Bringing New Medications to the Treatment of Addiction

Drug abuse and addiction continue to be among the largest and most challenging health and social problems facing society. They affect both the well-being of the individual and the health of the public. In 2001, 15.9 million Americans 12 years and older reported using an illicit drug in the past month, and more than 4.6 million met the DSM-IV criteria for requiring treatment (Substance Abuse and Mental Health Services Administration [SAMHSA], 2002). The encouraging news is that breakthrough discoveries in science continue to refine our understanding of drug abuse and addiction and are yielding new opportunities to translate basic research findings into tangible treatment products.

The processes underlying drug abuse and addiction are complex, and recent findings suggest that addiction does not just involve changes in the neural substrates of positive reinforcement but changes in motivational and cognitive systems as well. The challenge then, is to identify the mechanisms that dampen drug cravings or rewards without interfering with motivation for natural rewards.

The National Institute on Drug Abuse (NIDA) medications development program relies on two approaches to developing medications. The "top-down" approach takes advantage of screening medications, such as fluoxetine (Prozac) or venlafaxine (Zoloft), that have been already marketed and for which there is a good rationale for testing in addicted subjects. The second is a "bottom up" approach, which relies much more heavily on a discovery-driven process. It is in the combination of these two approaches where much of the work for developing treatments for cocaine addiction falls.

Progress in Opiate-Addiction Treatment

Since the inception of the medications development program in 1990, NIDA has established a large screening program and clinical research networks that allow us to co-develop new medications with pharmaceutical company partners. Our most recent success was the October 2002 approval by the U.S. Food and Drug Administration of buprenorphine (Subutex) and a combination of buprenorphine and naloxone (Suboxone) for opiate addiction. These products are the first medications to come out of NIDA's relatively short involvement in medications development since the approval of levomethadyl acetate hydrochloride (LAAM) in 1993. The partial agonist properties of buprenorphine products will allow qualified physicians to prescribe the medication in office-based settings, thus expanding the availability of treatment for opiate addiction.

New Treatments for Cocaine Addiction

An array of NIDA-sponsored projects are testing FDA-approved drugs as possible treatments for cocaine addiction. These drugs include medications that are already being used in the treatment and management of other ailments, including opiate addiction, alcoholism and Parkinson's disease. One that shows promise, disulfiram (Antabuse), is marketed as a therapy for treating alcoholism. Three efficacy trials conducted with different populations of cocaine-addicted individuals suggested that disulfiram in combination with a behavioral intervention (cognitive-behavioral treatment, 12-step facilitation or clinical management) might be effective in treating cocaine addiction (Carroll et al., 1998). A common abuse pattern in cocaine users is concomitant use of alcohol. In cocaine/alcohol abusers, disulfiram treatment showed sustained effect on reduced cocaine and alcohol use one year after cessation of the therapy. This may be because disulfiram may block the anti-anxiety effects of alcohol that lead to increased uses of cocaine. Moreover, McCance-Katz et al. (1998) have shown that disulfiram can increase the anxiogenic qualities of cocaine.

Petrakis et al. (2000) and George et al. (2000) showed a reduction in cocaine use in opiate-dependent cocaine users (a difficult-to-treat group) being treated with disulfiram in addition to methadone (Methadose, Dolophine) and buprenorphine, respectively. A large-scale, Phase III, multicenter trial of this medication is planned by NIDA.

The opioid antagonist naltrexone (ReVia), approved to treat alcohol and opioid addiction, is another potential treatment option being explored at the clinical level. A study by Schmitz et al. (2001) reported that abstinent cocaine-dependent patients showed less relapse to cocaine use over time in the group receiving naltrexone in combination with relapse-prevention therapy (but not another behavioral therapy). This intriguing finding suggests that medications may interact with certain behavioral therapies and not others.

Kampman et al. (1998) reported on the validity of the Cocaine Selective Severity Scale (CSSA), which maps the intensity of cocaine withdrawal signs and symptoms at treatment entry and during the treatment process. The investigators found that this scale, in combination with baseline urine results, predicts ability to attain three weeks of cocaine abstinence in 87% of the cases analyzed (Kampman et al., 2002). In addition to demonstrating the obvious merit of identifying patients who might need additional attention and more intense treatment, the researchers also showed that patients with high CSSA scores responded better to amantadine (Symmetrel) (Kampman et al., 2000) and propranolol (Inderal) (Kampman et al., 2001) in placebo-controlled trials. Follow-up studies are in progress.

Building on knowledge gained from animal studies suggesting that cocaine's blockade of the dopamine transporter plays a key role in producing its addictive and reinforcing effects, NIDA has been studying the compound GBR 12909 (Vanoxerine) as a potential medication for cocaine addiction.

