Prevention and Treatment of Addiction

In 2006, substance dependence or abuse was diagnosed in about 22.6 million persons in the United States.¹ Addiction-related morbidity and mortality pose a major burden to society, costing our economy more than $500 billion annually: about $181 billion for illicit drugs,² $168 billion for tobacco,³ and $185 billion for alcohol.⁴ Loss of productivity, broken families, jail time, HIV infection, hepatitis C, and death are common sequelae of drug addiction.

In addition, population surveys show a high prevalence of comorbid drug abuse and other mental illnesses,⁵ such as mood and anxiety disorders (especially in women), antisocial personality disorder (particularly in men), and schizophrenia (highly comorbid with nicotine dependence). Compelling evidence shows that the disease of addiction arises through the complex interaction of genetic, behavioral, and environmental factors and that it is most effectively prevented and treated through research-based approaches.⁶

Investment in addiction research and treatment is opening up avenues that are profitable not only to persons who are addicted but also to their families, communities, and society at large. It is a good investment: estimates show that every dollar spent on addiction treatment programs yields a $4 to $7 reduction in the cost of drug-related crimes. With some outpatient programs, total savings can exceed costs by a ratio of 12:1.⁷What do we know?
Over the past several decades, we have witnessed changing trends in the abuse of heroin, cocaine, methamphetamine and its derivative ecstasy (3,4-methylenedioxymethamphetamine), and other drugs of abuse. Influencing factors include the existence of purer and more potent formulations, which the illegal drug industry strives for and achieved with crack cocaine and heroin. Prepotent methamphetamine continues to afflict communities across the country, showing marked increases in abuse consequences and in treatment admissions over the past decade-from about 48,000 admissions a year in 1995 to more than 150,000 a year in 2005.⁸

Although cocaine use is viewed as having stabilized somewhat, there are still about 2.4 million current cocaine users aged 12 years and older in this country.¹ While marijuana use continues to decline among teenagers, it remains the most commonly used illicit drug.¹ Outside the illicit drug arena, prescription drug abuse continues to gather momentum; about 7 million US persons report current (in the past month) nonmedical use of prescription drugs, mostly pain relievers-more than the number of persons abusing cocaine, heroin, hallucinogens, and inhalants combined.¹

In the more than 30 years since the National Institute on Drug Abuse (NIDA) was established, major strides have been made in understanding addiction as a complex disease of the brain.⁶ Advances in molecular biology, genetics, and neuroimaging technologies have elucidated the complexity of the opioid, dopaminergic, and other systems, greatly improving our understanding of how the brain responds to and is altered by the acute and long-term use of illicit drugs. Imaging studies have shown that addicted persons have blood flow abnormalities in brain areas involved in impulse control, decision making, motivation, and reward mechanisms. These areas include the orbitofrontal cortex, amygdala, and ventral striatum.⁹

Hypotheses around these systems have helped explain some neurobiological underpinnings of addiction. Brain imaging studies by Volkow's group¹⁰ and others suggest that many types of addiction (including compulsive eating) share common neurobiological substrates and mechanisms. These findings center on the dopamine reward system and on dopamine D₂ receptor (DRD₂) density. Simply stated, the findings suggest an intrinsic diminished ability of some people to experience pleasure, which leads them to seek pleasurable experiences more reliably through the use of illicit substances that artificially reward them by powerfully stimulating the dopamine system.

Unfortunately, addictive drugs can be so reinforcing that no natural stimuli can compete with them. Common reinforcers-food, family, friends-lose their relative value as a person's reward circuitry becomes increasingly blunted and desensitized. Ironically and cruelly, even the drug eventually loses its ability to reward; continued use causes receptor down-regulation and neuronal depletion. Still, the compromised brain leads addicted persons to pursue the use of addictive drugs because by that point the memory of the drug has become more powerful than the drug itself. This compulsive craving, seeking, and use of drugs, even in the face of dire life consequences, is the essence of addiction -what addicts may describe as "chasing the high."

