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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions Appendixes

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions A Vaccines and Depot Medications for Drug Addiction: Rationale, Mechanisms of Action, and Treatment Implications Paul R. Pentel Hennepin County Medical Center and University of Minnesota OVERVIEW Immunotherapies and depot medications (dosage forms designed to release a drug gradually over a prolonged period of time) are of particular interest as approaches to treating drug addictions because of their long duration of action. Clinical effects may persist for months, eliminating the need for daily medication and potentially improving patient compliance. At the same time, a long duration of action could help prevent patients from opting out of treatment prematurely and could prolong the duration of any side effects of treatment. These possibilities raise unique questions regarding the therapeutic role for such medications and their ethical implications. The purpose of this appendix is to present the scientific basis for vaccines and depot medications as a background for addressing these unusual and challenging issues. IMMUNIZATION The first study of immunotherapy as a treatment for drug dependence was a report in 1974 that a vaccine directed against heroin reduced heroin self-administration in monkeys (Bonese et al., 1974). This new treatment approach was not pursued because of concerns about whether heroin addicts might simply switch to a different opiate. This appendix considers more recent and ongoing efforts directed at cocaine, phencyclidine, nicotine, and methamphetamine dependence. Initial clinical trials have begun on immunotherapies against cocaine and nicotine, but only preliminary

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions safety data and no efficacy data are available so far. The discussion below is based primarily on data derived from animal studies. Definitions There are two general strategies for immunotherapy: active immunization with vaccines and passive immunization with monoclonal antibodies. A vaccine is a chemical that can elicit an immune response consisting of the production of antibodies. Antibodies are large protein molecules that circulate in the blood and that can bind the chemical used in the vaccine. There are other features to an immune response, but they are not important for the treatment of drug addiction and will not be considered here. Vaccination is the process of administering a vaccine repeatedly to elicit an immune response and is sometimes referred to as active immunization. Thus an experimental animal or a person might be vaccinated to elicit antibodies that would potentially be of use as a treatment for drug addiction. It is also possible to vaccinate an experimental animal, remove and purify the antibodies, and administer these to an experimental animal or a person. This is referred to as passive immunization. Antibodies can also be produced in cell cultures rather than whole animals. To accomplish this, a single antibody-producing cell from a mouse is cloned (replicated) in a manner that allows it to grow in a flask and continue to produce antibody. Such antibodies are called monoclonal because they are all identical, in contrast to the antibodies produced by a vaccinated animal, which may have a range of abilities to bind the drug in question. In addition, monoclonal antibodies can be engineered to improve their properties. Because of these potentially advantageous features, monoclonal antibodies are generally considered the most suitable form of antibody for passive immunization. Vaccination has received the greatest attention as a potential treatment for drug addiction because it requires just a few doses and produces a long-lasting response. Vaccination is easy to perform, relatively inexpensive, is already widely used to prevent infectious diseases, and has an excellent safety record. However, the strength of the immune response varies among individuals and could be inadequate in some. In addition, vaccination requires a series of injections over several weeks to several months before it becomes effective. Passive immunization would likely be more expensive and require more frequent dosing than vaccination but would allow the antibody dose to be controlled and adjusted according to individual needs, and there is no lag time between administration and onset of action. However, clinical experience and safety data with the high antibody doses needed are limited. Both vaccination and passive

