Showing posts with label anti-craving drugs. Show all posts
Showing posts with label anti-craving drugs. Show all posts

Tuesday, April 30, 2013

Where Are All the New Anti-Craving Drugs?


The dilemma of dwindling drug development.

Drugs for the treatment of addiction are now a fact of life. For alcoholism alone, the medications legally available by prescription include disulfiram (Antabuse), naltrexone (Revia and Vivitrol)—and acamprosate (Campral), the most recent FDA-approved entry. A fourth entry, topiramate (Topamax), is currently only approved by the Food and Drug Administration (FDA) for other uses. But none of these are miracle medications, and more to the point, no bright new stars have come through the FDA pipeline for a long time.

New approvals for drugs in this category, like psychiatric drugs in general, have lately been confined to repurposed, “me-too” medications—which, insurance companies complain, are far too expensive. As health insurance giant Cigna explains on its website: “If anticraving medications are not covered by your insurance plan, keep in mind that the price of anticraving medications is usually small compared to the cost of alcohol and/or other drugs.” Perhaps so, but evidently not small enough for the expense to be routinely covered by the prescription portion of insurance policies.

Federal health officials have the same complaints. In a 2004 report entitled “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” the U.S. Food and Drug Administration called for increased public-private collaboration and a “critical development path that leads from scientific discovery to the patient.”

As detailed by Professor Mary Jeanne Kreek, a senior attending physician at the Laboratory of the Biology of Addictive Diseases at Rockefeller University and one of the primary developers of methadone therapy:

Toxicity, destruction of previously formed synapses, formation of new synapses, enhancement or reduction of cognition and the development of specific memories of the drug of abuse, which are coupled with the conditioned cues for enhancing relapse to drug use, all have a role in addiction. And each of these provides numerous potential targets for pharmacotherapies for the future.

In other words, when an addiction has been active for a sustained period, the first-line treatment of the future is likely to come in the form of a pill. New addiction treatments will come—and in many cases already do come—in the form of drugs to treat drug addiction. Every day, addicts are quitting drugs and alcohol by availing themselves of pharmaceutical treatments that did not exist twenty years ago.

But things have changed. “This scientific stall may have seemed to come out of the blue,” writes Dr. Steven E. Hyman, Professor of Stem Cell and Regenerative Biology at Harvard University, in the Dana Foundation publication, Cerebrum. Hyman sketches a dismal picture:

The molecular and cellular underpinnings of psychiatric disorders remain unknown; there is broad disillusionment with the animal models used for decades to predict therapeutic efficacy; psychiatric diagnoses seem arbitrary and lack objective tests; and there are no validated biomarkers with which to judge the success of clinical trials. As a result, pharmaceutical companies do not see a feasible path to the discovery and development of novel and effective treatments…. progress for the many patients who respond only partially or not at all to current treatments requires the discovery of medications that act differently in the brain than the limited drugs that we now possess…. and regulatory agencies have given up their willingness to accept even more expensive new drugs.

Genes aren’t simple, and the kinds of studies that would lead to new anti-craving drugs are not cheap. Moreover, the medications themselves do not represent cures. Even if drugs that block dopamine receptors treat psychotic symptoms, Hyman writes, “it does not follow that the fundamental problem is excess dopamine any more than pain relief in response to morphine suggests that the original problem is a deficiency of endogenous opiates.”

What can change this picture for the better? “One exciting recent development is the emerging recognition that genes involved in schizophrenia, bipolar disorder, and autism do not represent a random sample of the genome,” Hyman writes. “Rather, the genes are beginning to coalesce into identifiable biochemical pathways and components of familiar neural structures…. Many researchers hope that such efforts will help attract the pharmaceutical industry back to psychiatry by demonstrating new paths to treatment development. The emerging genetic results may be the best clues we have ever had to the etiology of psychiatric disorders.”

Detractors worry, naturally enough, about the shrinking pie of funds available for this sort of endeavor. According to Steven Paul, president of Lilly Research Laboratories, “I am worried that obtaining the kind of molecular probes required for even in vivo testing may prove to be too time-consuming and expensive, and may divert precious NIH funds away from basic or clinical biomedical research.”

But Hyman remains optimistic, “based partly on the extraordinary vitality of neuroscience and perhaps, even more important, on the emergence of remarkable new tools and technologies to identify the genetic risk factors for psychiatric disorders, to investigate the circuitry of the human brain, and to replace current animal models that have failed to predict efficacious new drugs that act by novel mechanisms in the brain.”

Photo Credit: http://www.insidecounsel.com/

Friday, January 21, 2011

Personalizing Addiction Medicine


Gene variants make anti-craving drugs a hit-or-miss affair.

Rather than taking on another broad hunt for the genes controlling the expression of alcoholism, noted addiction researcher Dr. Bankole Johnson and co-workers at the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia took a different tack. The researchers focused, instead, on investigating whether genetic variations among alcoholics might affect their responses to a specific anti-craving medication.

