Addiction Is a Disease

October 1, 2002

Addiction-as-disease or addiction-as-choice may be better defined by delineating initial experimentation with addictive drugs from ongoing drug use. Repeated exposure to addictive substances changes the molecules and neurochemistry of the addict. Addiction-as-disease accepts the responsibility of the health care professional to treat the patient and precludes the stigmatization that addiction is a choice.

(Please see Point article by Jeffrey A. Schaler, Ph.D.)

The practice of medicine obligates physicians to accept the responsibility of promoting the overall health of their patients. When dealing with patients who abuse substances, we can find direct and indirect adverse consequences from such use. Lung cancer, although rare in the general population, is linked to chronic tobacco smoking, for example. Cigarette smokers who begin this addiction in their teen years appear to have a higher incidence of adult depression (Goodman and Capitman, 2000); so, either early tobacco use is a marker for later mental illness or, more ominously, this legal drug of abuse may promote the development of mental illness. Multiple warning labels describing tobacco's toxicity and other risks to health have been printed for decades on each pack of cigarettes sold, yet more than 20% of Americans continue to "choose" to smoke (Centers for Disease Control and Prevention [CDC], 2001). Despite the hundreds of millions of dollars spent in anti-tobacco messages and education, the ever-increasing state and federal "sin" taxes collected on every pack of tobacco product sold, the harsh restrictions on tobacco advertisements by legislative mandate, and the high-profile lawsuits and settlements, the median prevalence figures of current tobacco use in the United States have held steady for the last five years.

Perhaps, then, "choice" has little to do with the decision to continue tobacco use. Cigarette smokers are so concerned about their drug use that each year some 1 million of them attempt to quit; but, sadly, less than 15% succeed in abstinence for a full year (Rose, 1996). Despite understanding that risks outweigh perceived benefits, addicted individuals compulsively continue their drug use in a chronic, relapsing fashion. It is not that these individuals are devoid of any choice when engaging in behaviors that support and reinforce continued drug use; rather, we must accept that not all choices are equally easy to make, especially when there exists a host of genetic, environmental and non-environmental factors supporting continued drug use.

Clinical research reveals that some individuals may be more vulnerable to drug dependence than others due to genetic and developmental risk factors. The best-validated risks are family history and male gender (Hyman, 2001). Studies of separated, adopted twins, for example, have found the risk for alcoholism and other addictive drugs is greater for those twins whose biological parents also had drug dependence, regardless of drug use status in the adoptive parents (Cadoret et al., 1995; Kendler et al., 2000; Tsuang et al., 1996). Drug craving and relapse are triggered by exposure to drug-related cues (e.g., photos of drugs and paraphernalia), as well as stress. Neuroimaging studies of former cocaine-dependent individuals have, for example, identified neural correlates of cue-induced craving for cocaine (Childress et al., 1999; Wexler et al., 2001).

Preclinical studies also indicate that repeated exposure to highly addictive substances alters, perhaps permanently, a number of molecular and neurochemical indices, thereby changing physiologic homeostasis. In other words, even after detoxification, an individual may be sensitized to relapse because of changes in the brain from prior repeated use. We know the molecular targets in the central nervous system for most of the addictive drugs. As examples, opioids are agonists at µ opioid receptors; alcohol is an agonist at g-alphabutyric acid-A (GABA-A) receptors and an antagonist at

-methyl-D-aspartate (NMDA) glutamate receptors; and tobacco's nicotine is an agonist at nicotinic acetylcholine receptors (Hyman, 2001). We also know that the principal CNS pathway for processing reward, punishment and reinforcement extends from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), mediated, in particular, by the release of the neurotransmitter dopamine (Spanagel and Weiss, 1999). Preclinical evidence supports the "final common pathway" theory that addictive drugs, despite discordant molecular targets, all result in an increased release and dysregulation of synaptic dopamine in this region of the brain (Nestler, 2001). For example, the same dose of cocaine administered weekly to monkeys results in increased extracellular release of dopamine in the CNS, a phenomenon called neurochemical sensitization. When a second dose of cocaine is administered after the first dose is wearing off, a decreased release of extracellular dopamine is found in the CNS, a phenomenon called acute tolerance (Bradberry, 2000). As tolerance builds, increased amounts of the drug are ingested in an attempt to achieve the same rewards, which, in turn, will also further drive molecular changes in the brain. Drug dependence, then, is reinforced at the cellular level as the CNS adjusts to continued drug exposure. Such conditioning may be unmasked by abrupt cessation of drug use, resulting in a period of observable and reproducible symptoms of withdrawal.