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions immunization may therefore prove to have their own advantages, limitations, and potential uses for the treatment of drug dependence. For the purposes of this discussion, chemical compounds that produce addiction will be called drugs, and chemical compounds used to treat addiction will be called medications. Scope of Discussion The antibodies discussed in this appendix act by binding drug and altering its fate in the body. Immunization can also be used to produce catalytic antibodies, which act by breaking down the drug (Mets et al., 1998; Baird et al., 2000). This appendix considers only binding antibodies because this application is better studied and because the ethical issues raised by catalytic antibodies are analogous. Rationale Drugs of abuse produce their addictive effects by acting on specific neural pathways in the brain. Most medications that have been developed or studied as treatments for drug addiction also act in the brain to reduce the effects of addictive drugs or substitute for them in order to reduce withdrawal and cravings (Kreek, LaForge, and Butelman, 2002). While this approach has had substantial successes (nicotine replacement therapy, bupropion, and nortriptyline for tobacco dependence; opiate agonists and antagonists for opiate dependence; naltrexone for alcohol dependence), each of these medications has inherent limitations. The brain pathways targeted by these medications are involved in mediating many normal and essential functions apart from drug addiction, including cognition, emotions, memory, and movement. Medications used to target these pathways can therefore affect these normal functions as well, leading to adverse effects or limits on the usable medication dose. Immunotherapies represent an attempt to exploit a very different treatment strategy in which the therapeutic target is the drug rather than the brain (Pentel and Keyler, 2004). Vaccines directed against drugs of abuse stimulate the immune system to produce drug-specific antibodies that circulate in the blood and are capable of binding the drug tightly. Antibodies themselves cannot enter the brain because of their large size. Thus any drug bound to antibody also cannot enter the brain. If a sufficient amount of antibody is present when a drug is administered, a substantial fraction of the dose will bind to antibody in the blood so that the fraction of the dose entering the brain is reduced (Figure A-1). Because addictive drugs act in the brain, limiting the amount of drug entering the brain should

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions FIGURE A-1 Effects of vaccination on drug distribution to the brain, illustrated for nicotine derived from cigarettes. When nicotine is administered alone (top) it rapidly enters the blood and is delivered to the brain. Vaccination elicits the production of nicotine-specific antibodies in the blood (middle). Because antibodies are large molecules, they are excluded from the brain. If a vaccinated animal is given a dose of nicotine (bottom), a substantial fraction of that dose is bound and sequestered in the blood by the antibody and less nicotine enters brain. SOURCE: Pentel and Keyler (2004). also reduce the drug’s effects. The hope in using this strategy is to reduce the rewarding effects of the drug that lead to and sustain addiction. For example, a cocaine addict who is vaccinated and then takes a puff of crack cocaine would feel little effect and therefore be less likely to continue using it. Attractive Features of Immunotherapy as a Treatment for Drug Dependence Vaccines or passive immunization have several potential advantages compared to other medications for drug addiction.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions Long Duration of Action Vaccination may elicit therapeutic concentrations (titers) of antibodies in the blood that persists for 3 to 6 months, perhaps longer (Cerny et al., 2002; Kosten et al., 2002a). If needed, satisfactory antibody concentrations could be maintained by periodic booster doses (e.g., every several months). A long duration of action could potentially improve treatment compliance by providing a measure of protection without the need for patients to return frequently to a clinic or remember to take daily medication. Novel Mechanism of Action The mechanism of action of vaccines as treatments for drug abuse is unique and distinct from that of currently used medications. Two treatments acting via different mechanisms often have additive effects such that the combination is more effective than either one alone. Vaccines may target different aspects of drug addiction than available medications. For example, nicotine replacement therapy reduces the severity of withdrawal symptoms, while vaccination (based on animal studies) may be more helpful for preventing the rewarding effects of a cigarette that can lead to relapse. Combining medications that have different types of effects may expand the spectrum of therapeutic actions that can be achieved and improve overall results. Safety Because the antibodies produced by vaccination do not appreciably enter the brain, vaccination should circumvent the central nervous system side effects that limit the use of other medications (Killian et al., 1978). Because the drug-specific antibodies elicited by vaccination bind to the addictive drug and nothing else, vaccination should also be relatively free of side effects outside of the central nervous system (Owens et al., 1988; Hieda et al., 1997). The generally excellent safety record of vaccines used to prevent infectious diseases supports this notion. Immunology of Vaccination Composition of a Vaccine Small molecules such as drugs of abuse are not by themselves immunogenic and cannot stimulate the immune system to produce antibodies. A commonly used strategy for eliciting antibodies to small molecules such as these is to chemically link the drug to a larger protein molecule

