National Institute on Drug Abuse (NIDA)

Overview of Rare Disease Research Activities

The National Institute on Drug Abuse provides national leadership and conducts and supports biomedical and behavioral research, health services research, research training, and health information dissemination with respect to the prevention of drug abuse and treatment of drug abusers; plans, conducts, fosters, and supports a comprehensive program of research and research training relating to the causes, prevention, treatment, patterns, and consequences of drug abuse and addiction, through research performed in its own laboratories and through contracts and grants to scientific institutions and to individuals; supports training in fundamental sciences and clinical disciplines relating to drug abuse by individual and institutional research training awards; coordinates with other research institutes and with other Federal health and other agencies in activities relevant to drug abuse and addiction; conducts and fosters health information dissemination activities, including the collection and dissemination of research findings and related educational materials for health professionals and the lay public; coordinates with institutions and professional associations and with international, national, state, and voluntary agencies working in these areas; and collaborates with the Substance Abuse and Mental Health Services Administration on services research issues as well as on other programmatic issues.

History of Rare Diseases Research

Currently there are four drug abuse treatment medications that have received orphan product designation. Levo-alpha-acetylmethadol (LAAM, trade name ORLAAM) an alternative to methadone used for opiate maintenance therapy received NDA approval in 1993. Naltrexone, an opiate antagonist for use in detoxified patients, was approved in 1985 and no longer enjoys orphan exclusivity. The opiate partial agonist buprenorphine and a combination of buprenorphine plus naloxone have also received orphan designation (see details below) but do not currently have approved NDAs.

Incidence and prevalence figures for dependence on controlled substances (not alcohol or nicotine) are always difficult to estimate, as they vary from type of drug, community, and supply availability (generally a function of supply interdiction/law enforcement). Unlike other disease conditions, illicit marketers have a reason (profit) to introduce and infect the population with abusable and/or dependence producing substances. Illicit drugs utilized in some communities are not always available or in vogue in other communities. Thus, there may be various drug dependence indications which, in and of themselves, may affect less than 200,000 persons in the United States. It is very clear, however, that abuse of opiates (heroin and other narcotics) and stimulants (such as cocaine and "crack cocaine") are endemic in the United States. Even lowest estimates put dependence levels of these substances at figures well above the 200,000 threshold generally used for defining orphan products. The total disease burden of drug abuse in the United States has been estimated to exceed $68 billion per year. Additionally, injection drug use and sexual contact among users is a highly correlated vector in the spread of HIV, hepatitis, and tuberculosis. This creates a public health problem of enormous magnitude while at the same time being treated as an orphan disease by the pharmaceutical industry.

Despite the enormous public health burden of this disease state, there exists little or no incentive for pharmaceutical companies to pursue research and development of new treatment medications for this population. Although total numbers of persons afflicted may seem sufficient in the aggregate, unlike other disease states many of these persons are not treatment seeking at the same time. Therefore, the actual population who may be a potential market for medications is actually only a fraction of the total number who could benefit. Additionally, many of these persons will be treated in publicly funded clinics where reimbursement is perceived by companies as modest or inadequate and subject to artificial control. Some treatment agents may themselves be abusable and will be strictly controlled (witness methadone, classified as a Schedule II controlled substance for use in opiate maintenance therapy -- some 900 U.S. clinics are licensed to dispense methadone and serve approximately 117,000 persons per year with a pharmaceutical market value of approximately $30 million per year). This is simply not an attractive market to most manufacturers based on projected return on investment when compared to nearly any other indication they could pursue. Each of these points is well-documented in the recent Institute of Medicine's Report on the Development of Medications for the Treatment of Opiate and Cocaine Addiction, 1995, and are well-known to the pharmaceutical and market research industries.

Finally, pharmacological treatment of drug dependent populations is not the dominant treatment modality in the United States. Most therapeutic regimens are non-pharmacologically based. As there are no medications which have as yet demonstrated efficacy for the treatment of cocaine dependence, NIDA's orphan product experience to date has focused on medications to treat opiate dependence.

