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Evidence-Based Reviews


Vaccine for cocaine addiction: A promising new immunotherapy

Blocking cocaine from reaching the brain may help curb use

Vol. 9, No. 9 / September 2010

The cocaine vaccine: How will it be used?
Drs. Anthenelli and Somoza discuss adherence to the TA-CD vaccine, and more

Discuss this article at currentpsychiatry.blogspot.com/2010/09/vaccine-for-cocaine-addiction.html

Unlike opioid or alcohol abuse, for cocaine dependence there are no FDA-approved pharmacotherapies, which leaves psychosocial treatment as the standard of care for the estimated 1.6 million individuals in the United States who abuse cocaine.1 However, researchers are developing a novel way to help cocaine-dependent patients reduce their drug use. Therapy for addiction–cocaine addiction (TA-CD) is thought to curb cocaine use by engaging the body’s immune reaction and stopping cocaine molecules from reaching the brain, thereby reducing the drug’s pleasurable effects. One researcher working on this vaccine, Eugene Somoza, MD, PhD—the principal investigator of the Ohio Valley Node of the National Institute on Drug Abuse clinical trials network of 16 universities and treatment programs—discusses with Current Psychiatry Section Editor Robert M. Anthenelli, MD, how TA-CD works and how it might be used in clinical practice.

DR. ANTHENELLI: How is immunotherapy being applied to treating cocaine addiction and how does TA-CD work?

DR. SOMOZA: Our bodies have a very efficient immune system that can recognize foreign proteins and other complex molecules and develop specific antibodies against them that join irreversibly to these molecules to make them inactive. Immunotherapy usually is used to treat disorders that involve very complex molecules. Cocaine is a very simple molecule, but you can attach a simple molecule to a complex molecule and still trigger the immune system. You can use this method to develop antibodies to cocaine. When an individual uses cocaine, the antibodies will bind to the cocaine in the blood stream and the drug never reaches the brain because the molecule is now too large to pass the blood-brain barrier. The reinforcing properties of addictive agents depend on how fast they get into the brain. By slowing down or even stopping this process, you decrease the pleasurable effect individuals get from cocaine.

The cocaine vaccine that is being tested makes use of the B subunit of the cholera toxin molecule. It is highly immunogenic, and a recombinant of it is available in large quantities.2 Cocaine molecules are connected to various areas of this complex cholera toxin subunit with covalent bonding. This makes the cocaine a larger target for an antibody response.

The interesting aspect of this process is that the vaccine acts outside of the brain. Other pharmacotherapies being tested, such as modafinil and disulfiram, target receptors or enzymes within the brain, which means that these 2 types of treatment would be synergistic. An early article on cocaine vaccines by Fox et al3 emphasized that this therapy is compatible with other treatments.

DR. ANTHENELLI: After receiving the vaccine, how long does it take for antibody levels to be high enough to produce a therapeutic effect?

DR. SOMOZA: Typically about 8 weeks.

DR. ANTHENELLI: Some trials have shown that patients display high variability in antibody levels. Only 38% of subjects in a 24-week, randomized, double-blind, placebo-controlled trial by Martell et al4 achieved high antibody levels (≥43 μ/mL). Are there ways to predict who will achieve the higher antibody titers and to increase the percentage of people who might develop the antibodies?

DR. SOMOZA: Right now there are not. In the Martell study, subjects’ antibody response curves—the increase and subsequent decrease in antibody concentration—were very different from individual to individual. We estimate that 40% of patients receiving the vaccine will develop ≥40 μ/mL of antibodies; this level is necessary for heavy cocaine users. However, not all patients take large amounts of cocaine, so we expect that even if a patient develops 30 μ/mL of antibodies, the amount of cocaine reaching the brain will be reduced— although the process may be slower—and using will not be as enticing.5

DR. ANTHENELLI: How long will the effects of TA-CD last, and how often will patients need to receive booster shots to keep antibody titers high?

DR. SOMOZA: The antibodies stay high for approximately 10 to 30 weeks, so you have to give boosters periodically. We need to carefully study if one can give a patient a booster every few months and, if so, how many booster shots would be required.

DR. ANTHENELLI: What are the known side effects of the vaccine?

DR. SOMOZA: In phase 1 and phase 2 studies, there haven’t been any problems at all.6 Theoretically, we could see some reaction at the injection site such as bruising or red or inflamed skin. In some cases with protein vaccines they’ve seen systemic reactions like fever. There’s also a risk of serum sickness, but this is theoretical based on other protein-based vaccines.7

DR. ANTHENELLI: Are there any data that address the safety of long-term TA-CD use?

DR. SOMOZA: We do not have any data on long-term use, but we know what happens over several months. When this project began 12 years ago, investigators worried that if the vaccine prevents cocaine from getting to the brain, cocaine-dependent individuals would just take more and more of the drug and suffer serious consequences. However, in preliminary studies, people have taken as much as 10 times their “normal” amount of cocaine with no adverse events. It looks like the vaccine may ameliorate some of cocaine’s effects on the heart. We’re certainly not encouraging study subjects to try to override the vaccine blockade, but these preliminary data at least minimize some of those concerns.

DR. ANTHENELLI: In clinical trials of TA-CD, during the 8-week ramp-up period where you’re waiting for patients’ antibody titers to get high enough to have a therapeutic effect, do trial participants receive other treatment?