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions (Figure A-2). The resulting molecule, consisting of drug linked to protein, is called an immunogen because it is now capable of eliciting an immune response. When used as a vaccine, this type of immunogen is referred to as a conjugate vaccine because it represents a small molecule conjugated (linked) to a protein. Vaccination Vaccination consists of injecting an immunogen, usually into the muscle of the upper arm, or less commonly administering it as a nasal spray or oral liquid. A single injection of vaccine generally does not stimulate significant immunity, and one or more booster injections at intervals of several weeks to months are needed to achieve a satisfactory response. This response consists of the production of antibody molecules by the cells of the immune system. An immune response may include other components in addition to antibody production, but they do not contribute to the effects of vaccines on drugs of abuse. FIGURE A-2 Immunogen structure. Drugs are too small to be recognized by the immune system. To render them immunogenic, drugs must be linked to a large foreign protein. The resulting complex is the complete immunogen. A vaccine consists of the complete immunogen mixed with a chemical adjuvant that enhances the immune response. Because drugs of abuse by themselves are not complete immunogens, they do not elicit antibodies, nor can they boost an immune response in a vaccinated animal or individual. The complete immunogen is needed to boost the immune response.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions Antibodies Antibodies are protein molecules that have the ability to bind tightly to the portions of the immunogen used to stimulate their production. This is achieved through a binding pocket that is complementary in size, shape, and electrical charge to a part of the immunogen, such that the immunogen and antibody fit together in a lock-and-key fashion (Figure A-3). The antibody binding pocket is not large enough to bind the entire immunogen. Rather, immunization produces many antibodies that can bind many different parts of the immunogen. Some of these antibodies may bind the part of the immunogen that has drug linked to it, and these antibodies can also bind drug that is not linked to carrier protein. Thus a portion of the elicited antibodies will be capable of binding the free (unbound) drug. FIGURE A-3 Binding of drug to antibody. The binding site on the antibody consists of a pocket that is complementary to the drug in size, shape, and electrical charge, such that the drug fits into the binding pocket in a lock-and-key fashion. The result is tight (high-affinity) binding that is quite specific for that particular drug. Each antibody molecule has two identical binding sites. The upper site in the figure illustrates antibody binding to the complete immunogen that was used to stimulate antibody production. The lower site illustrates that the drug alone can also bind to this site.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions The binding of drug to antibody is typically very tight (high affinity) and very specific. For example, antibodies to nicotine elicited by a vaccine bind only nicotine and do not bind nicotine metabolites (breakdown products), other molecules normally present in the body such as neurotransmitters or hormones, or other drugs or medications (Pentel et al., 2000). This exquisite degree of specificity suggests that the actions of these antibodies should also be quite specific. Measuring the Response to Vaccination The three antibody characteristics of greatest interest are the antibody concentration in blood, how tightly the antibodies bind the drug (affinity), and whether the antibodies bind anything other than the drug in question (specificity). All three are readily measured from small blood samples. Antibody concentration is often expressed as a titer, or dilution; higher titers indicate higher antibody concentrations. Measurements are typically obtained from serum or plasma, the liquid portion of blood exclusive of red blood cells. Initiation of Vaccination It is likely that a series of two to four injections over 1 to 2 months will be needed for vaccination to produce a satisfactory immune response (Hieda et al., 2000; Byrnes-Blake et al., 2001; Kantak et al., 2001; Kosten et al., 2002a). This 1- to 2-month interval is a potentially important disadvantage since the onset of therapeutic effect would be similarly delayed. However, vaccination can be accomplished even while drug use continues; the presence of drug does not diminish the immune response (Hieda et al., 2000; Byrnes-Blake et al., 2001). Thus individuals could be vaccinated in preparation for stopping drug use by starting 1 to 2 months in advance. When this is not possible, the use of counseling and, when available, other medications with more immediate effects could be used until the vaccine becomes effective. Duration of Response to Vaccination Because drugs of abuse by themselves cannot elicit an immune response, drug abusers do not normally have antibodies directed against these drugs. It is only after a series of vaccinations that antibodies are formed. Because the antibody response fades with time, the concentrations of antibodies in serum will fall over a period of months to years. To maintain satisfactory antibody concentrations in serum, it will be necessary to