Therefore, while de jure opiate and cocaine dependence do not fit the definition of orphan products, de facto they certainly do. As an instructive example, consider the development and approval of LAAM, an alternative to methadone. Despite the fact that human data on 6,000 subjects from government-sponsored studies was available for LAAM, despite the fact that LAAM was off-patent, and despite the fact that the government had a large supply of LAAM available for anyone interested in obtaining an NDA for LAAM, no private sector entity attempted to finish the development of LAAM until NIDA paid a contractor to do so. Similarly, the development of naltrexone was largely a NIDA-funded effort. Therefore, these products should be viewed as entirely "orphan-like" in so far as their ability to attract private sector sponsors, and until recently this was also persuasive to the Food and Drug Administration (FDA).

In the case of pharmacological treatment for opiate dependence, the population in treatment cannot at present exceed 117,000 per year (Institute of Medicine Report on the Development of Medications for the Treatment of Opiate and Cocaine Addiction, 1995, page 122). Given these facts, historically orphan designation was permitted for two products substantially developed by NIDA (naltrexone, 1985, and Levo-alpha-acetylmethadol, 1993) as treatments for opiate dependence. LAAM received orphan designation based on the fact that it could be used to transfer patients from methadone (and there were less than 200,000 receiving methadone) and naltrexone received designation based on the fact that there were less than 200,000 detoxified addicts at any given time.

In the more recent designation of buprenorphine (1994), FDA appeared to be taking a more restrictive view via application of their more recently promulgated regulations. Although the issue was not definitively answered in the case of buprenorphine, FDA expressed the view that orphan designation where the population in question exceeded 200,000 would be difficult unless there was a medical/biological reason why the product could not be utilized by 200,000. In other words, treatment capacity or the number of persons seeking treatment might not suffice for orphan designation.

In the case of buprenorphine, this did not prove to be an insurmountable burden because that product's sponsor could prove to the FDA that based on historic, current, and projected expenditures, it would not recoup its investment during 7 years of exclusive marketing in the United States. Thus, a unique situation exists where the preclinical efforts are completed, NIDA is supporting clinical trials, and the sponsor has the expertise to manufacture new formulations. Buprenorphine became the first product to receive an orphan designation based on an economic, rather than a population, rationale. This route was selected by the sponsor since there was less certainty that the FDA would continue to allow orphan designation based on the capacity of the treatment system as opposed to the actual incidence and prevalence of opiate dependence.

Recent Scientific Advances in Rare Disease Research

The discovery of opiate receptors by NIDA-funded scientists in the 1970s opened a new era of neurobiological research which is ongoing today. Scientists continue to map brain receptor system types and subtypes, continuously gaining understanding of their structure and function. This information will allow the design of interventions (behavioral, chemical, and genetic) which may be useful in the treatment of a huge number of disorders of mankind, all of which are mediated in the brain.

A generation of research has shown that drug addiction is a complex biomedical and behavioral disease that has its roots in those parts of the brain that underlie, mediate, and allow us to have the emotions that make us human. Just as we have learned that depression is a brain disease that can be treated with medicine, so too have we learned that drug addiction is a brain disease that can and should be treated with medicine.

There is a critical distinction between drug abuse and drug addiction. Drug abuse is a voluntary behavior; the casual user makes a free and conscious decision to break the law and use an illicit, mind-altering substance. Drug addiction is a disease of the brain, resulting from repeated and prolonged self-administration of such a substance. Addiction is brought on by drug-taking behavior in much the same sense that lung cancer is brought on by cigarette smoking and heart disease is brought on by excessive fat intake. Once the disease is established, however, be it in the brain, in the lung, or in the heart, the physiological dysfunction must be corrected to restore health.

The role of a medication is to reestablish normality to brain function and behavior so that the addicted patient has the opportunity for rehabilitation through counseling, psychotherapy, vocational training, and other therapeutic services.

