For the six million people suffering from drug addiction in this country, research shows that medications can be an important part of recovery, especially when combined with behavioral therapies. In this way, addiction is similar to other chronic relapsing diseases like hypertension, diabetes, and certain forms of cancer, also treated and managed with medication, in tandem with behavioral and lifestyle changes. With addiction, medication and behavioral therapy are aspects of an overall therapeutic process that often begins with detoxification, followed by treatment and relapse prevention.

Sometimes, as with other chronic conditions, episodes of relapse may require a return to prior treatment components. Easing withdrawal symptoms can be important in the initiation of treatment; preventing relapse is necessary for maintaining its effects. A continuum of care that includes a customized treatment regimen and follow-up options — e.g., community- or family-based recovery support systems — can be crucial to a person’s success in achieving and maintaining a drug-free lifestyle.

The National Institute on Drug Abuse (NIDA) supports research addressing all of the complex issues associated with the disease of addiction. Here, though, we highlight several promising approaches to development of addiction medications aimed at easing craving, preventing relapse, and enhancing the cognitive processes compromised by drug abuse and addiction, so that addicted people can recover and learn to live without drugs.

Because drug addiction is complex, we depend on a multi-pronged approach to medications development, targeting in a “top-down” manner commercial medications already approved by the U. S. Food and Drug Administra-tion (FDA) for other indications, as well as discovering promising compounds from the “bottom-up” through a basic science approach. Our robust science program, augmented by innovative research tools, from molecular neurobiology, to “in vivo” neuroimaging technologies, shows us where and how drugs of abuse exert various effects in the brain to produce addiction, which allows the development of medications with countervailing effects. These are eventually tested in clinical trials with human subjects to determine their safety and efficacy for real-world use. Our vision is broad and seeks to understand not just one molecule or one pathway at a time, but rather how pathways interact with each other as part of an intricate system, affecting brain regions that mediate reward and motivation, emotional learning and response, and memory. And while the body’s diffused and interactive response to addictive drugs makes treatment of addiction challenging, it also offers multiple avenues for potential intervention and calls for new angles of approach for medications development.

The push to develop effective addiction medications is particularly important to NIDA, as efforts to enlist the private sector have been only partially successful, largely because of financial disincentives for pharmaceutical companies, as well as the continuing stigma associated with addiction medications. One heralded success, however, is the recent approval of buprenorphine for the treatment of opiate addiction (see sidebar). The story of buprenorphine illustrates how long-term investments in research can result in tangible products that dramatically impact the health of the public.

Zeroing in on specific brain targets
NIDA researchers have now identified the specific sites of action in the brain where every major drug of abuse, including opiates, methamphetamine, cocaine, and THC (the active ingredient in marijuana), have their initial effects. This has led to the development of targeted medications with the potential to affect particular addiction processes in humans. Several examples of these are described below.

Opiate Receptors. Around 30 years ago, researchers discovered the existence of endogenous brain receptors that bind opiate drugs, such as heroin and morphine. Subsequent studies were able to localize the distribution of these opiate receptors, and found them to be highly concentrated in areas of the brain that control pain and emotions. When opiate drugs bind to these receptors, they can drive up dopamine levels in the brain’s reward areas, producing a “high” or state of euphoria and relaxation. Pharmacological treatments can target this system with medications that act at opiate receptors by either supplanting (agonists) or blocking (antagonists) the effects of opiate drugs. Buprenorphine is unique because it does both: as a partial agonist, it binds to opiate receptors but elicits a weaker response than other opioid drugs like heroin, morphine, and even methadone. Its distinctive pharmacology makes it safe and effective in preventing withdrawal symptoms and in helping to control an addicted person’s drug cravings and use. NIDA is now conducting clinical trials with buprenorphine to test its safety and efficacy in vulnerable populations, including pregnant women and adolescents, and in pain patients addicted to their medications.