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions administer booster doses of vaccine periodically. The frequency of boosting needed is not known, but an interval of approximately every 2 to 6 months is likely (Cerny et al., 2002; Kosten et al., 2002a). It is important to note that vaccines for drug addiction differ in this respect from vaccines for infectious diseases. Infectious microorganisms (bacteria or viruses) are complete immunogens, so exposure to the infectious agent automatically boosts the immune response. In contrast, a drug addict relapsing to drug use would not boost his or her immune response but would require additional vaccination. Sustained-release vaccines have been studied in animals as a means of reducing the number or frequency of required vaccine injections (Gupta, Singh, and O’Hagan, 1998; Langer, Cleland, and Hanes, 1997). With this technology, one injection might substitute for several monthly injections. This technology has not yet been applied to humans. The time course of the antibody response to vaccination is critical to determining its duration of action. At some point the concentration of antibody in blood will fall below that needed to have any effect on drug action (Carrera et al., 2000; Kantak et al., 2000; Proksch, Gentry, and Owens, 2000). Thus for practical purposes the effects of vaccination are not permanent. It is difficult at present to estimate the duration of action for any of the vaccines discussed in this chapter. In a Phase I study of a cocaine vaccine, antibody concentrations in serum declined to nearly the prevaccination level by 10 months after the last vaccine dose (Kosten et al., 2002b). It cannot categorically be said, at this point, that these minimal antibody concentrations would have no effect, but the likelihood is very high that this is so. As a result, vaccination can be viewed as a medication with a potentially long duration of action, most likely measured in months, rather than a permanent effect. While very low levels of antibody persisting months to years after vaccination are unlikely to have any effect on drug use, they may still be detectable. If so, their detection could potentially identify a person as an addict (someone previously treated with vaccination). The length of time that antibodies could be reliably detected at a level sufficient to indicate previous vaccination is unknown. It is important to note that having a long duration of action, with therapeutic and possible toxic effects that cannot be reversed for periods of weeks to months, is not confined to vaccines, passive immunization, or depot medications for drug addiction. Table A-1 lists several medications in common clinical use that have long durations of action and that have proven to be acceptable and valuable treatments for certain indications.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions TABLE A-3 Key Features of Immunotherapy for Drug Dependence That Require Special Consideration Commitment to therapy Long duration of action of immunization commits a patient to its effects until antibody levels in the blood decline sufficiently (up to several months for passive immunization, possibly longer for vaccination). Blockade of therapeutic drug effect When a drug of abuse is also used for therapeutic purposes (e.g., nicotine for replacement therapy), immunization may block those actions as well until antibody levels decline. Compensation Attempts to overcome the blockade-of-drug effect from immunization could lead to greater drug use, overdose, or toxicity from adulterants. Pregnancy Immunization could alter the amount or duration of fetal drug exposure. Insufficient data are available to adequately assess risk. Primary prevention The presumed safety and long duration of action of vaccination allow consideration of its use for this purpose. Privacy Detection of antibodies using simple blood tests could identify recipients of vaccination for months or longer after the last booster dose. and the decision to resume drug use could be thwarted or made more difficult (requiring higher drug doses) until the effects of vaccination wane. In addition, the duration of persistence of antibody after vaccination is likely to vary among individuals and be difficult to estimate precisely. The duration of action of passive immunization with monoclonal antibodies is also not known in humans but is likely to be several weeks to several months after the last dose, depending on the dose size (Hardin et al., 2002). Commitment to therapy would be analogous to that following vaccination. Blockade of Therapeutic Drug Effects In addition to the use of pharmaceutical nicotine as a treatment to aid smoking cessation, nicotine is being studied as a treatment for dementias and other neurological disorders (Lopez-Arrieta et al., 2000). If it proves to have a therapeutic role, vaccination could temporarily block the ability to gain therapeutic benefit from nicotine. Since the disorders in question