While the mechanisms of many central nervous system disorders are still to be elucidated, scientists working in the field of drug abuse have now identified and cloned the putative site of action in the brain for every major drug of abuse. Thus, the potential to develop new treatments is enormous. For example, having cloned the dopamine transporter mechanism where cocaine exerts its action, NIDA scientists are now designing molecules which will block cocaine's effects at this site without disrupting essential neurotransmitter functions of dopamine.

Additionally, NIDA and other scientists have developed pharmacological agents for the treatment of opiate dependence in various functional categories. For example, methadone and LAAM are mu agonist medications currently approved for opiate treatment. Naltrexone is an opiate antagonist approved for treatment, and naloxone is approved for use in the treatment of opiate overdose. NIDA is currently working on a partial mu agonist (buprenorphine) which will further contribute to the arsenal of agents available for treatment.

Rare Disease Research Initiatives

As described in the history section above, NIDA considers medications for the treatment of dependence on controlled substances to be de facto orphans. Thus, the development of medications for the treatment of these conditions may well be considered as rare disease research within the context of an urgent public health need with a wholly inadequate private sector response. Therefore, NIDA's medications development program effort may (until facts prove otherwise) be considered as part of a rare disease research initiative.

In 1990 the Medications Development Division (MDD) was established in NIDA. This division conducts studies necessary to identify, develop, and obtain FDA marketing approval for new medications for treatment of drug addiction and other brain and behavior disorders; develops and administers a national program of basic and clinical pharmacological research designed to develop innovative biological and pharmacological treatment approaches; supports training in fundamental sciences and clinical disciplines related to the pharmacotherapeutic treatment of drug abuse; collaborates with (a) the pharmaceutical and chemical industry in the United States and other nations, and (b) the Federal medications development programs of other institutes and entities; and works closely with the FDA in assuring that research designed to show the clinical efficacy of new compounds is evaluated and approved in the most expeditious manner possible.

The Division operates within the larger context of a NIDA-wide Medications Development Program which incorporates basic research discoveries from other divisions (intramural and extramural) in the quest to development new pharmacological treatments. Application of research results from the intramural and extramural community allow the Division to have access to the latest theoretical bases and an opportunity to test new hypotheses in controlled clinical settings. Significant areas of research and development are summarized below:

Buprenorphine/Buprenorphine-Naloxone Combination

A 16-week, 735-patient, 12-center trial of buprenorphine, an opiate partial agonist medication for the treatment of heroin dependence, has been completed. Data from this study, and other previous and ongoing studies, have been analyzed. These data demonstrate the effectiveness of buprenorphine in reducing illicit opiate abuse and in retaining patients in treatment.

Under development is a combination dosage of buprenorphine plus naloxone, which would be useful as a potential "non-narcotic" or "take home" treatment medication. Testing is currently under way to determine the abuse potential of buprenorphine plus naloxone. A tablet form of buprenorphine and of buprenorphine plus naloxone is also under development, and commercial sponsorship for these products has been negotiated. A 12-site, 52-week trial of the tablet products is currently under way. An NDA for buprenorphine was submitted in 1997. The NDA for buprenorphine combined with naloxone may be submitted in 1998.

Depot Naltrexone

Naltrexone, a marketed long-acting, orally effective opioid antagonist, was approved in 1985 for the indication of blocking the pharmacological effects of exogenously administered opiates. It is an adjunct to the maintenance of the opioid-free state in detoxified, formerly opioid-dependent individuals.

One of the major obstacles to the success of naltrexone has been patient compliance with therapy. Naltrexone must be taken three times per week and has no effect other than to block the effects of heroin, a drug that the patient is not supposed to use. Because of this, many patients forget to take or stop taking their medication. Therefore, the greatest success with naltrexone has been in the limited population of highly motivated formerly opiate-dependent patients.

To overcome the problem of patient compliance, NIDA is developing a depot preparation of naltrexone. A single injection of this dosage form would "immunize" patients against the effects of opiates for 30 days or longer. Preliminary results show high human acceptability and a good sustained-release plasma profile for the injectable formulation.