Although opioid receptor antagonist medications offer another approach, they are not effective for everyone. Part of the reason is that antagonists serve only to “block” opioid effects, such that when heroin addicts take the opioid antagonist naltrexone, for example, heroin has no effect; and in an addict not currently detoxified, naltrexone can trigger severe withdrawal symptoms, effects that can impede compliance. Antagonists therefore work best in people who are highly motivated to quit. To help with compliance, new depot formulations of buprenorphine and naltrexone — with effects that last for weeks instead of hours — are being studied in different patient populations. Recent findings showed depot naltrexone to be effective in formerly dependent, medically withdrawn opiate addicts (Comer et al., 2006). Long-acting forms of medications promote adherence because patients who are on them do not need to motivate themselves on a daily basis in order to stick to a treatment regimen. In addition, sustained-released formulations also decrease the potential for diversion and abuse, since there are no take-home, daily medications. Treatment also can be more cost-effective due to decreased clinical support with fewer clinical visits; however, diminished therapeutic support also has its down side and warrants consideration as these longer acting medications come into practice.

Cannabinoid receptors. NIDA-supported marijuana research has been instrumental in the discovery, characterization, and use of the endogenous cannabinoid system — an extensive communication network distributed throughout the brain and body made up of naturally produced compounds called cannabinoids, which are chemically related to marijuana’s active ingredient, and their receptors. It is an influential system, spawning research that is being translated into a variety of promising new treatments to affect the rewarding properties of many different drugs of abuse and influence other processes, such as those involved with pain, learning, memory, and cognitive performance. Rimonabant, which targets cannabinoid receptors and was recently approved by the FDA as a medication to help people lose weight, has been shown to block marijuana’s subjective effects in humans (Huestis et al., 2001) and to prevent relapse in drug-seeking in animals (De Vries et al., 2001, Shalev et al, 2002). Such findings will inform medications development efforts aimed at relapse prevention.

Dopamine transporters. Potential medications for stimulant addiction build on animal studies suggesting that blocking the dopamine transporter — the body’s mechanism for recycling excess dopamine — plays a key role in producing cocaine’s addictive and reinforcing effects. Cocaine disrupts the natural processes that clear dopamine from brain synapses, resulting in cocaine’s euphoric effects. NIDA has, therefore, been studying medications that show a strong affinity for the dopamine transporter but have different temporal characteristics (i.e., they bind more slowly and stick to the receptors for a longer period of time than drugs of abuse). Medications with these properties can help to dampen euphoric effects and reduce craving. Reducing craving is the fervent quest of addicts in recovery (i.e., not to want the drug with your whole being). These compounds, known as long-acting dopamine uptake inhibitors, may also help to restore the brain’s chemical equilibrium and thus, help addicts overcome negative mood symptoms and loss of energy.

Approaching medications development by restoring brain function
In addition to identifying the specific molecular sites where drugs of abuse act in the brain, scientists also have identified the human brain circuits involved in craving, euphoria, and other effects of addictive drugs. One thing is clear: it is more than simply an increase in dopamine. Addiction affects multiple brain functions, and the reason people start abusing drugs is usually not the reason they continue. As people continue to use drugs, more brain systems get usurped, with effects extending beyond the reward pathway that channels the well-known dopamine “rush” to pull in multiple brain regions, circuits, and transmitter systems. Along with reward, brain processes affecting motivation, learning, memory, and inhibitory control also substantially contribute to the compulsive nature of drug abuse. The “thinking” and decision-making parts of our brains, which are not even fully developed until our mid-twenties, govern our ability to inhibit behavior and control impulse. Therefore, NIDA is currently studying medications that strengthen inhibitory control and accelerate the extinction of cravings, in combination with therapies to facilitate new learning.

One goal of a potential addiction medication is to reestablish normalcy to brain function and behavior, to increase the effectiveness of behavioral treatments. Because the pleasurable feelings that people experience from drugs are “remembered” and reinforced in the brain such that they eventually outstrip the natural rewards of food, sex, family, and friends — and can even induce people to forego the loss of them — NIDA is interested in developing medications and therapeutic approaches to increase the saliency of natural reinforcers. Additionally, given that drug cues (i.e., environmental “triggers” that a person associates with drug taking), drug priming (i.e., re-exposure to the drug), and stress are among the most well established causes of relapse, compounds that affect these processes are also of great interest to NIDA. We are studying several different categories of drugs with efficacy in these areas. These are described below, in the context of the treatment phases where they might be most applicable.

