treatment of cocaine addiction (for example Topiramate and Amphetamine) [32]. The combination of the two drugs seems to be particularly promising because of the synergistic action performed on the clinical field. This can be explained by considering that, according to Koob and Roberts [33], dopamine is involved in reinforcement mechanisms of craving, glutamate may play a role in neuroadaptation, as well as gaba and serotonin has been implicated in stress and impulsivity mechanisms. It is likely that these neurotransmitter systems play multiple role in generation of craving [34] and the drugs we chose for the present study show complex action on these circuits.
This study shows certain limitations as regards the relative smallness of the sample, the limited period of observation and the comparability between groups. Nevertheless, it represents an important stimulus to deepen clinical trial with this type of drugs. The clinical significance of an evident action of this combination of drugs on cocaine craving requires the continuation of the study on larger samples of subjects suffering from cocaine addiction.

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