The knowledge of the neurobiology of drugs and the adaptive changes that occur with addiction is guiding new strategies for prevention and treatment and identifying areas in which further research is required.
The greater vulnerability of adolescents to experimentation with drugs of abuse and to subsequent addiction underscores why prevention of early exposure is such an important strategy to combat drug addiction. Epidemiologic studies show that the prevalence of drug use in adolescents has changed significantly over the past 30 years, and some of the decreases seem to be related to education about the risks of drugs. For example, for marijuana, the prevalence rates of use in the United States in 1979 were as high as 50%, whereas in 1992, they were as low as 20% (100) (Fig. 1-4). This changing pattern of marijuana use seems to be related in part to the perception of the risks associated with the drug; when adolescents perceived the drug to be risky, the rate of use was low, whereas when they did not, the rate of use was high. Similarly, the significant decreases in ecstasy use as well as cigarette smoking in adolescents (100) seem to partly reflect effective educational campaigns. These results show that, despite the fact that adolescents are at a stage in their lives when they are more likely to take risks, interventions that educate them about the harmful effects of drugs with age-appropriate messages can decrease the rate of drug use (101,102,103). However, not all media campaigns and school-based educational programs have been successful (104,105). Tailored interventions that take into account socioeconomic, cultural, and age and gender characteristics of children and adolescents are more likely to improve the effectiveness of the interventions.
At present, prevention strategies include not only educational interventions based on comprehensive school-based programs and effective media campaigns and strategies that decrease access to drugs and alcohol but also strategies that provide supportive community activities that engage adolescents in productive and creative ways. However, as we begin to understand the neurobiologic consequences that underlie the adverse environmental factors that increase the risks for drug use and for addiction, we will be able to develop interventions to counteract these changes. In addition, as we deepen our knowledge of how different genes (and their encoded proteins) make a person more or less vulnerable to taking drugs and to addiction, more targets will be available to tailor interventions for those at higher risk.
Finally, we can also expect a renewed focus in the near future in the research and development of interventions that increase general resilience leading to universally better outcomes. Particularly promising in this context are the recent results of a major longitudinal study showing a dramatic positive influence of childhood self-control upon a wide range of life outcomes, including substance abuse risk, overall health, and financial status (106).
The adaptations in the brain that result from chronic drug exposure are long-lasting; therefore, addiction must be viewed as a chronic disease. This is why long-term treatment will be required for most addiction cases, just as it is for other chronic diseases, like hypertension, diabetes, or asthma (107). By recognizing the likelihood of relapse, this perspective radically modifies our expectations of addiction treatment outcomes, establishing the need for a more rational, chronic management model for addiction treatment (108). First, discontinuation of treatment, as for other chronic diseases, is likely to result in relapse. Also, as for other chronic medical conditions, relapse should not be interpreted as a failure of treatment (as is the prevailing view in most cases of addiction), but instead as a temporary setback due to a lack of compliance or tolerance to an effective treatment (107). It is rather telling that the rates of relapse and recovery in the treatment of drug addiction are equivalent to those of other medical diseases (107).
The involvement of multiple brain circuits (reward, motivation, memory, learning, interoception, inhibitory control, and executive function) and the associated behavioral disruptions point to the need for a multimodal approach in the treatment of the addicted individual. Therefore, interventions should not be limited to inhibiting the rewarding effects of a drug but also explore and include strategies to enhance the saliency value of natural reinforcers (including social support), strengthen inhibitory control, decrease conditioned responses, improve mood if disrupted, and strengthen executive function and decision making. For example, a recent report details an apparently successful targeting of executive function by exposing the left dorsolateral prefrontal cortex of smokers with repetitive transcranial magnetic stimulation, a single session of which significantly reduced subjective craving induced by smoking cues in these nicotine-dependent participants (109). However, more work is required to determine if these effects are sustained outside the laboratory setting and to determine if they result in decreased smoking.
Among the recommended multimodal approaches, the most obvious rely on the combination of pharmacologic and behavioral interventions, which might target different underlying factors and therefore yield synergistic effects. Such combined treatment is strongly recommended because behavioral and pharmacologic treatments are thought to operate by different yet complementary mechanisms that can have additive or even synergistic effects. Thus, it could be expected that addiction treatments that use behavioral interventions would be more effective if complemented with medications to help the patient remain drug free. For example, behavioral approaches complement most tobacco addiction treatment programs. They can amplify the effects of medications by teaching people how to manage stress, recognize and avoid high-risk situations for smoking relapse, and develop alternative coping strategies (e.g., cigarette refusal skills, assertiveness, and time management skills) that they can practice in treatment, social, and work settings (110,111). Thus, it is rather unfortunate that most alcohol and drug abuse treatment programs in the United States are, because of their 12-Step orientation, more often than not adamantly opposed to taking advantage of effective pharmacotherapies (112).