Naltrexone was approved in 1994 for the treatment of alcohol abuse; the depot preparation may also be of value in the treatment of that disease.

Inhibition of Nitric Oxide Synthase as a Treatment for Opioid Withdrawal

The enzyme nitric oxide synthase (NOS) catalyzes the conversion of L-arginine to nitric oxide, a freely diffusible gas that plays a role in neurotransmission. Inhibitors of NOS attenuate opioid withdrawal in rats and offer a new approach to pharmacological intervention in the opioid withdrawal syndrome.

Based on this finding, 7-nitroindazole, a selective inhibitor of brain NOS, has been identified as a candidate medication. The effect of this compound on withdrawal is similar to that produced by clonidine. However, unlike other inhibitors of NOS, 7-nitroindazole does not increase blood pressure in morphine-naive or morphine-dependent rats. Because 7-nitroindazole is more effective than other NOS inhibitors and does not cause hypertension, it warrants further testing as a treatment for opioid withdrawal.

The efficacy of NOS inhibitors in attenuating opioid withdrawal provides new insight into the neurochemical systems involved in opioid dependence and withdrawal and suggests that nitric oxide is a neuromodulator of opioid withdrawal.

Cocaine Addiction Treatment

Several small studies of potential cocaine addiction treatment agents have been completed and are in various stages of data analysis. Clinically significant findings will be followed up in larger controlled trials as warranted. The development of anti-cocaine medications has proven to be a daunting task, and to date, only one potential medication has been identified that justifies a Phase III trial. A retrospective analysis of a Phase II trial of selegiline in cocaine addicts indicated a differential outcome in favor of selegiline versus placebo. However, this finding needs to be replicated in a larger and more statistically powerful clinical trial. The Medications Development Division,(MDD) NIDA, intends to conduct a Phase III multi-center trial of selegiline beginning in the fall of 1998.

Additionally, there is a conflicting body of evidence generated by NIDA grantees concerning the potential use of amantadine in the treatment of cocaine dependence. While several studies were negative, two studies involving addition of psychotherapy to the pharmacotherapy have shown a positive effect. MDD plans to conduct studies to further define these effects.

Cocaine Receptor: Imaging Studies

Structure-activity investigations have revealed highly selective and potent binding ligands for the dopamine transporter. NIDA intramural researchers have identified three "generations" of such compounds, with each succeeding generation being more selective and potent than the previous one. RTI-55, the first potent compound, was shown to be an effective in vivo labeling agent in animal studies and was subsequently examined in human imaging studies by SPECT. A second compound, RTI-121, was found to be more selective for the dopamine transporter but had a higher apparent lipid solubility and exhibited lower specific to nonspecific binding in vivo. NIDA researchers are testing new compounds and are also utilizing some older compounds (e.g., WIN-35,428) in brain imaging studies. Procedures have been developed for estimating the occupancy of transporter sites in vivo. Dopamine transporter imaging studies of cocaine abusers are planned.

Excitatory Amino Acids and Cocaine Self-Administration

Recent evidence suggests that the excitatory amino acids play a role in cocaine self-administration. In particular, drugs that act as antagonists at the N-methyl-D-aspartate (NMDA) receptor can block cocaine self-administration as well as cocaine-induced sensitization on locomotor activity. However, the use of these compounds in humans is limited because they often have phencyclidine (PCP)-like psychotomimetic side effects. Agonist action at the glycine receptor, however, modulates action at the NMDA receptor to produce effects similar to the NMDA receptor antagonists without the PCP-like side effects.

Recently, NIDA scientists have investigated the effects of a glycine partial agonist on cocaine self-administration and on locomotor sensitization. The compound blocked the development of sensitization to the locomotor stimulant properties of cocaine and attenuated cocaine self-administration. Thus, compounds that act at the glycine receptor may be useful in the treatment of cocaine abuse.

