Elsevier

Pharmacology & Therapeutics

Volume 111, Issue 3, September 2006, Pages 855-876
Pharmacology & Therapeutics

Associate editor: D.M. Lovinger
Pharmacological treatment of alcohol dependence: Target symptoms and target mechanisms

https://doi.org/10.1016/j.pharmthera.2006.02.001Get rights and content

Abstract

Alcoholism is a major public health problem and resembles, in many ways, other chronic relapsing medical conditions. At least 2 separate dimensions of its symptomatology offer targetable pathophysiological mechanisms. Systems that mediate positive reinforcement by alcohol are likely important targets in early stages of the disease, particularly in genetically susceptible individuals. In contrast, long term neuroadaptive changes caused by chronic alcohol use primarily appear to affect systems mediating negative affective states, and gain importance following a prolonged history of dependence. Feasibility of pharmacological treatment in alcoholism has been demonstrated by a first wave of drugs which consists of 3 currently approved medications, the aldehyde dehydrogenase blocker disulfiram, the opioid antagonist naltrexone (NTX) and the functional glutamate antagonist acamprosate (ACM). The treatment toolkit is likely to be expanded in the near future. This will improve overall efficacy and allow individualized treatment, ultimately taking in account the patient's genetic makeup. In a second wave, early human efficacy data are available for the 5HT3 antagonist ondansetron, the GABA-B agonist baclofen and the anticonvulsant topiramate. The third wave is comprised of compounds predicted to be effective based on a battery of animal models. Using such models, a short list of additional targets has accumulated sufficient preclinical validation to merit clinical development. These include the cannabinoid CB1 receptor, receptors modulating glutamatergic transmission (mGluR2, 3 and 5), and receptors for stress-related neuropeptides corticotropin releasing factor (CRF), neuropeptide Y (NPY) and nociceptin. Once novel treatments are developed, the field faces a major challenge to assure their delivery to patients.

Section snippets

Alcohol dependence—a chronic relapsing disease

Substance use disorders continue to be viewed by many as defects of character not amenable to medical treatments. One of the objectives of the present paper is to reinforce the point so well argued by others (McLellan et al., 2000) that drug and alcohol dependence are, in fact, chronic relapsing disorders which share numerous characteristics with other chronic relapsing medical conditions such as hypertension, diabetes or asthma. While it is true that alcoholism cannot be treated without regard

Disulfiram

For many years, disulfiram was the only medication available to aid sobriety. Disulfiram blocks the enzyme aldehyde dehydrogenase, leading to an accumulation of acetaldehyde following intake of alcohol. This in turn causes flushing, shortness of breath, tachycardia, headache and nausea. It has been thought that anticipation of these symptoms would help patients abstain from alcohol. Importantly, the idea is not that the patients will actually experience aversive symptoms, and because of them

Ondansetron

The introduction of SSRIs and realization of their broad therapeutic spectrum, together with the isolation of serotonergic receptors greatly increased serotonin research during the late 1980s and early 1990s. During this era, it was expected that compounds targeting various components of central 5HT systems would also be evaluated for their ability to affect EtOH drinking. Early studies indicated that SSRIs and the 5HT3 antagonist ondansetron both suppressed various parameters of EtOH drinking

Animal models for target discovery and validation

First and second wave pharmacological treatments for alcoholism were defined as having demonstrated efficacy in humans in some fashion. It is more challenging to identify a third wave of compounds predicted to be effective in humans. Many animal paradigms in current use model various characteristics of alcoholism, but we are only beginning to use them effectively to differentiate clinically effective from clinically ineffective compounds (Egli, 2005, Heilig & Egli, 2005). How, then, are we to

Conclusion

Lessons learned from each wave of compounds will facilitate the development of additional medications. To be successfully marketed and widely prescribed in appropriate patients, first wave compounds will need to overcome multiple barriers such as lack of patient awareness and misperceptions concerning efficacy and side effects. Once these obstacles are overcome, it will be easier to navigate these potential barriers more efficiently as second wave target compounds become available. In addition,

References (218)

  • M. Heilig et al.

    Models for alcohol dependence: A clinical perspective

    Drug Discovery Today: Disease Models

    (2005)
  • G.A. Higgins et al.

    Effect of drugs influencing 5-HT function on ethanol drinking and feeding behaviour in rats: studies using a drinkometer system

    Neurosci Biobehav Rev

    (1992)
  • G.A. Higgins et al.

    Pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent

    Neuropharmacology

    (2004)
  • B.H. Hwang et al.

    Corticotropin-releasing factor gene expression is down-regulated in the central nucleus of the amygdala of alcohol-preferring rats which exhibit high anxiety: a comparison between rat lines selectively bred for high and low alcohol preference

    Brain Res

    (2004)
  • B.A. Johnson et al.

