New, improved therapies to treat and protect against drug dependence and abuse are urgently needed. In the United States alone, about 50 million people regularly smoke tobacco and another 5 million are addicted to other drugs. In a given year, millions of these individuals attempt—with or without medical assistance—to quit using drugs, though relapse remains the norm. Furthermore, each year several million teenagers start smoking, and nearly as many take illicit drugs for the first time.
Research is advancing on promising new means of treating drug addiction using immunotherapies and sustained-release (depot) medications. The aim of this research is to develop medications that can block or significantly attenuate the psychoactive effects of such drugs as cocaine, nicotine, heroin, phencyclidine, and methamphetamine for weeks or months at a time. The promise of the new medications rests not only on their longer action, but also on differences in the way they operate. Unlike most existing treatments, which are active in the brain itself, immunotherapies act by binding the drug in the bloodstream and preventing it from reaching the brain. This represents a fundamentally new therapeutic approach that shows promise for treating drug addiction problems that were difficult to treat in the past. Despite their potential benefits, however, several characteristics of these new methods pose distinctive behavioral, ethical, legal, and social challenges that require careful scrutiny.
At the request of and with support from the National Institute on Drug Abuse (NIDA), the National Research Council and Institute of Medicine established the Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction to develop recommen-
dations for research in this emerging field. Specifically, the committee was charged with identifying and defining distinctive behavioral, ethical, legal, and social issues that are likely to arise if and when these medications become available for treating drug addiction. Such issues can be considered unique aspects of safety and efficacy that are fundamentally related to the distinct nature and properties of these new types of medications. The committee was not charged with determining whether or not immunotherapies and sustained-release formulations represented an efficacious approach for treating drug addiction. Nor was it asked to determine whether or not NIDA should continue to fund research on these types of therapies. Rather, the committee was charged with identifying and defining issues that are likely to arise if and when these medications become available. Essentially, the committee was charged with formulating a research agenda. The result of that work is presented herein. This research agenda has been informed by a series of commissioned papers, comments when these papers were presented at a public workshop, and the expertise and judgment of the committee.
The committee examined three different types of therapeutic agents: active immunotherapies, passive immunotherapies, and depot formulations of opioid antagonists. Active immunotherapies use periodic injections to stimulate the body’s own protective immune system to generate antidrug antibodies, which then bind drugs of abuse in the bloodstream before they can reach the brain. Passive immunotherapies use preformed antidrug monoclonal antibodies that are produced through advanced biotechnology techniques; they also bind drugs of abuse in the bloodstream and can be infused for immediate treatment for drug overdose. Depot medications are long-acting formulations of existing drugs that are slowly released over time, typically administered as injections.
To date, the new medications have been studied primarily for their efficacy in the treatment of drug dependence, chronic drug use, and drug overdose. It is plausible that they will prove efficacious in protecting against initiation and escalation of drug use. However, the immunotherapies are still quite new, and there is very limited research. The research to date suggests that the concept might work, but that limited research does not constitute evidence that this therapeutic approach or any particular new molecular entity is safe or efficacious. Although there is much more research on depot medications against opiate addiction, the committee was also not charged with a review of the safety or efficacy of depot medications.
Immunotherapy and depot medications can block or significantly
attenuate the psychoactive effects of drugs of abuse by either reducing the amount of drug in the brain (immunotherapies) or by blocking drug effects at their site of action in the brain (sustained-release medications). Research in both human and animal subjects demonstrates that consumption of a blocked drug can fall dramatically or even cease. Another important characteristic of these medications is that they have long durations of action—a month or even longer per administration—which should reduce the problem of nonadherence found with medications that must be taken daily.
Recommendation 1 The National Institute on Drug Abuse should support basic immunology studies on increasing the stability and longevity of antibody blood levels and on developing combination therapies to simultaneously treat a variety of abused drugs.
Clinical trials for Food and Drug Administration (FDA) approval of these medications will likely be performed in limited populations—such as adult males and nonpregnant females being treated for drug dependence or drug overdose—because the companies sponsoring such trials seek the least costly way to obtain FDA approval. Once a pharmaceutical is approved, however, the FDA has little effective control over the way it is used in the practice of medicine. However, it is foreseeable that parents and physicians will be interested in using immunotherapies “protectively” with children and adolescents—before they have ever used tobacco or illicit drugs or when use is still at subclinical levels of severity—even if these medications have not been approved for such purposes. Likewise, addiction programs with pregnant patients will be inclined to use these new medications despite the lack of testing in that population. The perception of potential benefits from protective use of immunotherapies for adolescents and pregnant women may be quite high, because the consequences of drug use or addiction can be long-lasting and severe in these populations, and they pose unique challenges. Moreover, the general record of safety of immunotherapies when established for some populations might lead health professionals to expect such safety for these therapies with populations not yet tested.
The potential unwanted behavioral responses from off-label uses of these new medications point to a need to consider expanding the criteria for evaluating pharmaceutical products by the FDA. The means now used by the FDA to measure safety and efficacy in clinical trials may not provide an accurate picture of the costs to society or benefits that these medications will produce in actual use.
