New Treatments for Addiction Behavioral, Ethical, Legal, and Social Questions (2004) / Chapter Skim
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Appendix A: Vaccines and Depot Medications for Drug Addiction: Rationale, Mechanisms of Action, and Treatment Implications
Appendix A: Vaccines and Depot Medications for Drug Addiction: Rationale, Mechanisms of Action, and Treatment Implications
Pages 61-97
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Appendixes
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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)
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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.
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. 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)
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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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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)
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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.
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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.
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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.
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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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Blood levels of antibody after vaccination are maintained because new antibody is continually produced. After passive immunization with monoclonal antibodies, a steady decline in antibody level with a half-life of about 3 weeks is expected, so repeated antibody doses every few months would probably be needed to maintain antibody levels in blood.
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Nevertheless, the amount of antibody elicited by vaccination is very important, and greater amounts confer greater efficacy in altering drug distribution and reducing drug effects. Thus individuals with better responses to a vaccine (higher titers, implying greater total amounts of antibody elicited)
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Three minutes later the concentrations of nicotine in the blood were substantially higher in the vaccinated rats than in nonvaccinated controls owing to the binding and sequestration of nicotine in the blood. Brain nicotine concentration at the same time was reduced by 65 percent.
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If rats trained to self-administer cocaine are given single doses of cocaine-specific monoclonal antibody, cocaine self-administration over the next few days can be completely blocked (Fox et al., 1996)
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Vaccination also reduces cocaine self-administration. In this case, vaccination administered during continued daily access to cocaine became maximally effective only after the second booster dose was administered, as would be expected since it takes that long for the maximal antibody concentration in blood to be achieved (Kantak et al., 2001)
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One group had saline substituted for cocaine, resulting in decreased lever pressing. A third group continued to have access to cocaine but received an injection of cocaine-specific monoclonal antibodies.
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Rats with lower antibody concentrations may show either no effect or a paradoxical increase in self-administration, presumably to compensate for the partial blockade of its effects. Whether compensation occurs likely depends on the concentration of antibody in blood and the cocaine dose.
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. Phencyclidine Studies of immunization against phencyclidine have focused on the use of passive immunization with high-affinity monoclonal antibodies or antibody fragments and on the treatment of phencyclidine toxicity (Valentine, Arnold, and Owens, 1994; Hardin et al., 1998)
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and were challenged with a phencyclidine injection at various times afterward. The top five lines represent control animals, which received saline treatment, showing locomotor activation at all phencyclidine doses.
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. Summary of Animal Data In aggregate the available animal data provide strong proof of principle that both vaccination and passive immunization can block or attenuate a variety of drug effects in animals that are relevant to drug addiction in humans.
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Preventing or reducing drug effect In the context of this discussion, the ability of vaccination to block or reduce the addictive effects of drugs is the desired therapeutic outcome. However, if a cigarette smoker decided to abandon his or her attempt at cessation and wanted to resume smoking, vaccination could interfere with the ability to do so until antibody concentrations in the blood declined sufficiently.
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In any event, compensation would remain important only so long as antibody concentrations in the blood remain high and would wane and presumably disappear over time. One particular concern with compensation, even if transient, is that a drug user might escalate his or her drug use sufficiently to cause an inadvertent overdose.
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No important adverse effects have been noted to date in animal studies of either polyclonal or monoclonal antibodies to reverse or prevent drug effects. Passive immunization is used for many therapeutic purposes other than drug addiction, but the doses of antibody required are generally lower.
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Rather than supplementing the body's immune response to an infection, it is simply reducing the access of drug to the brain. Immunization for drug abuse is more likely to reduce than to completely block drug effects and is unlikely confer the complete protection afforded by vaccines for infectious diseases.
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This strategy should be feasible because passive immunization would not be expected to interfere with the ability of vaccination to stimulate a satisfactory immune response. Summary of Features of Immunotherapies Requiring Special Consideration Immunotherapy as a treatment for drug dependence differs from most other medications, even those used for other purposes, because of its unusual mechanism and long duration of action.
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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.
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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)
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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.
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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.
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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.
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. 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.
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I Monoclonal antibody 15A10 and the reinforcing effects of cocaine in rats.
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. Active immunization with cocaine protein conjugate attenuates cocaine effects.
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Paper prepared for the College on Problems of Drug Dependence Annual Meeting, June 8-13, Quebec City. Kreek, M.J., LaForge, K.S., and Butelman, E
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. Paper presented at the College on Problems of Drug Dependence Annual Meeting, June, Quebec City.
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. Antiphencyclidine monoclonal antibody therapy significantly changes phencyclidine concentrations in brain and other tissues in rats.
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