Pharmacologic interventions can be grouped into two classes. First, there are those that interfere with the reinforcing effects of drugs of abuse (i.e., medications that interfere with the binding to a target, drug-induced dopamine increase, postsynaptic responses, or with the drug’s delivery to the brain like antidrug antibodies, or medications that trigger aversive responses). Second, there are those that compensate for the adaptations that either preceded or developed after long-term use (i.e., medications that decrease the prioritized motivational value of the drug, enhance the saliency value of natural reinforcers, or interfere with conditioned responses, stress-induced relapse, or physical withdrawal). The usefulness of some addiction medications has been clearly validated; for others, the data are still preliminary, and for these, most results are limited to promising preclinical findings. Table 1-1 summarizes proven medications and medications for which there are preliminary clinical/preclinical data. Many of these promising new medications target different neurotransmitters (such as GABA, serotonin, or glutamate) relative to older drugs, offering a wider range of therapeutic options. Also combining medications may increase their efficacy as recently shown for the treatment of smoking cessation (154). Thus, future studies are needed to determine if medications that by themselves have not been shown to be effective for treatment of addiction (i.e., amphetamine for cocaine addiction) might provide benefits when combined with drugs with different mechanisms of action (i.e., amphetamines + topiramate).
In a similar fashion, behavioral interventions can be classified by their intended remedial function, such as to strengthen inhibitory control circuits, provide alternative reinforcers, or strengthen executive function. Traditionally, behavioral therapy has focused on symptom-based targets rather than underlying causes of addiction. However, for other brain disorders, new views of brain plasticity, which recognize the capacity of neurons in the adult brain to increase synaptic connections and in certain instances to regenerate (155), have resulted in more focused cognitive–behavioral interventions designed to increase the efficiency of dysfunctional brain circuits. This has been applied in attempts to improve reading in children with learning disabilities (156), memory-related brain activity in Alzheimer patients (157), to strengthen voluntary cortical control in children with ADHD (158), and to facilitate motor and memory rehabilitation after brain injury (58). We are beginning to see the first glimpses of this general approach as potentially applicable for the treatment of drug addiction. For example, a small positive relationship has been found between cognitive-specific strategies, such as using positive self-talk and an increased ability to cope with the urge to smoke (159). Similarly, a recent imaging study of cocaine abusers showed that specific instructions to purposefully inhibit cue-induced craving was associated with inhibition in the (limbic) NAc, insula, and orbitofrontal and cingulate cortices and did indeed reduce cocaine craving (160). Dual approaches that pair cognitive–behavioral strategies with medications to compensate or counteract the neurobiologic changes induced by chronic drug exposure are also a promising area of translational research that might, in the near future, provide more robust and longer-lasting treatments for addiction than either given in isolation (161). A new and exciting area of research in this context has emerged to address the question of whether putative cognitive enhancers (e.g., galanthamine, modafinil, atomoxetine, methylphenidate, and guanfacine) could improve treatment outcomes when used as adjuvants for substance users with discernible cognitive impairments (162). An additional emerging area of translational research focuses on understanding how and why behavioral interventions work in terms of neurobiologic function and structure (163,164).
Abuse of multiple substances, such as alcohol and nicotine or alcohol and cocaine, should be considered in the proper management of the addicted individual. Similarly, comorbidities with other mental illnesses will require treatment for the mental illness concurrent with the treatment for drug abuse. Because drugs of abuse adversely affect many organs in the body (Fig. 1-5), they can contribute to the burden of many medical diseases, including cancer, cardiovascular and pulmonary diseases, HIV/AIDS, and hepatitis C, as well as to accidents and violence. Therefore, substance-abuse treatment will help to prevent or improve the outcome for many medical diseases. The HIV/AIDS epidemic provides one of the best examples: Drug abuse and addiction has been fueling the global spread of HIV from the very beginning of the AIDS epidemic. This inextricable connection is predicated on at least three major threads: (a) the direct effects of contaminated injection drug use on infection rates, (b) the indirect impact of abused drugs on high-risk sex behaviors and treatment adherence, and (c) drugs’ ability to worsen the neurologic complications stemming from an HIV infection. Fortunately, recent research has now shown conclusively (a) that HIV prevention among drug users (which includes HIV treatment) is effective in reducing HIV prevalence and (b) that treating substance use disorders (particularly with the aid of new and more effective medications) improves HIV treatment outcomes can and should be parlayed into global instruments for severing those threads once and for all. A particularly promising approach in this context has emerged in the form of the Seek, Test, Treat, and Retain paradigm that seeks out hard-to-reach/high-risk populations, including substance abusers and those in the criminal justice system; tests them for HIV; links those who test positive to HIV treatment and other services; and provides the necessary support to ensure these individuals remain in the care system (165,166).
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