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USPMHC 2014

New Therapies to Fight Addiction

For more than 70 years, standard care for those addicted to alcohol or drugs has called for the afflicted person to abstain from the substance completely, and to become immersed in a community of fellow sufferers for support. This is particularly true in the early months, when the "phenomenon of craving" remains acute.
For more than 70 years, standard care for those addicted to alcohol or drugs has called for the afflicted person to abstain from the substance completely, and to become immersed in a community of fellow sufferers for support. This is particularly true in the early months, when the “phenomenon of craving” remains acute.

While some alcoholics and addicts succeed in staying sober, the failure rate for this approach is stubbornly high,1 and medicine has long looked for other ways to interrupt the craving mechanism that drives some to continue consuming alcohol or using drugs, even to their deaths. It has been clear that alcoholism and addiction run in families, suggesting a role for pharmacogenetics.

Thomas R. Kosten, MD, professor of Psychiatry, Pharmacology, and Neuroscience at  Baylor College of Medicine, Baylor University, reviewed new treatments for alcohol and cocaine addiction Saturday at the US Psychiatric and Mental Health Congress, being held at the Rosen Shingle Creek Hotel in Orlando, Florida.

He discussed the role of pharmacogenetics, especially naltrexone’s capacity to help those with alcoholic addiction stop drinking or at least limit their intake, as well as the use of disulfiram in helping those with cocaine addiction. “Pharmacogenetics is still in its infancy for addictive disorders,” he said.

Dr Kosten also discussed his groundbreaking work in immunotherapy, which involve vaccines that have been shown to help wean cocaine addicts away from the drug.

Naltrexone. The opioid receptor agonist has been approved for alcohol dependence since 1994, but the drug was not initial prescribed without psychotherapy. Today, it is used both with and without psychotherapy and was just approved in combination with bupropion, as Contrave, to combat obesity.2

When a person with alcohol dependency drinks, the alcohol boosts the release of β-endorphins, triggering the brain’s reward mechanisms. It was understood early on that naltrexone interfered with this craving phenomenon, and taking the drug daily could reduce craving over time.3

But, as Dr Kosten explained, naltrexone does not work for everyone. In recent years, he said, research has shown that naltrexone has the greatest effect on those patients with more complex and more severe addiction, particularly those with a strong family history of alcoholism, which Dr Kosten defined as at least half the family members having problems with alcohol. Studies published since 2008 have found that persons whose genetic background is from the northernmost regions, whether it is Scandinavia or the northern reaches of China, have a variant of the gene OPRM1, polymorphism Asn40Asp, which predicts response to naltrexone.

Naltrexone’s disruption of the craving mechanism is now better understood: it raises β-endorphin levels through feedback inhibition via presynaptic opioid receptors; thus, alcohol’s effect stimulating this endorphin effect is reduced, and craving diminishes. Hence, in one controversial treatment method, some patients take naltrexone after a drink to disrupt the craving mechanism.

Disulfiram. According to Dr Kosten, the mechanism of disulfiram in treating cocaine addiction is straightforward: the drug is believed to inhibit conversion of the dopamine in DBH (dopamine β-hydroxylase) to norepinephrine; as with the studies in naltrexone and alcohol, the mechanism of action is believed to reduce craving.

Dr Kosten presented results showing randomized clinical trials involving the administration of disulfiram, along with cognitive behavior therapy, which showed the drug produced better results; disulfiram increased cocaine-free urines (55%) compared with placebo (40%). Patients with genetically high plasma DBH levels were associated with had twice as many cocaine-free urines as a group of unselected patients, showing the pharmacogenetic link with disulfiram.

A Vaccine for Cocaine. Dr Kosten’s work with vaccines to combat cocaine addiction have received widespread attention. Similar to the work with the pharmacogenetic drugs, the principles at work seek to interrupt the mechanism that attract what he calls “drugs of abuse” to receptors in the brain.

“Drugs get into the brain very easily,” he said. His vaccines are designed to perform like giant sponges in the blood stream, flushing the tiny cocaine particles away from brain receptors so they cannot attach.

“It doesn’t eliminate the desire for cocaine, but it keeps the user from getting high,” Dr Kosten explain. Repeated injections over 3 months allow antibodies to build up in the bloodstream, so even if the patient should use cocaine, the drug particles don’t attach to the brain or go out into the blood stream. The effect of the vaccine does not last forever, and boosters are needed.

Dr Kosten has been working with cocaine vaccines for some time; he has studied a variety of dose levels and schedules and determined that the extended dosing period of 3 months is key to ensuring that sufficient antibodies build up in patients.

“The current results are encouraging,” he said. The current therapy, which is derived from a cholera vaccine, has been demonstrated to be safe, and is has been shown to produce greater antibody effects as the dose increases. Those patients with reliable antibody production have shown a substantial decrease in cocaine intoxication, and those with the highest anti-body levels have experienced the greatest reduction in cocaine use, Dr Kosten said.

Still, the results of a study just published show the intractable nature of cocaine addiction, he said. While the vaccinated group had greater success in achieving a 2-week period without cocaine use, overall, “there was no significant difference,” between the high-dose, low-dose, and placebo groups among 300 subjects in the 16-week trial.4 This particular trial recruited heavy cocaine users, Dr Kosten said.

 “These are vaccines meant for people who are motivated to stop using,” he said. If clinicians give them to people who want to keep using, “You are wasting your time.”

References

  1. Flanagan J. The surprising failure of 12 steps. The Atlantic. http://www.theatlantic.com/health/archive/2014/03/the-surprising-failures-of-12-steps/284616/. Published March 25, 2014. Accessed September 21, 2014.
  2. Husten L. FDA approves Contrave weight loss drug from Orexigen and Takeda. Forbes. http://www.forbes.com/sites/larryhusten/2014/09/10/fda-approves-contrave-weight-loss-drug-from-orexigen-and-takeda/. Published September 10, 2014. Accessed September 21, 2014.
  3. Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP. Naltrexone in the treatment of alcohol dependence Arch Gen Psychiatry. 1992;49(11):876-880.
  4. Kosten TR, Domingo CB, Shorter D, et al. Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. Drug Alcohol Depend. 2014;140:42-47.


 
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