Chronic exposure to addictive substances also shifts signal transduction pathways within neurons, thereby altering gene expression (Matsumoto et al., 2001; Walton et al., 2001). New or different concentrations of regulatory proteins, in turn, are synthesized, directing neurons to form new synaptic branches and altered concentrations of cellular receptor density. Cocaine, for example, has been found to increase spine density and dendritic branching of neurons in the NAc and prefrontal cortex of rats (Robinson and Kolb, 1999). The remodeling of neurons involved with the maintenance of the brain's reward center also may continue long after drug use has ceased (Hyman and Malenka, 2001; Ungless et al., 2001). There are probably hundreds of transcription factors involved in gene regulation; already the cyclic-AMP response-element-binding protein (CREB) and

FosB are implicated in addiction (Nestler, 2001). Interestingly, biochemically modified isoforms of

FosB appear only slightly after acute drug exposure, but they accumulate over time with repeated drug administration. Other regulatory proteins of the Fos family rapidly break down after synthesis, but

FosB is highly stable, persisting for months after drug withdrawal. Here, then, is one example of a molecular mechanism for drug-induced changes in gene expression persisting long after last use. Preclinical models reveal that chronic, but not acute, administration of cocaine, amphetamine, phencyclidine, alcohol, nicotine and opiates induces

FosB release in the NAc and dorsal striatum (Kelz and Nestler, 2000).

In short, both human and preclinical data converge to suggest that addiction is associated with frank biological abnormalities that cannot be easily explained by a simple hypothesis of "choice." It is a strange set of societal circumstances that people may still consider the ingestion of some drugs as outside the purview of physicians, when clearly the practice of medicine deals with the impact of exogenous substances upon the human body and mind. Those individuals who abuse drugs do so absent the legal mechanisms for which society provides, i.e., a prescription or recommendation from a physician. Whether legal or not, all addictive substances should be carefully reviewed with our patients precisely because physicians must obtain all information that may assist in the diagnosis and treatment of disease and in the improved preventive health of patients.

Drug dependence changes the lives of users and those around them. Tobacco, for example, is the single greatest cause of preventable death in the United States (CDC, 2001). Certainly, then, tobacco is a menace to public health and its continued popularity supports nicotine dependence as a chronic, relapsing disease in which volitional choice becomes but one negotiable variable in the struggle to achieve good health throughout the life cycle.

Moral rejectionists mislabel drug dependence as a failure of volition only and, thereby, claim a right to assign judgment and blame. The absurdity of looking through such a narrow lens is that if addiction really were merely a choice, people would stop after experiencing more harm than perceived benefits!

Accepting drug dependence as another mental illness does not typically abrogate responsibility for an addict's actions: Thousands each year are arrested, prosecuted and sentenced to serve jail time for simple drug possession, and, as for mental illness in general, consider that the two psychiatric inpatient facilities in the United States in which the largest numbers of patients reside are the Los Angeles County Jail and New York City Rikers Island Prison (Geller, 2000; Torrey, 1999; Watson et al., 2001). Obviously, such individuals' moment-to-moment decision-making can have long-term consequences that were never wished for or accurately anticipated.