Studies show that GBR 12909 (Vanoxerine) has a strong affinity for the dopamine transporter, greater than that of cocaine. Unlike cocaine, however, which produces a dramatic spike of dopamine, causing a burst of euphoria, GBR 12909 binds more slowly to the transporter and produces a relatively modest and long-lasting increase in dopamine (Tsukada et al., 2000), an indication that it could be used as a medication to dampen cocaine's euphoric effects and be especially useful in reducing cocaine craving. A self-administration study in monkeys using GBR 12909 as a pretreatment showed an elimination of cocaine self-administration (Glowa et al., 1995a, 1995b). More recent studies showed the effect of GBR 12909 was enhanced in conditions where lower unit doses of cocaine were available or response requirements for cocaine were high (Stafford et al., 2000). The drug is currently being tested in a cocaine-experienced population to determine its effects in this population, including subjective effects. An interaction study testing the effects of GBR 12909 on the subjective and cardiovascular effects of cocaine will then precede any outpatient studies.

Another compound NS2359 also known for its ability to modulate the dopamine transporter is being tested in a cocaine-dependent population as part of a Phase I safety study. Both compounds (GBR 12909 and NS2359) may restore the brain's neurotransmitter homeostasis, and, as a result, these potential medications may help cocaine addicts overcome negative mood symptoms and loss of energy.

Recognizing that the dopamine system appears to be the critical substrate for both the reinforcing effects and the psychomotor stimulant effects of cocaine and amphetamines, much work is being done at all three dopamine receptor subtypes: D₁, D₂ and D₃. For example, researchers are using high throughput screening procedures to screen vast libraries of chemical compounds with potential for use as D₁ receptor agonists. These compounds have been shown to block cocaine priming, and NIDA has already screened three libraries containing some 65,000 compounds.

Several D₃ receptor partial agonist compounds are being looked at for their potential in preventing relapse to cocaine. Tests in rats by two different groups have found that D₃ compounds suppress cocaine self-administration (Pilla et al., 1999; Vorel et al., 2002). Researchers are particularly interested in how the compound can suppress the "conditioned cueing" phenomena, wherein cocaine users react to conditioned prompts that they relate to their previous pleasures and experiences with cocaine use.

Additionally, NIDA is supporting the development of an anti-cocaine vaccine. Preclinical tests show the vaccine can block a significant percentage of cocaine from reaching the brain by preventing it from passing through the body's protective blood-brain barrier (Kosten et al., 2002). An outpatient study of this vaccine is scheduled to begin in spring 2003.

New Areas of Methamphetamine Research

Building on the knowledge gained from developing medications for cocaine addiction, NIDA is making progress on treatments for methamphetamine. It has initiated a number of activities to stimulate more research on this particular drug, including launching the Methamphetamine Treatment Discovery Program to identify, evaluate and recommend potential treatments to manage methamphetamine addiction. Several medications are under development for treating different consequences of methamphetamine abuse. Many of the drugs under development target the brain's dopamine system. For example, two FDA-approved drugs, selegiline (Elderpryl) and bupropion (Wellbutrin), are being tested in Phase I interactions studies in methamphetamine users before proceeding to Phase II evaluations for safety and efficacy. Bupropion has already been shown to be effective in treating nicotine addiction (and is approved for that indication under the brand name Zyban) and may be helpful in treating methamphetamine addiction as well. There are approximately a dozen other medications that are currently under development for methamphetamine addiction.

National ClinicalTreatment Network

As part of its treatment research portfolio, NIDA supports a national research infrastructure that can test research-based behavioral and pharmacological treatments in diverse patient and community treatment settings. The National Drug Abuse Treatment Clinical Trials Network (CTN) was established in 1999 to rapidly translate new science-based treatment components into practice.

Utilizing the model set by other National Institutes of Health institutes, the CTN is a cooperative undertaking of NIDA, university scientists studying drug abuse and community treatment providers to test research-based treatments in community settings. The CTN consists of research "nodes," comprising regional research and training centers based in university medical and research facilities. The centers partner with community-based treatment programs that represent a variety of treatment settings and patient populations available in the region. From its original five sites in 1999, the CTN has grown to now include 17 regional nodes spread across the county (encompassing 27 states), including three new sites to be operational in fall 2003 (Southwest node, California/Arizona node and a northern New England node) (Figure). Each node works with five to 10 community treatment programs to deliver evidence-based treatments at the community level. Currently there are 115 community treatment programs involved in the CTN.

In addition to supporting eight active treatment protocols in the CTN, NIDA is committed to enrolling over 8,000 patients for the 18 new protocols that are in various stages of development. These new protocols will include studies of pregnant drug-abusing women, adolescent drug abusers, drug-abusing women with posttraumatic stress disorder, a study conducted in Spanish for Spanish-speaking drug abusers, several HIV risk-reduction interventions and a cigarette smoking cessation intervention for in-treatment drug addicts. Readers who would like additional information on the latest research findings can visit NIDA's Web site at <www.drugabuse.gov>.

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