Effects of biperiden on the treatment of cocaine/crack addiction: A randomised, double-blind, placebo-controlled trial
Introduction
Cocaine use affects approximately 13.4 million people, or 0.3% of the world׳s population between 15 and 64 years of age. Addiction to that substance is a public health issue worldwide, characterised by relapses, several health problems and psychosocial complications (European Monitoring Centre for Drugs and Drug Addiction, 2012, United Nations Office on Drugs and Crime, 2012). Till date, there is no effective treatment to address this problem.
On the other hand, there has been a growing body of preclinical evidence in recent years showing that the cholinergic system plays an important role in cocaine addiction onset and its maintenance and aspects of reward, learning and memory (Adinoff et al., 2010, Williams and Adinoff, 2008).
Several studies have shown that cocaine-related reward effects are mediated by M5 muscarinic receptors in the tegmental area (Fink-Jensen et al., 2003, Thomsen et al., 2005, Yeomans et al., 2001). Additionally, M4 receptors influence dopaminergic neurotransmission regulation. Schmidt et al. (2011) demonstrated that knockout mice lacking those receptors presented an increase in cocaine self-administration. In addition to directly inhibiting dopamine reuptake, cocaine acts on M1 and M2 receptors (Flynn et al., 1992).
Itzhak and Martin (2000) showed, in an animal model, that the administration of scopolamine (an anticholinergic substance) changed the cocaine-conditioned place preference, an effect that is not observed with the administration of only scopolamine. Our studies revealed that biperiden (an irreversible antagonist of muscarinic receptors) reduced both the expression of cocaine-conditioned place preference in mice and memory consolidation in this animal model (Ramos et al., 2012, Zacarias et al., 2012). Biperiden is a white powder chemically known as 3-piperidin-1-phenyl-1- bicycloheptenyl -1-propanol, an anticholinergic agent which acts predominantly in the central nervous system. It has a prominent central blocking effect on M1 receptors, being prescribed for the treatment of the side effects of neuroleptics and other drugs that block dopamine receptors (Penttilä et al., 2005).
Clinical studies in humans proved that muscarinic acetylcholine receptor (mAChR) M2 gene (CHRM2) polymorphism is involved in a phenotype that is predictive of substance use disorders (Dick et al., 2008). Adinoff et al. (2010) reported that regional cerebral blood flow (rCBF) in the limbic regions of cocaine-addicted individuals was altered after the administration of both physostigmine (a cholinergic agonist) and scopolamine (a muscarinic antagonist) compared with rCBF in the control group. The nicotinic cholinergic receptors have also been the target of researchers. A double-blind placebo controlled study with varenicline (an alpha4beta2 partial agonist) that lasted nine weeks showed a significantly greater decrease in the rates of cocaine reward when compared with the placebo group (Plebani et al., 2012). Therefore, there appears to be evidence of a certain degree of participation of the cholinergic system in cocaine addiction.
The cholinergic system projects into several brain areas and regulate cognitive, affective and behavioural functions (Williams and Adinoff, 2008). The limbic and paralimbic regions contain intense cholinergic innervation and are supposed to be the most relevant to the process of addiction (Bonson et al., 2002, Goldstein and Volkow, 2002). These cholinergic interactions with the reward circuit might interfere with the learning and memory processes, which are related to relapse and craving (Hoebel et al., 2007, Mark et al., 2011, See et al., 2003).
The present study evaluated the efficacy of biperiden (a muscarinic antagonist) in reducing consumption and craving and in improving compliance with the psychotherapeutic treatment of cocaine/crack-addicted individuals.
