1
Introduction and Background

Drug use is one of the nation’s most expensive health problems, costing $109.8 billion in 1995 alone (Harwood, Fountain, and Livermore, 1998). In addition to the financial costs, drug use also exacts a human cost with thousands of lives being damaged and forever changed by drug use and addiction. Prevention and treatment research, as well as clinical experience, have shown that it is often possible to intervene successfully in addiction. However, such interventions must be grounded solidly in research and must also provide long-term behavioral and sometimes pharmacological support to ultimately achieve abstinence.

As part of these research-based interventions, the National Institute on Drug Abuse (NIDA) is funding the development of new classes of medications to treat drug addiction. These medications include immunotherapies and sustained-release formulations. Immunotherapies involve products that are introduced into the body to stimulate an immune response either through active immunization (e.g., vaccines) or passive immunization (monoclonal antibodies). This immune response counteracts the effects of the target drug. Currently, immunotherapies are being developed to counteract the effects of cocaine (see Carerra et al., 2001; Fox et al., 1996; Kantak et al., 2001), methamphetamine (see Aoki, Hirose, and Kuroiwa, 1990); phencyclidine (“angel dust” or PCP) (see Proksch, Gentry, and Owens, 2000), and nicotine (Hieda et al., 1997; Pentel et al., 2000; Tuncok et al., 2001). Sustained-release formulations, also known as depot medications, involve a slow, timed release of medications that counteract the effects of illicit drugs. Sustained-release preparations of naltrexone (Kranzler, Modesto-Lowe, and Nuwayser, 1998) for opioid addiction and



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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions 1 Introduction and Background Drug use is one of the nation’s most expensive health problems, costing $109.8 billion in 1995 alone (Harwood, Fountain, and Livermore, 1998). In addition to the financial costs, drug use also exacts a human cost with thousands of lives being damaged and forever changed by drug use and addiction. Prevention and treatment research, as well as clinical experience, have shown that it is often possible to intervene successfully in addiction. However, such interventions must be grounded solidly in research and must also provide long-term behavioral and sometimes pharmacological support to ultimately achieve abstinence. As part of these research-based interventions, the National Institute on Drug Abuse (NIDA) is funding the development of new classes of medications to treat drug addiction. These medications include immunotherapies and sustained-release formulations. Immunotherapies involve products that are introduced into the body to stimulate an immune response either through active immunization (e.g., vaccines) or passive immunization (monoclonal antibodies). This immune response counteracts the effects of the target drug. Currently, immunotherapies are being developed to counteract the effects of cocaine (see Carerra et al., 2001; Fox et al., 1996; Kantak et al., 2001), methamphetamine (see Aoki, Hirose, and Kuroiwa, 1990); phencyclidine (“angel dust” or PCP) (see Proksch, Gentry, and Owens, 2000), and nicotine (Hieda et al., 1997; Pentel et al., 2000; Tuncok et al., 2001). Sustained-release formulations, also known as depot medications, involve a slow, timed release of medications that counteract the effects of illicit drugs. Sustained-release preparations of naltrexone (Kranzler, Modesto-Lowe, and Nuwayser, 1998) for opioid addiction and

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions lofexidine (Rawson et al., 2000) to treat nicotine addiction are currently being developed. All three therapies—vaccines, monoclonal antibodies, and sustained-release formulations—are long acting, but time limited, with durations from weeks to months. The availability of these medications will raise a host of issues. Some of these issues will marry traditional vaccine concerns, such as establishing and monitoring safety, ensuring efficacy, and financing and distributing the medications, with traditional drug abuse treatment issues, such as ensuring patient adherence to treatment, using these therapies in a variety of settings, and dealing with coercive legal methods that are sometimes used to “motivate” treatment initiation. In addition, less traditional issues may also be raised, such as who should be immunized or treated with a depot medication and when, and who will decide. COMMITTEE CHARGE AND REPORT NIDA requested the advice of the National Research Council and the Institute of Medicine of the National Academies about behavioral, ethical, legal, and social issues likely to arise as a result of research they are funding to develop immunotherapies and sustained-release formulations. The Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction was formed to identify and define the behavioral, ethical, legal, and social questions that will be raised in determining who should be given these medications and under what circumstances, given the major issue of therapeutic safety. This study was not intended to be a safety review of immunotherapies and sustained-release formulations, which are still under development, but safety forms a necessary backdrop for all of the issues the committee considered. Morover, the committee was not asked to evaluate the actual or potential efficacy of immunotherapies and depot medications for treating drug addiction. These therapies are still under development, and none has even been submitted to the Food and Drug Administration (FDA) for approval. The committee was not expected to achieve consensus about how all of the issues should be resolved. Rather, the committee was expected to achieve consensus about what the issues are likely to be and which are likely to be the most pressing Indeed, the committee was charged with anticipating issues that may or may not bear upon the assessment of safety and efficacy of these medications. The committee has attempted to forecast issues that may arise in the therapeutic use of these medications if and when they are approved by the FDA for use. The committee believes that the nature and importance of many of these issues are such that NIDA may wish to encourage research into these issues in parallel with—if not integrated into—clinical trials that are done in order to test and demon-