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions are chronic, their presence would likely be known at the time of vaccination rather than appearing abruptly and requiring immediate treatment. Compensation The blockade of drug effect provided by immunization may be incomplete. The concurrent use of counseling and perhaps other medications may be helpful in achieving a therapeutic benefit despite incomplete blockade. However, some patients may try to overcome the partial blockade by using higher or more frequent drug doses. Aside from thwarting the therapeutic intent, increased drug use could be harmful if it is sustained after antibody levels decline. Adverse effects could result if patients do not know how much drug is required to overcome immunization and inadvertently overdose. If a drug is mixed with an adulterant, immunization would reduce the effect of the drug but not the adulterant, and toxicity from the adulterant could result. Targeting immunization to motivated patients who are treated with concurrent counseling would seem the best approach to minimizing such occurrences. Pregnancy Vaccines or passive immunization per se are unlikely to harm a fetus, but they could alter the amount of abused drug transferred to a fetus. Limited data suggest, if anything, a protective effect with lesser drug transfer, but these data are very preliminary (Shoeman et al., 2002; Keyler et al., 2003). In addition, antibodies can potentially prolong exposure to a drug because the antibody-bound drug is more slowly eliminated from the body (Keyler et al., 1999; Proksch et al., 2000). Thus a pregnant woman who stops smoking will have unmeasurable nicotine levels in her blood (and presumably in her fetus) within several days, but a woman vaccinated against nicotine who stops smoking could have low levels of nicotine persisting in her blood for weeks. Whether this bound nicotine would be harmful to the fetus is not known. The main point with regard to fetal exposure to a drug is that current data are insufficient to judge whether vaccination or passive immunization will increase, decrease, or have no effect on exposure and harm. The use of potentially fetotoxic or teratogenic medications during pregnancy is commonly dealt with by recommending that adequate contraceptives be used during the period of exposure. While this strategy could also be applied to immunization for drug dependence, compliance may be lower in drug-dependent women. Thus studying and understanding the potential risks (or benefits) of immunotherapy in women who could become pregnant will be very important.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions Primary Prevention The use of medications for primary prevention (preventing the initial acquisition) of drug dependence has received little consideration because most medications have potential adverse effects, the target population is predominantly young and still undergoing neural development, and the period of risk is protracted, so the duration of treatment and expense would be considerable. In contrast to many other candidate medications, vaccination so far appears free of adverse effects, the resulting antibodies do not enter the brain and therefore should not affect neural development, and the need for only infrequent dosing makes a prolonged period of treatment conceivable. This potential application is of course quite speculative, since efficacy has not yet been demonstrated in humans, and much more toxicity testing would be needed to assure the high level of safety required for administration to teenagers or young adults. However, vaccination could be targeted to high-risk groups—for example, teenagers who already smoke a few cigarettes weekly and who have a very high likelihood of becoming regular smokers over the next 1 to 2 years (Institute of Medicine, 1994). In addition to the issues raised above, this would involve vaccination of minors. While other vaccines are routinely administered to minors, the issue of “choice” discussed above could be raised. Privacy Patients who have been vaccinated could potentially be identified as drug abusers by virtue of detection of antibodies from a simple blood test. Because these tests are quite sensitive, antibody from previous vaccination might be detectable long after the therapeutic effect of the vaccination has subsided. This problem is no different from the ability to identify an opiate addict by detecting methadone in urine, or identifying someone as a cardiac patient by detecting the antiarrhythmic agent amiodarone in blood, except that the period during which this may be possible could be considerably longer. Passive immunization would also allow its recipients to be identified by a blood test, but antibody levels would decline in a more predictable manner and probably be undetectable within 6 months. DEPOT MEDICATIONS Formulations Depot medications are formulations of standard medications designed to release a drug slowly and over a long period of time, typically days to weeks. Depot medications can be formulated as a liquid mixture or sus-