Not all choices can be equally entertained at every given moment either, and sometimes other options are not even known. For example, a young woman, supporting herself and her drug habit through prostitution, may not know of the different "ethical" choices available to her, especially when as a child she had been introduced to both drugs and her career by her mother's example. The reasons for experimenting with addictive drugs, then, may be quite different from the motivations fueling continued use. Relapse is not due to an absolute loss of volitional control but rather to loss of a perspective that cherishes good health and mental well-being above other, less healthy choices. In high-risk situations, this long-term desire for maintaining better health through abstinence is overwhelmed by the cued wish to re-experience a known, anticipated "high" available at that moment.

Stigmatization of illness continues against many patients afflicted with brain pathology. Substance dependence is particularly stigmatized by those who wish to make this illness a debate over volition while denying the biological underpinnings of behavior. Moreover, demands for precise linguistic definitions of addiction and disease, as if they must forever be hermetically sealed within specific denotations of legalese and ethics, is of little value to physicians charged with the observation and treatment of pathology. History reveals many examples of debates over illness versus individual responsibility: Hansen's disease ("leprosy" from Mycobacterium leprae), seizure disorders ("epilepsy"), cancer and major depression are some examples of medical disorders now vindicated with the discovery of effective medications and procedures. Physicians, and psychiatrists in particular, are needed now more than ever to stand up and explain to the lay public how substance abuse and dependence can significantly alter brain function and physical health and that a variety of treatment modalities are available.

Effective management of drug dependence requires a medical model so as to tailor therapy according to the condition of the individual. Faith-based support groups, Alcoholics Anonymous and its affiliates, and long-term residential programs have a long history of assisting people in achieving and maintaining abstinence via a combination of direct therapy, education, cognitive skill-building exercises, expanded non-drug social supports and providing a drug-free environment. Contingency management skills can be taught to provide individuals with extra time to anticipate the high-risk situations and emotions for relapse and then, hopefully, re-script behavior to minimize such exposures (Carroll et al., 2001). This helps individuals learn to avoid night clubs or other users because such settings and people may make the choice for continued abstinence appear less valuable than the immediate reward anticipated with use.

Current pharmacotherapy for drug dependence includes screening for an underlying psychiatric condition after the patient has successfully completed detoxification. People may choose to self-medicate with an addictive drug, all the while unaware that they have a treatable psychiatric illness. For example, rates for alcoholism and other drug abuse are much higher in people with untreated bipolar disorder and depression. For motivated individuals, disulfiram (Antabuse) may particularly aid in maintaining sobriety from alcohol. Smoking tobacco while on the antidepressant buproprion (Zyban, Wellbutrin) is another aversive treatment, as the drug induces an undesirable taste when some smokers relapse. Agonist replacement medications assist with detoxification and/or offer a stable, safer maintenance therapy for those who repeatedly fail pure abstinence (e.g., methadone for opiate dependence, nicotine gum or patch for tobacco dependence). Many new medications are also in development including more opiate antagonists for the treatment of alcoholism and opiate dependence and NMDA antagonists such as acamprosate [Campral] for alcoholism (Tempesta et al., 2000). One day, perhaps there will even be a vaccine to confer natural immunity against cocaine (Schabacker et al., 2000). As Krystal et al. (2001) reported regarding the efficacy of naltrexone (ReVia), an opioid antagonist, in the treatment of alcoholism, sometimes medications do not prove to be as effective as promised. Evidence still suggests, however, that naltrexone may be quite effective if taken intermittently on the days that the individual feels at greater risk for relapse, rather than ingesting it every day (Boening et al., 2001).

Whether addiction is a disease or merely a choice, the utility of the medical model is needed to address resultant risks to public and individual health. A careful review of this growing body of scientific literature should offer hope that real solutions are possible. All other models for addressing drug dependence have, to date, proven to be costly failures, and doctors are not going to ignore viable treatment options for healing those suffering with drug dependence. Defining addiction as a choice only abdicates our responsibility for seeking health and true healing for our patients and, instead, leaves crushed lives dehumanized by a chronic relapsing condition with no hope for cure. As every doctor knows, "Remember to do some good" should quickly follow the first rule to "do no harm."

References:

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