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions strate the safety and efficacy of medications. The committee suggests that some or all of these issues be examined during the FDA approval process. This report reviews the behavioral, ethical, legal, and social issues likely to arise if, and when, immunotherapies and sustained-release formulations become available for treating drug addiction. It identifies the relevant issues and lays out a research agenda for NIDA. Because these therapies are still early in development, no literature exists that the committee could analyze or synthesize as a way of identifying and defining the behavioral, ethical, legal, and social issues. Rather, the committee reviewed similar, but related, literatures to better understand the potential implications of these new medications. This process required some creative thinking and use of judgment and members’ expertise about what the issues are likely to be and which of them are most pressing. The rest of this chapter provides a basic description of both immunotherapies and sustained-release formulations. In Chapter 2 the committee lays out considerations for clinical trials, focusing in particular on issues that are generally considered outside the usual FDA process. Chapter 3 then considers a range of treatment issues, including the organization and delivery of care in alternative treatment settings, privacy, financing, and costs. Finally, in Chapter 4 the committee looks at potential adverse behavioral responses to the use of immunotherapies and at the difficult practical, ethical, and legal issues of consent, particularly for vulnerable populations. MEDICAL BASIS OF IMMUNOTHERAPY Vaccination (active immunization) for the prevention and treatment of human disease has a long and distinguished medical history dating back at least to the pioneering work of Jenner nearly 200 years ago. The World Health Organization (2003) suggests that clean water and vaccines have been the two greatest contributions to worldwide public health. Indeed, vaccines prevent illness or death in millions of individuals each year. Vaccines work by stimulating an immune response to a disease-related organism or subunit(s). Over a period of weeks to months, immunization(s) lead(s) to the generation of protective antibodies in body fluids, which act as an early surveillance system to block or reduce the effects of an invading organism or substance, such as a toxin. The next advance in immunotherapy came in the early 20th century. Before the advent of antibiotics, polyclonal antibodies in the form of a specific immune serum were used to treat infectious diseases. Although these antisera were highly effective in treating diseases, such as pneumococcal pneumonia and tetanus, they sometimes produce a serious adverse

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions side effect called serum sickness (Devi et al., 2002). This allergic reaction resulted from the administration of animal antisera to humans, so animal antisera could only be used as a last treatment option. Later, the technique of plasmapheresis and the development of specific vaccines provided the possibility of immunizing human donors and then collecting human immune globulin for the purpose of treatment (Mallat and Ismail, 2002). Indeed, human immune globulins are still used under certain situations to treat hepatitis B, tetanus, and Varicella zoster (which causes chickenpox) (Terada et al., 2002). Advances in biotechnology and genetic engineering over the last 30 years have made it possible to generate the newest form of immunological medication, monoclonal antibodies. These antibodies are of uniform composition, well-characterized chemical properties (in terms of specificity, affinity, and amino acid composition) and can be produced by large-scale manufacturing techniques without the use of animals or animal proteins (Smith, 1996; Demain, 2000). Because monoclonal antibodies are not produced from human blood, they do not carry the risk of transmission of human infectious agents, such as HIV and hepatitis B and C viruses, and so represent an intrinsically safer product in that regard. The medical rational for using immunotherapies for treating or preventing drug abuse is similar in concept to more traditional immunological applications. However, the primary action of an antidrug antibody in the serum is to reduce drug levels in the brain by binding the drug before it enters the brain (Pentel and Keyler, 2004). Because the drug binds with high affinity to the antibody, the rewarding as well as the medically harmful effects of the drug are reduced or blocked. And because these therapies target only the drug, they are potentially safer than treatment with small molecule drug agonists, which bind directly to important receptor systems in the brain and other organs (Pentel, this volume). Current immunotherapies for drug abuse are of two types, active and passive. Although both treatments require highly specific, high-affinity antibodies, the medical use and the mechanisms of the therapies differ somewhat. In active immunizations, drug vaccines are used to stimulate the body to makes its own antibodies and to create a long-term immunological memory for a more rapid future response to the vaccine (Kosten et al., 2002a, 2002b) In passive immunotherapy, laboratory-generated antibodies (e.g., monoclonal antibodies) are injected: more antibody can be administered and the protection can be immediate, but it only lasts until the antibody is cleared, and there is no immunological memory against the drug (Owens et al., 1988). Depot medications are variations of currently available medications that are designed to release a drug slowly, over a long period of time. They act by binding to the drug receptor (in