Methadone, LAAM, and naltrexone are FDA-approved medications for the treatment of opiate addiction. There are currently no FDA-approved medications for the treatment of addiction to cocaine, amphetamine, and other controlled substances of the stimulant class. Accordingly, NIDA has initiated a high-priority program for discovering new medications to treat cocaine and "crack" cocaine abuse.

With the recent cloning (by scientists in NIDA's intramural research program and at academic institutions) of the gene for the dopamine transporter, the site that reportedly mediates the reinforcing effects of cocaine, the time is now ripe for the initiation of a medications development program to synthesize novel medications that will block or attenuate the actions of cocaine. In addition to the dopamine transporter, attention will be focussed on other neurotransmitter systems, on the vasoconstrictive effects of cocaine, and on the development of vaccines or membrane-permeability-altering compounds to prevent cocaine from reaching the brain or passing through the placenta.

Identification of Cocaine Abuse Treatment Medications

The Cocaine Treatment Discovery Program (CTDP) is currently obtaining approximately 100 compounds per year from the academic and industrial community. This preclinical program pales in comparison to drug discovery programs in the pharmaceutical industry, which typically screen more than 10,000 compounds to find a single "lead" candidate. The CTDP is severely limited in its ability to discover potential cocaine abuse treatment agents, primarily because of a lack of compounds for testing and because of inadequate quantities of existing compounds. New mechanisms to identify, test, and synthesize novel compounds--up to 100,000 per year--to combat cocaine addiction must be developed. NIDA is currently discussing screening chemical libraries as an approach to discover new compounds which may be cocaine antagonists. However, NIDA intramural researchers have discovered prototypic compounds that can block the effects of cocaine without interfering with the re-uptake of dopamine into the nerve cell. This finding suggests the possibility of the development of cocaine antagonists which do not alter normal physiological processes.

Treatment of Cocaine Addiction: Dopamine Antagonists

The development of dopamine antagonists to treat crack/cocaine abuse is progressing. Many marketed neuroleptics may facilitate the initiation of cocaine abstinence when used in low doses. At these doses, extrapyramidal side effects are likely to be minimized. The ability of dopamine antagonists to assist in maintaining abstinence needs to be demonstrated.

With the discovery of a multiplicity of dopamine receptors, selective antagonists have been synthesized and will be evaluated in out-patient clinical trials to test their efficacy in randomized, double-blind controlled settings.

Treatment of Cocaine Addiction: Dopamine Agonists

The activation of the dopaminergic reward system in the brain appears to be the principal neurochemical mechanism involved in the addiction to stimulants such as cocaine and amphetamine. Chronic abuse of these drugs results in dopamine deficiency in the brain, which has been hypothesized to lead to craving for stimulants, depression, anhedonia, and dysphoria.

Several clinical reports, such as that reported for amantadine, suggest that dopamine agonists may decrease cocaine use. NIDA proposes to clinically test several approved medications that would increase dopaminergic tone in the brain and to study novel compounds. Examples of these agents are (1) direct dopamine agonists and partial agonists; (2) dopamine precursors; (3) reversible monoamine oxidase inhibitors; and (4) drugs that inhibit dopamine, serotonin, and noradrenaline neuronal re-uptake (mimicking cocaine but which have a slower onset of action and, presumably, are less addictive).

Most recently, studies in rodents and to a lesser extent in monkeys, have differentiated the roles of D1 and D3 receptors with regard to cocaine. The D1 system may inhibit the effects of cocaine, while the D3 system may provide a cocaine substitute of lesser dependence potential. Compounds which affect both systems are under study.

Treatment of Cocaine Addiction: Kappa Opioids

Recent studies have shown that kappa opioid compounds exhibit effects opposite to that of cocaine in terms of dopamine release and neuron firing patterns. In animal studies, kappa opioids block drug discrimination and self-administration of cocaine and also prevent context-independent sensitization to cocaine. NIDA and NIDA grantees will be testing compounds of this class in clinical studies beginning in 1997.