Detoxification and withdrawal. Management of withdrawal may enhance treatment retention and overall response, with several medications showing promise in this regard. Buprenorphine, for example, capable of helping to maintain abstinence in opiate abusers, has also shown efficacy as a detoxification agent (Ling et al., 2005). Marinol, a cannabinoid agonist, used to stimulate appetite in AIDS and cancer patients, has proven helpful in reducing withdrawal symptoms in marijuana-addicted patients without producing intoxication, thus helping to get people through the first two weeks of marijuana abstinence (Haney et al., 2004). NIDA is studying the strategy of starting with an agonist to mitigate withdrawal and then following up with an antagonist to block drug effects and help patients maintain abstinence.

Treatment. Recovery from addiction is hard work that requires renewal of brain function and the regaining of emotional equilibrium, in addition to handling the multitude of other health, social and economic problems that often result from drug abuse. For many people, depression is another complicating factor in recovery. In fact, imaging studies show that during withdrawal, the brains of stimulant addicts resemble those of depressed patients (London et al., 2004). Antidepressants may help during these beginning stages of treatment. For example, Wellbutrin and Zyban — trade names for the antidepressant bupropion — have been shown to ease the transition for smokers trying to quit, and may now offer promise as anti-addiction medications for illicit drugs. In fact, combining bupropion with contingency management (i.e., rewarding positive behaviors) for cocaine addiction may significantly improve outcomes for cocaine-addicted patients maintained on methadone (Poling et al., 2006).

Other helpful treatment medications include antiepileptic drugs like topiramate (i.e., TOPAMAX®), which may help “shore up” cortical function, or gamma-vinyl-GABA (GVG) (i.e., Vigabatrin or Sabril®), shown to decrease methamphetamine and cocaine use. Antiepilep-tic medications modulate glutamate and GABA — neurotransmitter systems that are affected by drugs of abuse and involved in many of the functions compromised by addiction — and have been shown in both animal models and early clinical trials to have potential as treatments for cocaine and methamphetamine addiction (Kampman, 2004; Brodie et al., 2005).

Addiction changes the parts of the brain that affect our ability to think straight, to control impulses, and understand consequences. Addiction also compromises the capacity to learn new positive associations and unlearn old habits, to express emotions, and regain control and responsibility of one’s life – strategies needed to achieve recovery and appreciate the value of natural rewards. Because drug-impaired cognitive function, such as verbal memory and learning skills, can predict treatment dropout and lead to continued abuse and relapse (Aharonovich et al., 2006; Grohman and Fals-Stewart, 2004), people undergoing addiction treatment also need medications to help them recover cognitive functioning to give behavioral therapies the best chance to work.

A “rising star” in this arena is modafinil, a drug used to treat narcolepsy. It appears to improve cognitive functioning in people with schizophrenia and attention deficit hyperactivity disorder (ADHD) (Turner, Danielle et al., 2004; Turner et al., 2004), and may also complement behavioral counseling for methamphetamine abuse, which exceeds other drugs in its disruption of cognition, especially the ability to focus and ignore or inhibit distractions. Deficits in this area will undermine a person’s effective engagement in cognitive-behavioral therapy (Salo et al., 2005). Modafinil shows promise in early results for cocaine treatment, with additional clinical trials now underway in cocaine and methamphetamine abusers. In one trial, patients receiving modafinil with cognitive behavioral therapy to treat cocaine addiction were more than twice as likely as placebo-treated patients to achieve abstinence for three weeks or more, an encouraging signal that modafinil can help patients avoid relapse in the critical first weeks of treatment (Dackis 2005). Other medications being studied as potential cognitive enhancers include Methylphenidate (i.e., Concerta®) and atomoxetine (i.e., Strattera®), typically used to treat ADHD, and bryostatin, a cancer drug — the first two for improving dopamine function in the frontal cortex, and the latter to enhance new learning (Alkon et al., 2005).