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions the brain or elsewhere in the body), “locking out” the drug from the site of action. In all cases, however, these medications only target the pharmacological effect of particular licit and illicit drugs. They do nothing to counteract the effects of craving and overlearned drug-seeking behavioral responses that frequently lead to relapse (Robinson and Berridge, 2000; Berke and Hyman, 2000; O’Brien et al., 1998). Consequently, their use is expected to require the concomitant availability of psychosocial and behavioral treatment programs to maximize their effectiveness. We discuss these issues in more detail in Chapter 3. Active Immunotherapy In active immunotherapy, a chemical derivative of the drug of abuse (called a hapten) is coupled to an antigenic protein carrier, which is then used as a vaccine (with or without an immune enhancing adjuvant) for immunization. Because stimulation of an immune response requires multiple interactions on the surface of an antibody-forming B lymphocyte, a single, small drug molecule (like cocaine or nicotine) cannot produce cross-linking of cell surface antibodies on a B cell to activate it to produce more antibodies. Consequently, drug haptens must be irreversibly bound to their large protein carriers for use as vaccines. The molecular orientation and spacing of the drug haptens on the protein surface are critical factors that scientists must control for an optimal immune response. The antibody response will not increase if a vaccinated individual uses the small drug molecule itself; only the circulating antibody at the time of drug use will be protective. Because cross-linking of surface antibody on B cells is required to stimulate antibody production, the same drug hapten-protein vaccine must be used for boosting the immune response on later occasions. Periodic boosting with the vaccine is required to keep serum antibody levels high (Pentel, this volume). The actual serum level of an antibody is affected by the quality of the drug-protein vaccine, the dose of the vaccine, the frequency of vaccinations, the time interval between immunizations, and poorly understood genetic variations among individuals (Pentel, this volume). On the basis of results from prior vaccine regimens, it is anticipated that the immune response will not be adequate for at least 3-6 weeks after the start of vaccination, and booster immunizations will be required every 1-6 months to maintain a sufficient level of drug-specific antibodies (Cerny et al., 2002; Hieda et al., 2000; Byrnes-Blake et al., 2001; Kantak et al., 2001). Improper timing of vaccinations could result in a poor response or a significant reduction in the amount of circulating antibody. Thus, the timing and dura-

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions tion of vaccinations will need to be carefully coordinated with patient needs and other medical interventions, such as counseling or behavioral modification programs. Passive Immunotherapy In passive immunotherapy, rather than vaccinating an individual to stimulate his or her antibody response, preformed antidrug antibody medications are administered directly. Although this antibody medication could be a polyclonal serum or a purified immunoglobulin fraction from the serum of an individual who has been vaccinated against a drug of abuse, a monoclonal antibody is more likely to be used. Given today’s technology for making and selecting monoclonal antibodies, it should be possible to make high-affinity antibodies to most drugs. The monoclonal antibodies that have been safely used in humans are chimeric monoclonal antibodies (comprised of 34 percent mouse protein and 66 percent human protein), humanized monoclonal antibodies (comprised of more than 90 percent human protein), and fully human antibodies (Villamor, 2003). All of these types of antibodies are currently made by advanced biotechnological techniques called antibody engineering. As of mid 2003 there are 10 FDA-approved therapeutic monoclonal antibodies and one FDA-approved monoclonal antibody approved. Of relevance to the therapeutic strategies for using immunotherapies for drugs of abuse is Synagis® (Simoes and Groothuis, 2002). This monoclonal antibody is approved for the prevention of serious lower respiratory disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of the disease. This antibody is administered before and then monthly throughout the RSV season to maintain protective circulating antibody levels (Simoes and Groothuis, 2002). For treating drug abuse, monoclonal antibodies could be used in three clinical scenarios: to treat drug overdose, to prevent drug use relapse, or to protect certain at-risk populations who have not yet become drug dependent (e.g., adolescent children who have begun using cocaine). Other special populations, such as fetuses of drug-abusing mothers, might also warrant protective immunotherapy of the mother to prevent fetal exposure to the abused drug. Active vaccination could be used to prevent drug-use relapse or to protect at-risk individuals, though not for drug overdose. Depending on the particular situation, active vaccination or monoclonal antibody therapy (or a combination of the two) could be administered. For example, antibody fragments (of a size that would be cleared by the kidney) could be used to treat overdose so that not only would the antibody bind the drug and lower the amount in the brain, but also so the drug-antibody complexes would be cleared quickly from the