DR. SOMOZA: Participants receive state-of-the-art cognitive-behavioral therapy (CBT) once a week. We do this to help patients look for triggers to cocaine use and how to handle them, but also to encourage them to stay in the study. It’s important that people who enroll in our trials are motivated to stop using. Many patients who have been using cocaine for years haven’t been able to own a house, get married, or even buy a car because all of their money is spent on cocaine. Eventually they decide it’s not a good idea to keep using forever. These are the participants we’d like to find.

There are other ways of increasing retention, such as rewarding patients for coming to appointments, providing urine for toxicology screens, or getting the boosters. We’re hoping contingency management will help keep patients in the trial.

How TA-CD will aid treatment

DR. ANTHENELLI: How do you envision TA-CD could be used in clinical practice?

DR. SOMOZA: It could become another tool in our armamentarium for treating cocaine dependence. Currently, there are no FDA-approved medications for cocaine dependence, although some pharmacologic treatments are being studied (Table).8-13 When a patient comes in to be vaccinated, he or she also could receive other treatments if they are available, and the effect potentially would be additive. We would also use CBT because cocaine dependence is a very complex disorder. In CBT patients identify triggers that cause them to want to use and learn how to combat them and make better decisions.

DR. ANTHENELLI: Some research shows that TA-CD doesn’t stop cocaine use altogether but reduces use. Will that be a deterrent for clinicians who wish to help patients achieve absteinence?

DR. SOMOZA: That’s true about any medication we develop for addictions. I think it is magical thinking to say that you can give patients a pill and they will be abstinent for the rest of their lives. If you look at tobacco or alcohol, in practice abstinence is an end point that one has to approximate successively. In addition, permanent abstinence from cocaine is virtually impossible to measure. Because the half-life of benzoylecgonine (BE), the principle metabolite of cocaine, is 6 to 8 hours, this limits the effectiveness of urine toxicology screens in monitoring abstinence. Cocaine-dependent patients might not have used the drug the day before a urine toxicology screen. If a patient says he is abstaining from cocaine, it would be difficult to document it quantitatively without obtaining urine BE levels every day or every other day.

I think clinicians need to get used to the fact that we have to treat cocaine dependence in an incremental manner. A pharmacotherapy that would reduce use and hopefully limit the problems people are having as a result of cocaine use would be a positive step.

DR. ANTHENELLI: If TA-CD is found to be effective, what is the earliest it might come into clinical use?

DR. SOMOZA: I would speculate that it would be 7 to 10 years.

DR. ANTHENELLI: What other kinds of research are going on as far as vaccines for cocaine?

DR. SOMOZA: There is a strain of transgenic mice that when stimulated produce human, as well as mice, antibodies. At the University of Cincinnati, Andrew Norman, PhD, was able to immunize these mice and they generated human antibodies against cocaine (Box 1).14,15 Then you’ll have vials of monoclonal antibodies that you can administer to your patient. However, this is still in early testing.

DR. ANTHENELLI: We’ve talked about immunotherapy and how it might work for the treatment of cocaine addiction. How might these types of vaccines be used for treating other substances of abuse?

DR. SOMOZA: Investigators are currently working on a vaccine for nicotine dependence (Box 2)4,16-20 and there’s a vaccine being developed for methamphetamine,21 but it is not as advanced as cocaine. A similar methodology has been used for some time to treat digitalis overdose. There is no antidote for digitalis toxicity, so researchers have developed an antibody—digoxin immune fab—that attaches to the drug, which is then excreted through the kidneys. I fully expect that this methodology eventually will work for cocaine, meth-amphetamine, and nicotine dependence. My hunch is that producing human antibody in industrial quantities would be the most sensible way to eventually make this work.

Table

Pharmacotherapy for cocaine dependence: Most evidence is weak

Study

Design

Results

Disulfiram

Pani et al, 20108

Meta-analysis of 7 studies with 492 cocaine-dependent patients

Researchers found ‘low evidence’ supporting disulfiram for treating cocaine dependence

Modafinil

Dackis et al, 20059

62 cocaine-dependent patients randomized to modafinil, 400 mg/d, or placebo for 8 weeks

Patients receiving modafinil provided significantly more BE-negative urine samples and were significantly more likely to achieve ≥3 weeks of cocaine abstinence

Anderson et al, 200910

210 cocaine-dependent patients randomized to modafinil, 200 mg/d or 400 mg/d, or placebo for 12 weeks

Modafinil significantly reduced cocaine craving but did not significantly improve the average weekly percentage of cocaine non-use days

Tiagabine

Winhusen et al, 200711

141 cocaine-dependent patients randomized to tiagabine, 20 mg/d, or placebo for 12 weeks

No significant changes in cocaine use vs placebo as measured by self-report and urine BE

Baclofen

Kahn et al, 200912

Cocaine-dependent patients randomized to baclofen, 60 mg/d, or placebo for 8 weeks

No significant difference between groups in cocaine use as measured by urine BE

Ondansetron

Johnson et al, 200613

63 cocaine-dependent patients randomized to ondansetron, 0.25 mg, 1 mg, or 4 mg twice daily, or placebo for 10 weeks

The odansetron 4 mg group had a significantly greater rate of improvement in percentage of patients with a cocaine-free week compared with the placebo group

BE: benzoylecgonine

Box 1

Next step in addiction vaccines: A human anti-cocaine monoclonal antibody

Promising clinical trials of therapy for addiction–cocaine addiction (TA-CD) and nicotine conjugate vaccines show that immunotherapy may be effective for addictive disorders. However, immune response varies among patients and the vaccines are effective only in those who produce high concentrations of anti-drug antibodies. Our multidisciplinary translational research project has generated a predominantly human sequence monoclonal antibody (mAb) with high affinity (Kd

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