Attempts at quitting give way to withdrawal symptoms so severe, as in the case of opioids (eg, heroin) and nicotine, that they can lead patients to relapse. As with other chronic diseases, such as high blood pressure or diabetes mellitus, sustained positive health outcomes (in this case, abstinence) may require repeated treatment episodes to counter relapse triggers. In persons who are addicted, common daily life stressors and cues in their environment, such as the people, places, and things associated with their former drug abuse, can trigger a relapse.

New findings from animal models of addiction reveal a major role of the corticotropin-releasing factor (CRF) system in stress-induced relapse. This system belongs to a complex neural circuitry that regulates behavioral and autonomic responsiveness to stressful stimuli. Recent findings also suggest that manipulation of dopamine D₃ receptors can block cue-induced relapses.¹¹Where has it led us?
Research discoveries that reveal the effects of drug abuse and addiction on the brain and body have led to major advances in our understanding of how to best prevent and treat this disease. The relatively recent FDA approval of the use of buprenorphine to treat her-oin and other opioid addiction has changed the way we treat addiction in this country and exemplifies how long-term investments in research can result in tangible products that have a dramatic effect on public health. In particular, approved physicians can now prescribe buprenorphine in office settings rather than in specialty clinics, which will result in greater access to and choices for people who are addicted to opiates. This, in turn, can bring different kinds of patients into care and can reach communities that previously did not have access to appropriate treatment. Given that most persons with substance abuse or dependence are not in treatment and are more likely to come into contact with general medicine or psychiatric services than with a specialty clinic,¹² this is a cultural change of great consequence.

 

Other examples come from research on behavioral therapies drawn from the theoretical framework of the psychological sciences. Techniques and modalities such as contingency management and motivational enhancement, alone and in combination with medications, have been shown to be highly efficacious in treating addiction.¹³ Research has also revealed brief interventions to be as effective as lengthy weekly individual or group therapies. All of these techniques are easily learned and are extremely cost-effective.¹⁴

Another innovative strategy in which NIDA is investing is immunotherapy, or the use of vaccines, to treat methamphetamine, cocaine, and nicotine dependence; the latter already is in commercial development.¹⁵ Addiction immunotherapy causes the body to generate antibodies that bind to specific drugs while they are still in the bloodstream, blocking their entry into the brain. Immunotherapies such as vaccines and monoclonal antibodies are showing promise in early development in blocking priming-helping patients remain abstinent and avoid relapse-and in treating overdoses for cocaine, methamphetamine, and phencyclidine (PCP).¹⁶

Genetic studies are another area of great potential, unimaginable just a few years ago; addiction research is now routinely integrating the use of modern imaging with genetics tools to help tease the complex contributions of environmental and genetic risk factors through the life stages of childhood, adolescence, and young adulthood-periods of greatest vulnerability to drug experimentation and addiction. Many candidate genes are being zeroed in on, including the dopamine and opiate family of receptors, catechol-O-methyltransferase, and brain-derived neurotrophic factor.¹⁷ Pharmacogenetic studies, although in their infancy, are yielding promising candidate genes-for example, enhanced nicotine metabolism and the cytochrome P-450 2A6 polymorphism; and the DRD₂ variant and response to nicotine replacement therapies versus bupropion in smoking cessation.¹⁸ The A118G variant of the µ-opioid receptor may be a predictor of response to naltrexone in patients who are alcohol-dependent.

As with any medical illness, the ultimate goal with addiction is prevention. Research has already revealed different risk and protective factors that could lead to or shield persons from addiction. Targeted prevention programs, including school-based and family interventions, are highly promising and are already having an epidemiological effect on the use of methamphetamine and marijuana.^19,20Where are we going?
If the past predicts the future, we will continue to see different trends in substance abuse emerge over the next decade. Marijuana potency is predicted to increase with the increased availability of sinsemilla cannabis, and world market trends are already on the rise.²¹ Prescription drug abuse is predicted to escalate to epidemic proportions and may exceed marijuana abuse as the number one problem that we will face in the next decade.