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions pension of small particles that can be injected under the skin (e.g., depot medroxyprogesterone; see Table A-1) (Gupta et al., 1998; Putney and Burke, 1998; Hatefi and Amsden, 2002; Mantripragada, 2002). Slow release of medication can also be achieved by impregnating a device such as a small plastic rod with a drug and placing the device under the skin (e.g., the previously marketed Norplant contraceptive). One important difference between these two technologies is that only the latter is retrievable. An implanted plastic rod can readily be removed to terminate its action, whereas a liquid injected under the skin cannot. In addition, the potential durations of action of these technologies differ. Liquid formulation may release drug for up to several months, while impregnated devices can have durations of years (5 years for Norplant). Thus a wide range of durations is potentially available through the use of depot formulations. Not all medications can be formulated in this manner. Depot formulations are best suited to high-potency medications where the required daily dose is low and only a modest amount of drug needs to be incorporated into the formulation or device. Low-potency medications, requiring higher amounts of drug to be incorporated, may prove too bulky to be practical. Depot Naltrexone for Opiate or Alcohol Dependence There are no depot medications currently in clinical use to treat drug dependence. One depot medication being studied for opiate dependence is the opiate antagonist naltrexone. Naltrexone is an effective oral therapy approved by the Food and Drug Administration for opiate dependence that acts by blocking the access of opiates to their brain receptors. It is possible to give a high enough dose of naltrexone orally to block the actions of typical heroin doses, but its duration of action is modest so daily dosing is required (Modesto-Lowe and Van Kirk, 2002). Compliance with naltrexone for the treatment of opiate dependence is lower than with methadone because naltrexone lacks the pleasant receptor-activating effects of methadone. Measures to improve long-term compliance with naltrexone are needed. Naltrexone has been experimentally formulated as a slow-release suspension of microspheres administered by intramuscular injection that can deliver therapeutic doses over a period of up to 4 weeks after a single injection (Chiang et al., 1985; Comer et al., 2002). Its actions are identical to those of orally administered naltrexone, but daily dosing is not required and substantial blockade of heroin effects is achieved for up to 1 month (Figure A-7). Clinical trials of depot naltrexone for opiate dependence are ongoing (J. Cornish, personal communication, 2003). Once administered, the naltrexone dose cannot be retrieved, so recipients are obligated to its effects for that period of time. The implications of this prolonged effect

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions FIGURE A-7 Blockade of heroin effects by depot naltrexone. Subjects were given a single injection of depot naltrexone and were then given increasing doses of heroin at weekly intervals. The “good drug effect” associated with heroin was substantially blocked for a month, more so with the higher naltrexone dose. SOURCE: Adapted from Comer et al. (2002). are analogous to those discussed above for immunization, in particular passive immunization, because the dose is controlled and the duration of action is uniform and predictable. The therapeutic effect of naltrexone cannot be readily reversed during the month after dosing (Comer et al., 2002). One difference between depot naltrexone and immunization for other drugs of abuse is that opiates do have an important therapeutic use in the treatment of pain. Naltrexone blocks the pain-relieving ability of all opiates, so the use of this entire class of drugs is difficult after naltrexone is administered. In a hospital setting, higher opiate doses could partially overcome the blockade. In the setting of drug abuse, attempts to overcome the blockade could result in increased drug use, overdose, or toxicity from adulterants.

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions Naltrexone is also effective in treating alcoholism, and daily doses of oral naltrexone are widely used for this purpose (Streeton and Whelan, 2001). As with its use for opiate dependence, compliance is an issue (Modesto-Lowe and Van Kirk, 2002). Depot naltrexone is therefore being studied for this indication (Alkermes, 2003; Drug Abuse Sciences, 2003). Many other depot medications are in current clinical use. Depot formulations of several antipsychotic agents are available, with durations of action of several weeks (Adams et al., 2001). Like medications for drug dependence, depot antipsychotic medications are administered to a vulnerable population in order to improve compliance. Thus the clinical and ethical issues presented by depot naltrexone have