A vaccine made with succinylnorcocaine linked to recombinant cholera toxin is somewhat effective in reducing cocaine dependence, according to results from a small study.
The study's findings “are transfomative vis-à-vis our ability to demonstrate for the first time some results in cocaine addiction and may be promising to address other types of drug addiction,” Dr. Nora D. Volkow, director of the National Institute on Drug Abuse (NIDA), said at a teleconference announcing the study results.
In the study, Dr. Bridget A. Martell and her colleagues enrolled 115 men and women aged 18-55 years from October 2003 to April 2005 (Arch. Gen. Psychiatry 2009;66:1116-23). The study's primary objective was to evaluate the vaccine's efficacy in reducing cocaine use, compared with placebo, reported Dr. Martell, who is affiliated with Yale University, New Haven, Conn., and serves as a medical director for Pfizer Inc.
All subjects were in an outpatient methadone maintenance treatment program in West Haven, Conn. The researchers noted that they enrolled subjects from the methadone program because “retention in methadone maintenance programs is substantially better than in primary cocaine treatment programs, and we needed to retain these volunteers for 12 weeks to complete the vaccination series.”
Subjects also were offered $15 per week to enhance retention. Nearly 90% of subjects considered smoked cocaine their second drug of choice after opioids.
Subjects were randomized to receive either a placebo vaccine containing saline and aluminum hydroxide, or a vaccine that linked succinylnorcocaine covalently to recombinant cholera toxin B-subunit protein, which was then adsorbed onto aluminum hydroxide adjuvant. Subjects were given intramuscular deltoid injections at weeks 0, 2, 4, 8, and 12, with efficacy testing beginning at week 8, when most vaccine responders should have had significant IgG anticocaine antibody levels.
All subjects participated in individual weekly 30- to 45-minute cognitive-behavioral relapse prevention therapy sessions conducted by trained substance abuse counselors. The counselors reviewed urine toxicology results with patients.
Of the patients receiving the active vaccine, 38% attained antibody levels of 43 mcg/mL or greater, while 62% had levels below this threshold, including one subject who produced no antibodies. Only two subjects mounted antibody responses greater than 43 mcg/mL before week 8, and subjects' IgG levels declined after week 16, according to the researchers.
The researchers noted a dose-response relationship, with the patients having the highest antibody levels also being those with the greatest reduction in cocaine use.
The results suggest that patients using the vaccine would likely need a booster shot every 2-3 months, Dr. Thomas Kosten, a study coauthor, said at the teleconference. Overall, “most patients would need 2-3 years of treatment, and in some it would take longer than that,” said Dr. Kosten, of the Baylor College of Medicine and the Michael E. DeBakey VA Medical Center, both in Houston.
The frequency of cocaine-free urine samples did not differ between treatments in an intent-to-treat analysis at baseline or for the full 20 weeks, the study found. However, hierarchical linear modeling analyses of weekly cocaine-free urine samples for both the vaccine group and the placebo group for weeks 1-16 found significantly more cocaine-free samples as the study progressed, with frequency increasing more quickly in the vaccine group.
Once the vaccinations stopped and antibody levels began to fall off (weeks 16-24), the linear analyses showed no significant differences in the frequency of cocaine-free urine samples between the two groups.
Former NIDA director Robert L. DuPont, who is now president of the Institute of Behavior and Health, had a positive take on the results. “I welcome this successful initial study,” he said. “It goes a long way toward fulfilling the long-sought dream of a vaccine for addiction.”
But he added that this vaccine would not solve the cocaine abuse problem. “Few cocaine-dependent people only abuse cocaine. Even those who do can easily use another dependence-producing drug even if the vaccine were totally effective.”
Dr. DuPont noted that another drug, naltrexone, is safe and 100% effective for opiate addiction. “Despite this remarkable profile, naltrexone is virtually irrelevant to the treatment of opiate addiction, let alone the treatment of all drug addiction,” he said. But the work being done on these types of treatments “is important from a scientific point of view … because it demonstrates the remarkable strides being made in the brain science of substance abuse.”
Dr. William Greene, assistant professor of psychiatry at the University of Florida, Gainesville, was less enthusiastic. Dr. Greene said he was “thoroughly disappointed” with the study results, noting that the authors said the two groups showed no significant difference in the amount of abstinence from using cocaine.
“If you're treating someone addicted to cocaine, the goal is not for them to use less—we're looking for improved abstinence rates,” he said. “This study showed no effect on abstinence rates, which is terribly disappointing.”
One reason for the outcome may have been related to the fact that it was a placebo-controlled trial, Dr. Greene added. “Patients are told that they are either getting the drug or the placebo, so by not knowing [which one they are getting] people are left to wonder and may be more apt to continue to experiment in hopes of getting high. You might get a better response in real practice” when patients know they are getting the actual vaccine and may not even try to get high.
Dr. Kosten said the researchers think they could have gotten more patients to achieve the desired antibody levels by using a different carrier and adjuvant. “We used cholera toxin and the simplest of adjuvants, which was aluminum. The current technologies being developed by larger companies produce substantially higher levels of antibodies; if we [used those] in humans, we would have 80% of patients producing the threshold we need.”
The challenge is getting bigger companies interested, since the vaccine isn't likely to have as large a profit margin, he added. “Maybe [we could do it] if we could somehow indemnify them and make it in their interest to provide it as a public health service.”
Dr. Kosten disclosed one other interesting finding from the study: Some patients appeared to make antibodies to cocaine even though they had never been vaccinated against it.
“The people who had those antibodies seemed to be immune to the vaccine,” he said. “Why they have [immunity] is an intriguing question; it particularly occurs in people who smoke cocaine [as opposed to ingesting it in other ways].” One possible explanation might be lung damage that produces a self-immunization. “This opens up a whole new area of immunobiology that we're quite excited about.”
The researchers plan to begin a follow-up study in January 2010, aimed at increasing the proportion of subjects attaining higher antibody levels and a longer abstinence period, Dr. Kosten said.
The study was funded by NIDA and the VA Mental Illness Research, Education, and Clinical Center. Celtic Pharmaceutical supplied the vaccine and paid travel fees for Dr. Kosten. Other than Dr. Martell, no other researchers declared any potential conflicts.
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