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  • Review Article
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Pharmacotherapy of addictions

Nature Reviews Drug Discovery volume 1, pages 710–726 (2002)Cite this article

A Correction to this article was published on 01 November 2002

Key Points

  • Addiction can be defined as a compulsion to take a drug with loss of control over drug taking, despite its adverse consequences.

  • Although drugs of abuse have different initial targets and actions, the resultant addictions share several features, owing to their common effects on crucial neural circuits:

  • heroin acts primarily on the endogenous opioid system, but also affects the dopaminergic system;

  • cocaine acts primarily on the dopaminergic system, as well as the serotonergic and adrenergic systems, but also affects the opioid system;

  • alcohol affects the dopaminergic, serotonergic and opioid systems.

  • Goals for the treatment of addiction include preventing withdrawal symptoms, reducing drug craving, normalizing any physiological functions that are disrupted by drug use and targeting the treatment agent to a specific site of action, receptor or physiological system that is affected or deranged by the drug of abuse.

  • There are three effective pharmacotherapies for the long-term treatment of heroin addiction (>50% effectiveness in non-selected persons) — the opioid agonists methadone and levo-α-acetylmethadol, and the partial opioid agonist buprenorphine.

  • There are no pharmacotherapies that are effective in unselected groups of cocaine addicts, and so emphasis is placed on this need in this article.

  • Three medications have been shown to be effective in 20–50% of unselected alcoholics — the opioid antagonists naltrexone and nalmefene, and acamprosate, which probably acts as an N-methyl-d-aspartate (NMDA) antagonist.

  • Four groups of therapeutic targets that might be immediately applicable for developing medications are considered: the μ-opioid receptor and its endogenous ligands β-endorphin and the enkephalin peptides; the stress-responsive axis; the components of the dopaminergic system; and the κ-opioid receptor and dynorphin peptides.

Abstract

Addiction to drugs, such as heroin, cocaine and alcohol, exacts great human and financial costs on society, but the development of pharmacotherapies for addiction has been largely neglected by the pharmaceutical industry. With advances in our understanding of the underlying biology of addictions now opening the door for the development of novel pharmacotherapies, it could be time for a reassessment of involvement in this increasingly important therapeutic area. Here, we summarize the current approved and implemented pharmacotherapeutic approaches to the treatment of addiction, and then highlight the most promising areas for future drug development from the perspective of our laboratory and our National Institutes of Health (NIH) National Institute on Drug Abuse (NIDA) Research Center.

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Figure 1: Factors involved in addiction.
Figure 2
Figure 3: Potential targets for new medication development.

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Acknowledgements

We thank K. Lavoie for his invaluable help in the preparation of the manuscript, F. Vocci (National Institutes of Health (NIH) National Institute on Drug Abuse) for providing the medication-development information for table 3 and G. Bart, K. Bell, E. Ducat and J. Andersen for further annotation of sites of action and trade names. Funding support was received from the National Institutes of Health (NIH) National Institute on Drug Abuse and the NIH National Center for Research Resources.

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Authors and Affiliations

  1. Laboratory of the Biology of Addictive Diseases, Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Mary Jeanne Kreek, K. Steven LaForge & Eduardo Butelman

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  1. Mary Jeanne Kreek
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  2. K. Steven LaForge
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  3. Eduardo Butelman
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Correspondence to Mary Jeanne Kreek.

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DATABASES

LocusLink

ACE

ALDH2

COX-2

CRF

D1 receptor

D2 receptor

D3 receptor

DARRP32

dopamine β-hydroxylase

β-endorphin

enkephalin

GABAA receptor

GABAB receptor

11β-hydroxylase

17α-hydroxylase

luteinizing hormone

MAO

δ-opioid receptor

κ-opioid receptor

μ-opioid receptor

prolactin

Medscape DrugInfo

amantadine

amlodipine

d-amphetamine

baclofen

buprenorphine

bupropion

butorphanol

cabergoline

captopril

carnitine

celecoxib

clonidine

coenzyme Q

desipramine

dexamethasone

dextromethorphan

disulfiram

donepezil hydrochloride

fluoxetine

gabapentin

haloperidol

hydergine

hypericum

imipramine

isradipine

ketoconazole

labetalol

lamotrigine

Levo-Dopa

mecamylamine

methadone

methylphenidate

metyrapone

modafinil

morphine

nalbuphine

nalmefene

naloxone

naltrexone

nefazodone

oxazepam

paroxetine

pemoline

pentoxifylline

pergolide

pramipexole

propanolol

reserpine

riluzole

risperidone

selegiline

sertraline

sibutramine

taurine

tiagabine

tolcapone

tryptophan

valproate

venlafaxine

OMIM

Parkinson's disease

FURTHER INFORMATION

American College of Neuropsychopharmacology

Encyclopedia of Life Sciences

addiction

FDA

National Institute on Drug Abuse

Glossary

ADDICTION

Addictions have been defined by various scientific, national and international policy, and clinical groups. The most commonly used diagnostic criteria in the United States are those given by the Diagnostic and Statistical Manual IV (DSM-IV) for drug (or alcohol) abuse or drug (or alcohol) dependence.

POSITIVE REINFORCEMENT

Positive reinforcers (rewards) increase the frequency of behaviour that leads to their acquisition. Negative reinforcers (punishers) decrease the frequency of behaviour that leads to their encounter and increase the frequency of behaviour that leads to their avoidance, or alternatively might lead to an increase in the frequency of behaviour to offset the negative effects — for example, re-administration of an opiate to reverse or attenuate opiate-withdrawal signs and symptoms.

TOLERANCE

A progressive, reduced drug responsiveness with repeated exposure to a constant drug dose, therefore requiring an increase in dose to achieve the desired response.

SENSITIZATION

Enhanced drug responsiveness with repeated exposure to a constant drug dose; alternatively, a greater response on re-challenge with a lower dose of drug than used in the initial chronic-intermittent exposure.

DEPENDENCE

An altered physiological state that develops to compensate for persistent drug exposure, which could give rise to a withdrawal syndrome after drug use is stopped; also used by many to refer to psychological dependence that leads to compulsive drug use.

WITHDRAWAL

A collection of physiological signs and symptoms that appear after the sudden cessation of drug intake, which can include shaking, sweating and anxiety, depending on the drug.

MESOLIMBIC–MESOCORTICAL DOPAMINERGIC SYSTEM

This system is part of the motivational system that regulates responses to natural reinforcers, such as food, drink, social interaction and sex.

CONDITIONED PLACE PREFERENCE

The development in an experimental animal of a preference for a location that is repeatedly paired with a rewarding stimulus (for example, cocaine).

CUE-INDUCED RELAPSE

Relapse to drug taking ('reinstatement' in animal self-administration models) after a period of cessation can be induced by a drug-associated cue or specific environmental stimulus, such as a light or sound, which is not directly related to drug taking. Such a cue can elicit a neural response that leads to drug seeking or taking behaviours.

PRIMING

Re-administration of even a modest amount of the drug of abuse after chronic use, and then achievement of an abstinent state.

CROSS-TOLERANCE

The development of tolerance to the effects of a second drug, which results from the development of tolerance to a first drug after extended exposure to the first drug. For example, chronic treatment with methadone produces cross-tolerance to heroin.

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Kreek, M., LaForge, K. & Butelman, E. Pharmacotherapy of addictions. Nat Rev Drug Discov 1, 710–726 (2002). https://doi.org/10.1038/nrd897

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