a precedent in antipsychotic medications. Depot antipsychotic medications have proven to be acceptable to both patients and health care providers when used in select patients (Adams et al., 2001; Walburn et al., 2001). CONCLUSIONS The very long duration of action of immunotherapies and depot medications proposed for the treatment of drug dependence makes them attractive as potential treatments for drug dependence. A long duration of action could increase medication compliance and thereby facilitate a comprehensive treatment plan consisting of both medication and counseling. In addition, the unique mechanism of action of immunization may confer both safety and a distinct spectrum of therapeutic effects on this approach. However, a long duration of action raises issues that are not presented by other currently used medications. Patients receiving these long-acting treatments will be obligated to their therapeutic effects for weeks to months, so the decision to undergo treatment may not be readily reversed. Adverse effects could similarly persist for weeks to months. Insofar as some drugs of abuse also have therapeutic uses, these beneficial effects could be blocked during this period as well. The detection of drug-specific antibodies by simple blood tests after immunization, or of treatment medication after use of a depot formulation, could identify patients as drug abusers and compromise their privacy. Immunization may alter drug transfer to the fetus in a woman who subsequently becomes pregnant; present data are insufficient to asses any possible risk. With either immunization or depot antagonist medications, patients could try to overcome the blockade of drug effect by increasing their drug use, leading to overdose or toxicity due to adulterants. The potential use of vaccination for primary prevention of drug dependence is conceivable because of its safety but likely would involve minors. While these issues are new to the field of drug dependence, each has precedents in other areas of pharmacotherapy. The appropriate use of immunization and depot medications

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New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions to treat drug dependence will benefit from an understanding of their underlying mechanisms and consideration of approaches adapted for the use of long-acting medications for other purposes. ACKNOWLEDGMENTS This work was supported by Public Health Service grants DA 10714, DA 15668, U19-DA13327, and P50-DA-13333. REFERENCES Adams, C.E., Fenton, M.K., Quraishi, S., and David, A.S. (2001). Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry, 179, 290-299. Addis, A., Moretti, M.E., Ahmed, S.F., Einarson, T.R., and Koren, G. (2001). Fetal effects of cocaine: An updated meta-analysis. Reproductive Toxicology, 15(4), 341-369. Alkermes Inc. (2003). Vivitrex® background kit. Available at http://www.alkermes.com/news/background_kits.asp [August 22, 2003]. Baird, T.J., Deng, S.X., Landry, D.W., Winger, G., and Woods, J.H. (2000). Natural and artificial enzymes against cocaine. I. Monoclonal antibody 15A10 and the reinforcing effects of cocaine in rats. Journal of Pharmacology and Experimental Therapeutics, 295(3), 1127-1134. Benowitz, N.L., Jacob, P., III, Kozlowski, L.T., and Yu, L. (1986). Influence of smoking fewer cigarettes on exposure to tar, nicotine, and carbon monoxide. New England Journal of Medicine, 315(21), 1310-1313. Berger, M., Shankar, V., and Vafai, A. (2002). Therapeutic applications of monoclonal antibodies. American Journal of the Medical Sciences, 324(1), 14-30. Bonese, K.F., Wainer, B.H., Fitch, F.W., Rothberg, R.M., and Schuster, C.R. (1974). Changes in heroin self-administration by a rhesus monkey after morphine immunization. Nature, 252(5485), 708-710. Bradbury, M.W., and Lightman, S.L. (1990). The blood-brain interface. Eye, 4(Pt 2), 249-254. Byrnes-Blake, K.A., Carroll, F.I., Abraham, P., and Owens, S.M. (2001). Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats. International Immunopharmacology, 1(2), 329-338. Carrera, M.R., Ashley, J.A., Zhou, B., Wirsching, P., Koob, G.F., and Janda, K.D. (2000). Cocaine vaccines: Antibody protection against relapse in a rat model. Proceedings of the National Academy of Sciences, USA, 97(11), 6202-6206. Carrera, M.R., Ashley, J.A., Wirsching, P., Koob, G.F., and Janda, K.D. (2001). A second-generation vaccine protects against the psychoactive effects of cocaine. Proceedings of the National Academy of Sciences, USA, 98(4), 1988-1992. Cerny, E.H., Levy, R., Mauel, J., Mpandi, M., Mutter, M., Henzelin-Nkubana, C., Patiny, L., Tuchscherer, G., and Cerny, T. (2002). Preclinical development of a vaccine against smoking. Onkologie, 25(5), 406-411. Chiang, C.N., Hollister, L.E., Gillespie, H.K., and Foltz, R.L. (1985). Clinical evaluation of a naltrexone sustained-release preparation. Drug and Alcohol Dependence, 16(1), 1-8. Comer, S.D., Collins, E.D., Kleber, H.D., Nuwayser, E.S., Kerrigan, J.H., and Fischman, M.W. (2002). Depot naltrexone: Long-lasting antagonism of the effects of heroin in humans. Psychopharmacology, 159(4), 351-360.

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