    Oral topiramate for treatment of alcohol dependence: a randomised controlled trial

    Lancet

    (2003)
  • G. Addolorato et al.

    Ability of baclofen in reducing alcohol craving and intake: II-Preliminary clinical evidence

    Alcohol: Clin Exp Res

    (2000)
  • G. Addolorato et al.

    Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study

    Alcohol Alcohol

    (2002)
  • S. Ahlenius et al.

    Antagonism by alpha methyltyrosine of the ethanol-induced stimulation and euphoria in man

    Clin Pharmacol Ther

    (1973)
  • N. Ait-Daoud et al.

    Combining ondansetron and naltrexone treats biological alcoholics: corroboration of self-reported drinking by serum carbohydrate deficient transferrin, a biomarker

    Alcohol: Clin Exp Res

    (2001)
  • N. Ait-Daoud et al.

    Combining ondansetron and naltrexone reduces craving among biologically predisposed alcoholics: Preliminary clinical evidence

    Psychopharmacology (Berl)

    (2001)
  • Diagnostic and Statistical Manual of Mental Disorders

    (1994)
  • K.K. Anstrom et al.

    Effect of baclofen on alcohol and sucrose self-administration in rats

    Alcohol: Clin Exp Res

    (2003)
  • D. Bachteler et al.

    The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat

    Neuropsychopharmacology

    (2005)
  • P. Backstrom et al.

    mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior

    Neuropsychopharmacology

    (2004)
  • N.E. Badia-Elder et al.

    Effect of neuropeptide Y (NPY) on oral ethanol intake in Wistar, alcohol-preferring (P), and -nonpreferring (NP) rats

    Alcohol: Clin Exp Res

    (2001)
  • N.E. Badia-Elder et al.

    Effects of neuropeptide Y on sucrose and ethanol intake and on anxiety-like behavior in high alcohol drinking (HAD) and low alcohol drinking (LAD) rats

    Alcohol: Clin Exp Res

    (2003)
  • H.A. Baldwin et al.

    CRF antagonist reverses the “anxiogenic” response to ethanol withdrawal in the rat

    Psychopharmacology (Berl)

    (1991)
  • T.L. Bale et al.

    Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

    Nat Genet

    (2000)
  • T.L. Bale et al.

    Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior

    J Neurosci

    (2002)
  • A. Bandura

    Self-efficacy: toward a unifying theory of behavioral change

    Psychol Rev

    (1977)
  • A. Bandura et al.

    Negative self-efficacy and goal effects revisited

    J Appl Psychol

    (2003)
  • M.A. Baptista et al.

    Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer

    J Neurosci

    (2004)
  • G. Bart et al.

    Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden

    Neuropsychopharmacology

    (2005)
  • B.S. Basavarajappa et al.

    Chronic ethanol increases the cannabinoid receptor agonist anandamide and its precursor N-arachidonoylphosphatidylethanolamine in SK-N-SH cells

    J Neurochem

    (1999)
  • J.K. Belknap et al.

    Voluntary consumption of ethanol in 15 inbred mouse strains

    Psychopharmacology (Berl)

    (1993)
  • M. Berglund

    Treating Alcohol and Drug Abuse: An Evidence Based Review

    (2003)
  • J. Besheer et al.

    GABA(B) receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice

    Psychopharmacology (Berl)

    (2004)
  • P. Bice et al.

    Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines

    Mamm Genome

    (1998)
  • C. Bond et al.

    Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction

    Proc Natl Acad Sci USA

    (1998)
  • C. Bouza et al.

    Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review

    Addiction

    (2004)
  • G.R. Breese et al.

    Stress enhancement of craving during sobriety: a risk for relapse

    Alcohol: Clin Exp Res

    (2005)
  • K.D. Brownell et al.

    Understanding and preventing relapse

    Am Psychol

    (1986)
  • L. Caberlotto et al.

    Differential expression of NPY and its receptors in alcohol-preferring AA and alcohol-avoiding ANA rats

    Alcohol: Clin Exp Res

    (2001)
  • L.G. Carr et al.

    A quantitative trait locus for alcohol consumption in selectively bred rat lines

    Alcohol: Clin Exp Res

    (1998)
  • K.M. Carroll et al.

    Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial

    Arch Gen Psychiatry

    (2004)
  • C. Chiamulera et al.

    Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice

    Nat Neurosci

    (2001)
  • R. Ciccocioppo et al.

    Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats

    Psychopharmacology (Berl)

    (2004)
  • A. Cippitelli et al.

    Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats

    European Journal of Neuroscience

    (2005)
  • C.R. Cloninger

    Neurogenetic adaptive mechanisms in alcoholism

    Science

    (1987)
  • C.R. Cloninger et al.

    Inheritance of alcohol abuse. Cross-fostering analysis of adopted men

    Archives of General Psychiatry

    (1981)
  • Cited by (0)

    View full text