Relapse prevention. The major triggers of relapse include stress, environmental (drug-conditioned) cues, and priming, or re-exposure to drugs of abuse. Medications that block reinstatement of drug-taking in animals by these three triggers are now being tested in humans. They include many of the medications already discussed, along with CRF antagonists to target the stress response. CRF is a brain chemical that organizes our body’s response to stress. Its ability to activate reward systems and prompt relapse to drug-seeking in animals previously exposed to drugs highlights a link between stress mechanisms and drug reward pathways (Wang et al., 2005). Studies in animals show that compounds developed to block CRF can also block the initiation or reinstatement of drug-taking following stress cues (Liu X, Weiss F, 2002). Given that drug withdrawal syndromes, and the often chaotic lifestyles of drug abusers, are considered aversive or stressful states, blocking CRF may help mitigate the stress that often precipitates relapse in people trying to remain abstinent.

Medications currently available to treat a variety of other disorders are also proving useful for relapse prevention. For example, medications to treat schizophrenia have shown preliminary efficacy in decreasing cue-induced craving for cocaine (Smelson, 2006) and the antidepressant bupropion also has been shown to reduce cue-induced cravings for methamphetamine (Newton et al., 2005).

On the horizon
Medications development must be a continually evolving process, poised to take advantage of new research findings. NIDA is exploring several areas with exciting implications for the future including: individualized treatments based on a person’s genetic makeup; continuing discoveries of new mechanisms for restoring an addicted person’s capacity to appreciate the value of natural rewards, in lieu of drugs; and pharmacotherapies that can possibly “immunize” people against drug abuse or help prevent relapse to drugs, with cocaine and nicotine vaccines now undergoing efficacy testing in humans.

Animal studies already have shown that the dopamine system in the brain can be manipulated to reduce voluntary alcohol intake (Thanos et al, 2001). This knowledge could inspire new treatments that would seek to boost dopamine function in the brains of addicts to help them regain more normal ways of interacting with the world, and to restore their ability to appreciate natural rewards, such as those stemming from relationships, work, good food, etc. Other studies have shown that this system also can be manipulated by social factors. In a study of non-human primates, for example, those who became socially dominant also increased their dopamine receptors and were less inclined to self-administer drugs (Nader and Czoty, 2005). Such studies give us a greater appreciation of the role of environmental factors in affecting predisposition, continued drug use, and relapse triggers. This knowledge can give us new targets for restoring the value of natural rewards and preventing relapse, and new strategies for effecting behavior change.

Another key target for medications development is to translate our knowledge of human genes into human differences in susceptibility to addiction and effectiveness of treatment. Imagine being able to predict treatment outcome and improve treatment response based on genetic makeup. We have already seen exciting discoveries where carriers of a particular dopamine receptor variant had a better response to bupropion for smoking cessation than carriers of a different version (Lerman et al., 2006), and where individuals with one or two copies of a particular opiate receptor allele had significantly lower rates of relapse to alcohol abuse when treated with naltrexone (Oslin et al., 2003). Such findings provide a glimpse of a future in which a patient’s genetic background will be a major factor in selecting the most appropriate (and cost-effective) therapeutic course of action.

New tools also are opening up new horizons. Imaging technologies are continually being refined such that we may soon be able to “tell the future” in terms of addiction treatment. A pioneering study already has shown that brain images of regions involved in decision-making, taken early in the recovery period, could predict with a 90+ percent accuracy who would relapse and who would not (Paulus et al., 2005). If replicated, this approach can help providers better tailor treatments through identification of specific brain activation patterns as accurate predictors of relapse. Understanding such patterns is a necessary first step toward developing new treatment approaches that increase a patient’s chances of long-term abstinence.

NIDA continues to pursue these and other exciting lines of research.

NIDA’s scientific advances have revolutionized our understanding of drug abuse and addiction. NIDA researchers address the most fundamental and essential questions about drug abuse, ranging from the molecule to managed care, and from DNA to community outreach research.

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This article is published in Counselor,The Magazine for Addiction Professionals, August 2006, v.7, n.4, pp.33-40.

Readers have left 2 comments.

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family, Unregistered

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 Posted 2008-05-06 12:22:42

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Robert Davies, PhD/CADC/MISA I, Unregistered

This is a wonderful summary of very valuable information. It is sad, and actually criminal, that so many addiction therapists are still in the Dark Ages and staunchly oppose any medication therapy out of ignorance.

 Posted 2008-03-22 00:39:25

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