Recommendation 2 Recognizing that immunotherapy and sustained-release medications will be used in off-label situations that have not been specifically approved by the Food and Drug Administration, the National Institute on Drug Abuse should support preclinical studies addressing the potential safety and efficacy of these medications when given to vulnerable populations (e.g., pregnant women and their fetuses, adolescents, etc.). Long-term studies should be done with laboratory animals of different ages, as well as their offspring, before trials with vulnerable human populations are undertaken.
Recommendation 3 The National Institute on Drug Abuse should support studies of the likely extent and nature of off-label drug use, including factors and incentives that would promote or retard such use, and the opportunities for policy makers to intervene should the patterns of off-label use depart from what is in the best interest of the society.
Immunotherapy medications present unique and far-reaching challenges for our current system of medical and addiction treatment. The development of these therapies highlights the need to view addiction as a chronic medical condition requiring long-term management. As such, they will require the historically separate systems of medical care and addiction treatment to forge new partnerships to ensure that both medication and integrated psychosocial services are available to those in need. Offering these treatments in primary care settings should reduce the stigma of substance abuse treatment, but the potential for long-term markers of these treatments or false-positive markers of drug use may discourage treatment participation.
Recommendation 4 The National Institute on Drug Abuse should support studies of whether the potential for discrimination due to long-lasting markers in the blood or urine deters people with drug dependence from accepting immunotherapies. The effects of immunotherapies on false-positive and false-negative drug testing results should also be studied.
Recommendation 5 The National Institute on Drug Abuse should support clinical effectiveness studies and financing models that integrate the new pharmacotherapies with psychosocial services in specialty addiction and primary medical care settings.
The great potential of immunotherapy will prove problematic if these new medications are incorrectly viewed as “magic bullets.” The failure of these medications to meet expectations when used outside research settings could undermine their acceptance and the willingness of government agencies and private firms to finance the research needed to develop them. First, like any medications, these new therapies will not be completely effective for all patients. Second, some individuals may be unwilling to even accept the first dose if they fear making a commitment to sustained abstinence from their drug of addiction for a variety of reasons, including fear that they cannot easily reverse the medication or return to their drug use to relieve protracted withdrawal symptoms or for other needs. Third, for a variety of reasons, some patients will not remain in treatment but will relapse to smoking or drug use. Fourth, some individuals may refuse treatment because the therapies may leave long-lasting markers in their systems, thus subjecting them to possible adverse effects, such as denial for health insurance.
Fifth, some patients who receive these medications—even completely willingly—could behave in ways that would undermine their effectiveness, for example, by switching to drugs that are not targeted by the medication and by attempting to test or override the blocking effect of the medication by taking larger amounts of the drug. Moreover, the existence of what are seen as safe and effective treatments for addiction could make experimenting with drugs seem less risky and hence increase drug use. Conversely, if treatment programs using these new medications succeed in substantially reducing the number of existing addicts, dealers may aggressively attempt to interest new customer bases, as well as engage in violent “turf wars” to maintain profits in their existing markets.
Recommendation 6 The National Institute on Drug Abuse should support studies of behavioral consequences, such as the increased potential for accidental overdose and changes in drug use patterns, which may include switching drugs, increasing drug dosage or overall consumption, changing the route of administration (e.g. nasal to intravenous for greater bioavailability) or, conversely, avoiding use of other addictive substances.
Recommendation 7 The National Institute on Drug Abuse should support studies that examine the extent to which the availability of immunotherapy medications might reduce the perceived risk of drug use and the effects of such changes on drug use behavior in various populations.
Recommendation 8 The National Institute on Drug Abuse should support studies of the potential effect of immunotherapy medications on illicit drug markets and market-related behaviors.
CONSENT AND COERCED TREATMENT
Enthusiasm for the new medications should not obscure the fact that fully informed and voluntary consent is necessary under any and all circumstances. These medications can produce long-lasting biological markers (raising issues of confidentiality and potential for discrimination) and might interfere with drug-testing methods. The free and informed nature of consent is of special concern if the medications are used in settings and circumstances that are inherently coercive. These therapies may offer great benefit, even when used in such settings. However, any such benefit needs to be balanced against the rights to privacy and liberty that have long been recognized in the provision of medical care. Particular complications may arise in obtaining consent from persons in the criminal justice system, from pregnant women, from women who are already parents and involved with the child welfare system, and from adolescents and children whose parents or guardians seek to administer these medications for “protective” use.
Recommendation 9 The National Institute on Drug Abuse should support studies to determine the standards to be applied when immunotherapy medications are considered for use in the criminal justice and child welfare systems including due process protections when there is a government-imposed treatment requirement.
Recommendation 10 The National Institute on Drug Abuse should support studies to carefully articulate the behavioral, ethical, and social risks associated with treatment of pregnant women and their fetuses and protective therapy in minors and to develop clinical practice guidelines for such use or discouragement of such use.