In response to the prescription drug abuse epidemic, we will need to focus research on finding out more about those who are abusing prescription drugs, their reasons, and their sources. To minimize diversion of legal drugs for illegal use, we will also need to focus on developing formulations of pain medications that have diminished abuse liability. Pharmaceutical companies are already responding to guidance from the FDA, the Drug Enforcement Administration, and the Office of National Drug Control Policy with products such as combined buprenorphine/naloxone; combined oxycodone/ultra-low-dose naltrexone; and lisdexamfetamine, all of which have mechanisms that mitigate their abuse.²²

 

The next decades will witness the approval of medications currently in early development to treat various phases of addiction. Potential candidates include a CRF antagonist, a CB₁ receptor antagonist, and a D₃ partial agonist. All hold great promise for sustaining abstinence or preventing relapse. Examples of marketed medications being tested for treating withdrawal and facilitating early abstinence in patients who are actively using addictive drugs include buspirone and nefazodone for marijuana, and bupropion, modafinil, and extended-release methylphenidate for stimulants.¹¹ These are all in proof of concept or confirmatory trials as potential antiaddiction medications.

In the next decade, our understanding of the phenotypes of patients who are addicted will be greatly enhanced through research that is aimed at defining and measuring aspects of the social environment-culture, neighborhoods, schools, families, and peer groups-to better understand how genes can mitigate or amplify social influences that are known to powerfully affect individual choices and behaviors related to substance abuse. Complementing these efforts, NIDA will focus on pharmacogenomics, the study of how genes regulate an individual's response to drugs and medications. Clinical and genetic biomarkers are being pursued in genetic research and in pharmacogenetic studies and are being incorporated into enrichment medication and behavioral treatment trials. This research not only will illuminate the physiological mechanisms of drug abuse and addiction but also has the potential to empower clinicians by helping them tailor pharmaceutical interventions to a subgroup of the addicted population who will optimally respond to such treatment-from selecting the most effective medication and dosage regimen to anticipating and avoiding adverse effects.¹⁷

Immunotherapy is another very promising area, reflected in interim analysis data from the nicotine vaccine trial. In the next 3 to 5 years, we may have an approved vaccine for smoking cessation. Similar efforts are being pursued for cocaine, methamphetamine, and heroin vaccines. Monoclonal antibody research is still at the preclinical phase, but early data are encouraging and may possibly result in an approved monoclonal antibody to treat cocaine, methamphetamine, or PCP overdoses in emergency departments in the next decade.

Other treatments on the horizon offer promise for affecting the conditioned responses to drugs that go hand in hand with addiction and lead to relapse even after long periods of abstinence. New therapies include those targeting extinction, or the unlearning of conditioned responses,^23,24 and neurofeedback, the use of noninvasive real-time brain imaging technologies to teach patients to regulate neural activity in specific brain regions.²⁵ These novel approaches will take advantage of new technologies, medications, and basic and behavioral research to help us understand and modify the circuitry affected by addiction-part of a wider network in which pathways influence one another in highly complex ways.

For prevention research, the next decade holds promise for better identification of addiction vulnerabilities and high-risk populations based on family history, personality traits, and genetic markers, as these become better characterized. New findings will generate more effective early interventions, which, in turn, should have tremendous effect in preventing development of the full-blown disease. Family and school-based interventions, alone and in combination, offer promising prevention techniques that will be more widely applicable in the next decade.

There is hope for the future of the treatment of addiction, with the political landscape and the public's understanding and acceptance of addiction as a brain disease already changing. It is our hope that this will translate into funding for addiction research and treatment. Our work is cut out for us however:

• Understanding the interplay of genetic and environmental factors in influencing addiction risk will help identify those who are particularly vulnerable to the rewarding effects of drugs.
• Findings will aid the development of increasingly refined prevention strategies directed at selectively mitigating a patient's specific risk factors.
• In a similar vein, identifying patient characteristics that predict the relative efficacy of specific treatment interventions will allow treatment providers to better match patients with treatment services.
• And finally, the development of medications to curb craving-at the forefront of efforts to help drug-addicted patients establish and maintain abstinence in treatment-will be critical to effectively counter chronic, compulsive drug taking.

The reward to society will be tremendous, with many individual lives restored and families reunited. We will see fewer crimes and less jail crowding, fewer new cases of HIV infection and hepatitis C, more productive persons, and healthier and safer communities.

 

References:

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