Treatment of Cocaine Addiction: Glucocorticoid Antagonists

Studies have shown that cocaine causes the release of stress hormones known as glucocorticoids in both rats and humans. There is some evidence from rat studies that glucocorticoid antagonists reduce cocaine self-administration in a dose-related manner. NIDA will follow up on these basic research findings with additional studies aimed at developing a potential treatment for cocaine addiction.

Treatment of Cocaine Addiction: Immunology

Researchers funded by NIDA's Medications Development Division reported that they have successfully immunized rats against many of the stimulant effects of cocaine. Cocaine was prevented from entering the brain when rats were "vaccinated" with a substance that triggers the body to produce antibodies to cocaine. These antibodies then acted as biological "sponges" to which cocaine binds, thereby reducing the amount available in the blood to reach the brain. The results of this research are presented in "Suppression of Psychoactive Effects of Cocaine by Active Immunization" in the December 14, 1995, issue of Nature.

Researchers Kim Janda, Ph.D., Rocio Carrera, M.A., George Koob, Ph.D., and colleagues at The Scripps Research Institute demonstrated a greater than 70 percent reduction in cocaine uptake in the brains of rats inoculated with the antibody-producing compound as compared to a group which was not inoculated. Researchers designed the compound so that the antibodies produced would respond specifically to the cocaine molecule yet not affect normal brain chemistry.

In the study, Dr. Janda and colleagues used an "active immunization" approach by developing a substance that when administered to rats would trigger the immune system to produce antibodies that are specific for the cocaine molecule. The researchers inoculated the rats over a 35-day period and then tested their responses to cocaine. The immunized animals showed significantly lower responses to the stimulant effects of cocaine than control animals because the immunization prevented much of the cocaine from getting to the brain. Cocaine concentrations in the brain tissue of the immunized animals were found to be dramatically less than the concentrations of cocaine in brain tissue of controls.

Other immunotherapy research for drug abuse treatment has explored the use of catalytic antibodies and other external agents that can be used to treat cocaine dependence. The research reported in Nature differs by inducing the production of antibodies which remain in the bloodstream for an extended period of time and block cocaine's effects after it is used.

The biotechnology company ImmuLogic Pharmaceutical Corporation also recently announced having developed a cocaine vaccine. Dr. Barbara S. Fox of ImmuLogic Pharmaceutical Corporation (Waltham, Massachusetts) discussed some of the company's findings in Chemistry and Engineering News, December 18, 1995, and at a January 18, 1996, meeting of the Maryland Bioscience Alliance at the request of NIDA's Medication Development Division. ImmuLogic had previously received Phase I SBIR funding from NIDA. In 1996, NIDA awarded a $700,000 Small Business Innovation Research award to ImmuLogic to complete preclinical development of a vaccine to treat cocaine dependence. Results of ImmuLogic's early vaccine work in animals have received attention in national and trade press, were presented at the College on Problems of Drug Dependence (CPDD), and were published in Nature Medicine 2, 1129-1132: 1996.

The vaccine links a protein to cocaine, resulting in a molecule which induces antibody formulation. Once titers reach a certain level, cocaine's ability to cross the blood brain barrier is impeded. The award will expedite completion of preclinical design and testing of the vaccine with the anticipation that clinical trials could begin in 1997.

Treatment of Cocaine Addiction: Serotonin Antagonists

Cocaine increases extracellular levels of serotonin, dopamine, and noradrenalin in the brain. Serotonin is an extremely versatile neurotransmitter that activates numerous sub-receptors. Studies of two sub-types of receptors (5HT-2 and 5HT-3) suggest that these structures may be involved, directly and indirectly through an effect on dopamine, in the rewarding and, possibly, the mood-elevating effects of cocaine. Antagonists of these receptors, which decrease dopamine release, may reduce cocaine craving and use. Therefore, NIDA plans to test serotonin antagonists as potential medications for cocaine addiction.