Section snippets
Patients and trial design
This study was a randomised, double-blind, placebo-controlled trial. In total, 56 male patients received daily oral doses of biperiden capsules (6 mg divided into three doses), whereas 55 other patients, also male, received placebo (under the same regimen as biperiden). The total sample, therefore, comprised 111 patients. The patients reported to the research centre weekly to be evaluated and to receive capsules for the next days, ensuring that they were actually using the substances involved in
Study sample
A total sample of 166 patients was evaluated during the project. Of that number, 55 did not fulfil the inclusion criteria. The main reasons for exclusion were the presence of clinical comorbidities (active hepatitis, tuberculosis under treatment and epilepsy) or psychiatric comorbidities (anxiety or depressive disorder, schizophrenia and dependence on substances other than tobacco).
The mean age of the 56 patients who used biperiden was approximately 32.9 years (±7.6 years), whereas the mean age
Discussion
Patients who used biperiden had greater compliance with treatment and, therefore, nearly half of them (42.8%) followed through with the study, compared with only 20% of the patients in the placebo group. A comparison between the two groups showed 118% higher compliance in the biperiden group. Moreover, the decrease in the cocaine/crack doses used during treatment was significantly higher in the biperiden group. The reduction of craving was also higher in that group when compared with the
Role of funding source
AFIP and CNPq (process # 402657/2010-1) for financial support.
Contributors
The original idea was conceived by the corresponding author. All authors had significant involvement in the development of the study and preparation of the manuscript.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgements
None.
References (37)
- et al.
Modafinil for the treatment of cocaine dependence
Drug Alcohol Depend.
(2009) - et al.
Cocaine-induced alterations in dopamine receptor signaling: implications for reinforcement and reinstatement
Pharmacol Ther.
(2005) - et al.
Neural systems and cue-induced cocaine craving
Neuropsychopharmacology
(2002) - et al.
Cocaine dependence: a disease of the brain’s reward centers
J. Subst. Abuse Treat.
(2001) - et al.
The measurement of craving in cocaine patients using the Minnesota cocaine craving scale
Compr. Psychiatry
(1991) - et al.
Accumbens dopamine-acetylcholine balance in approach and avoidance
Curr. Opin. Pharmacol.
(2007) - et al.
Cholinergic modulation of mesolimbic dopamine function and reward
Physiol. Behav.
(2011) - et al.
Integrating systemic cue exposure with standard treatment in recovering drug dependent patients
Addict. Behav.
(1990) - et al.
Results of an initial clinical trial of varenicline for the treatment of cocaine dependence
Drug Alcohol Depend.
(2012) - et al.
Biperiden (M(1) antagonist) impairs the expression of cocaine conditioned place preference but potentiates the expression of cocaine-induced behavioral sensitization
Behav. Brain Res.
(2012)
Muscarinic receptor antagonism in the basolateral amygdala blocks acquisition of cocaine-stimulus association in a model of relapse to cocaine-seeking behavior in rats
Neuroscience
Atomoxetine does not alter cocaine use in cocaine dependent individuals: a double blind randomized trial
Drug Alcohol Depend.
M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation
Life Sci.
Biperiden (an M1 antagonist) reduces memory consolidation of cocaine-conditioned place preference
Neurosci. Lett.
Altered neural cholinergic receptor systems in cocaine-addicted subjects
Neuropsychopharmacology
Diagnostic and Statistical Manual of Mental Disorders
Acetylcholine-dopamine balance hypothesis in the striatum: an update
Geriatr. Gerontol. Int.
An inventory for measuring clinical anxiety: psychometric properties
J. Consult. Clin. Psychol.
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2016, Behavioural Brain ResearchCitation Excerpt :Because impaired learning, memory, and attention is one of the more well-validated actions of cholinergic antagonists, these agents have at least a relative contraindication for use in patients with substance abuse disorders due their potential for exacerbating cognitive deficits. Even so, recent findings of improved treatment compliance and decreased craving intensity after muscarinic blockade in treatment-seeking patients recovering from cocaine use [142] would support a lessor role of cognitive actions. It is also unclear whether use of cholinergic agonists or cholinesterase inhibition can ameliorate cognitive deficits in this setting.