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions body. In a drug abuse protection or relapse setting, where it would be desirable to have significant antibody present over a long period of time, one could envision administering a loading dose of an antibody medication with carefully timed periodic repeat doses to maintain the desired serum antibody concentrations. An example of a current successful medical therapy is Remicade® for the treatment of rheumatoid arthritis (Vizcarra, 2003). This chimeric monoclonal antibody is given at 0, 2, and 6 weeks as a loading dose and then every 8 weeks thereafter. Vaccinations with an antinicotine vaccine might be appropriate in patients who are attempting to stop cigarette smoking. Advantages and Potential Disadvantages of the Therapies Both active and passive immunotherapy require high-affinity antibody binding to be medically effective, and both have potential strengths and weaknesses. Advantages Antibodies target the drug, not the drug’s sites of action in the brain. The binding of drug to antibody inactivates the drug. An antibody can be highly specific for a drug or drug class. Immunotherapies can complement conventional therapies (such as behavioral modification) for a more comprehensive medical approach. The use of immunotherapy would not necessarily preclude the use of chemical agonist or antagonist, but an important exception is the combined use of a nicotine agonist therapy and antinicotine antibodies. Immunotherapy has a different pattern of side effects (in theory, fewer) than treatment with chemical agonist or antagonist. Antibodies are not addictive, as are some chemical agonists. Potential Disadvantages Monoclonal antibodies are time consuming and expensive to produce. The production of a high-affinity antidrug antibody is sometimes difficult. Vaccinations may lead to an inadequate response in some individuals.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions Vaccinations may not produce antibodies in a timely fashion for proper integration with other medical interventions (e.g., drug overdose). The beneficial effects of the therapy could be overcome by large amounts of drug. The immunotherapy could lead to allergic reactions. There are other potential problems with the use of antidrug antibodies for the treatment of drug abuse. Because in some cases the drugs of abuse are closely related in structure to either neurochemicals or approved medications (e.g., nicotine replacement therapy for cigarette smoking), it is possible that the therapies could lead to unexpected adverse reactions or reduced effectiveness of other medications. Some of these possible outcomes can be avoided or anticipated by careful screening of the antibodies for cross reactivity against known drugs and neurochemicals before they are used in humans. It is also possible that immunological responses against an antidrug of abuse antibody binding site (called an anti-paratype response) could lead to a second generation of antibodies, which are complementary to the antibody binding site and are capable of being druglike, thus, able to activate receptor systems just like the drug of abuse. It is known that monoclonal antibodies and other protein therapeutics do stimulate an immune response to the product in some individuals; therefore, they may not be suitable for life-long or even extended use in all individuals. Vaccines comprised of the drug-protein conjugate might also lead to entirely unexpected allergic reactions. However, it is expected that most of these potential problems would be anticipated, tested for, and dealt with during the clinical trails of new medications and the FDA approval process. Finally, there are ethical considerations, however remote, for the use of vaccines. Active vaccination can stimulate long-lasting immunologic memory that could serve as a marker of past immunization and could stigmatize an individual for extended periods of time, or even over their entire life if tests were available for detecting memory immune cells. Monoclonal antibodies, however, have a finite life span, and after some period of time following treatment would no longer be detectable. Depot medications would similarly be undetectable following treatment because of their finite life span. Depot therapies for opioid addiction pose a different set of advantages and challenges. A great deal is already known about the therapeutic agent (naltrexone) that is being developed for depot use because it has been used in non-depot form for more than 20 years. Naltrexone is known to be very effective as well as safe when patients adhere to the medication. For the depot versions, extensive work has been done by companies seek-

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions ing to develop and obtain FDA approval for their products. Their primary advantage is expected to be in greater adherence, since dosing will only be about once every 30 days, instead of daily. One noteworthy issue is that patients on depot therapies who need treatment for acute pain (e.g., due to trauma) will present problems because naltrexone blocks opioid analgesics as well as illicit opioids. Special protocols (medications, dosing) will be required to treat pain for patients on naltrexone. This consideration of the medical basis for immunotherapy and sustained-release formulations for treating drug addiction has led to one major recommendation by the committee, but several recommendations in subsequent sections are also related to the medical basis for these therapies. 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.