Treatment of Cocaine Addiction: Serotonin Re-uptake Inhibitors

A major symptom of cocaine addiction is anhedonia (inability to experience pleasure), which is clinically very similar to depression. In addition, it has been postulated that cocaine addiction is a form of self-medication for chronic depression. Initial results of studies of the potent serotonin re-uptake blocker fluoxetine (an antidepressant) have yielded mixed results in attempting to answer the suggestion that it may be efficacious in facilitating abstinence from cocaine use. Evaluation of serotonin re-uptake inhibitors as potential medications will continue.

Treatment of Cocaine Addiction: Calcium Channel Blockers

Calcium channel blockers are used to treat hypertension and may also be useful in reducing the neurological consequences of ischemia or stroke. Centrally active calcium channel blockers reduce the release of neurotransmitters stimulated by depolarization. Preclinical studies show that centrally active calcium channel blockers reduce the amount of extracellular dopamine in animals injected with cocaine and curtail cocaine-induced hypermotility. Some studies suggest that in humans calcium channel blockers reduce cocaine-induced euphoria. These medications may be useful in the management of cocaine abstinence. Further research will explore this possibility.

Reversal of Cocaine-Induced Neurotoxicity

Cocaine induces vasoconstriction and brain ischemia, which may result in neurological and cognitive deficits. Nootropic drugs are used in Europe and Asia to treat neuronal and cognitive deficits associated with aging or resulting from stroke or ischemia. NIDA plans to test several nootropic medications as potential treatments for cocaine-induced neurological deficits. The pharmacological profiles of two of these drugs, vinpocetine and piracetam, suggest that they may be effective in preventing or even reversing cocaine-induced brain damage, cocaine-induced dysfunction, or both.

Treatment of Opiate Addiction: Medication Systems for Neonatal Treatment

NIDA supports the development of medications and formulations to treat withdrawal symptoms in babies born to opiate-dependent mothers. Although many scientists are interested in novel drug-delivery systems, very few have considered the treatment of neonates. NIDA plans to focus specifically on narcotic skin patches for the treatment of neonates born to addicted mothers.

Infants born to mothers who abuse opiates or who are on methadone maintenance can go through withdrawal periods lasting for 3 or more weeks. Currently, there are no FDA-approved medications for the treatment of these neonates, although paregoric (opium solution) has been used.

A transdermal delivery system (patches) for opiate agonists, such as fentanyl or buprenorphine, offers advantages over oral or injectable dosage forms because of its convenience for use in neonates. This technology is available, is currently in use, and could be readily adapted for use in neonates undergoing withdrawal. Clinical trials will require careful planning, and both FDA approval and regulations concerning use in treatment may present unique problems not anticipated by the Narcotic Addict Treatment Act.

Treatment of Opiate Addiction: NMDA Receptor Antagonists

A revolutionary advance in our understanding of one of the basic neurochemical mechanisms underlying opiate addiction has resulted from recent animal investigations of the role of NMDA receptor antagonists in opiate addiction. Drugs that antagonize the NMDA receptor complex are capable of inhibiting opiate withdrawal and tolerance and, in some cases, of reversing tolerance.

As a first step, NIDA plans to assess the toxicity of NMDA receptor antagonists and to evaluate their effects on conditioned cues and drug abuse. It is hypothesized that this class of drugs has a unique pharmacological effect in decreasing the conditioned cues that appear to perpetuate opiate-seeking behavior. Furthermore, we anticipate that these compounds will not have the abuse liability associated with other opiate treatments, such as methadone and buprenorphine.

Treatment of Opiate Addiction: Opioid Peptides as Medications

There are three major types of opioid receptors in the brain: mu, delta, and kappa. Morphine, heroin, methadone, and LAAM bind to the mu receptor with high affinity. The naturally occurring ligand for the kappa opioid receptor is dynorphin A.

Animal studies indicate that dynorphin A alleviates opiate withdrawal and that this peptide also decreases tolerance to chronically administered mu opioid receptor agonists (e.g., morphine). Indeed, kappa opioid abnormalities in the central nervous system may underlie the drug-seeking behavior of heroin addicts. The effects of dynorphin on opiate withdrawal are currently being investigated by NIDA-funded scientists in opiate-dependent subjects.

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