This post was chosen as an Editor's Selection for ResearchBlogging.orgThe result, according to Kenneth Warren, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is a study that represents “an important milestone in the search for personalized treatments for alcohol dependence.”

For any addiction, once it has been active for a sustained period, the first-line treatment of the future is likely to be biological. New addiction treatments will come—and in many cases already do come—in the form of drugs to treat drug addiction. Every day, addicts are quitting drugs and alcohol by availing themselves of drug treatments that did not exist fifteen years ago. As more of the biological substrate is teased out, the search for effective approaches narrows along avenues that are more fruitful. This is the most promising, and, without doubt, the most controversial development in the history of addiction treatment.

The researchers were interested in variations in the gene controlling the expression of a serotonin transporter protein. Dr. Johnson’s earlier work had centered on teasing out the influence the serotonin 5-HTT transporter exerts on the development of alcoholism. Previous research had focused attention on the so-called LL and TT variants of this transporter gene. After performing genetic analyses to determine which test subjects were carrying which versions of the gene in question, Dr. Johnson and his colleagues conducted a controlled trial of ondansetron on a randomized group of 283 alcoholics.
The findings were published in the American Journal of Psychiatry.

Ondansetron is an anti-emetic medication that has shown promise in treating addictions, particularly alcoholism. Ondansetron (trade name Zofran), helps block the nausea of chemotherapy by altering serotonin activity in the GI tract. (Vomiting is a serotonin-mediated reflex.) The scientists found that “individuals with the LL geno-type who received ondansetron had a lower mean number of drinks per day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo.”  This put the ondansetron drinkers under five drinks a day. All of the placebo drinkers continued to exceed the five drinks per day mark.

But the strongest difference was found in the group of alcoholics who possessed both the LL and TT genetic variants. The LL/TT alcoholics taking ondansetron “had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other geno-type and treatment groups combined.” 

The goal here is straightforward. In an email exchange, Dr. Johnson told me: “I agree that it would be great if we could use a pharmacogenetic approach to study other anti-craving drugs. The idea of providing the right drug to the right person is definitely important for optimizing therapeutic effects and minimizing side-effects.” Here is a video of Dr. Johnson discussing the research, courtesy of the University of Virginia:

It won’t be easy. Such genetic testing is still in its infancy, and complications abound. For example, in an earlier study in the Journal of the American Medical Association, Dr. Johnson found that diagnosed patients who received ondansetron over an 11-week period increased their days of abstinence compared to alcoholics on placebo. However, in that study, “The researchers found no differences between ondansetron patients with late-onset alcoholism and those who received placebo.” This suggests that, along with genetic variations, ondansetron’s effectiveness with alcoholics may also depend on the type of alcoholism under consideration: early onset or late onset.

We have a long way to go, but individualized pharmaceutical assistance in the early stages of addiction recovery remains the Holy Grail for many addiction researchers. And hopes are running high.

Johnson, B., Ait-Daoud, N., Seneviratne, C., Roache, J., Javors, M., Wang, X., Liu, L., Penberthy, J., DiClemente, C., & Li, M. (2011). Pharmacogenetic Approach at the Serotonin Transporter Gene as a Method of Reducing the Severity of Alcohol Drinking American Journal of Psychiatry DOI: 10.1176/appi.ajp.2010.10050755

Graphics credit: Sergey Ivanov at http://pn.psychiatryonline.org/content/

Thursday, February 14, 2008

Fighting Fire with Fire


An introduction to anti-craving drugs

The early neurobehavioral research on addiction has been vindicated by the development of anti-craving drugs and new drugs for depression.

On the other hand, the psychopharmacology of addiction is not much studied in med school, and all but unknown among the general populace. Even the treatments now in existence are woefully underutilized. Moreover, there are good reasons to question whether these drugs are being prescribed with sufficient care and forethought in cases where they are being used. Legitimate, unanswered questions exist about pharmacotherapy for addictive disorders.

The most important effect--the reregulation of brain receptor arrays with time--is little understood. And we cannot say with certainty whether messing with Mother Nature’s receptors, in some cases, might disrupt other finely tuned immunological or neurological systems in the body. Finally, there is the possibility of side effects years down the road, which obviously cannot be predicted based on current studies. What we already know is that the “bodymind,” as Candace Pert refers to it, is a delicate and astonishingly complicated piece of organic machinery.

Researchers are confronted with the perpetual dilemma of designing out, or designing down, the side effects of any new class of drugs. The historical record of drugs like Thorazine, and darker cases like Oraflex and thalidomide, are reminders of the potential pitfalls of development races and corner-cutting practices in the pharmaceutical industry. The pharmacological sciences and the people who work in them are inextricably linked to the drug companies that sell the end products of any neurochemistry that yields marketable new medications. It cannot be otherwise: Market considerations drive much of the research. By 1990, the American pharmaceutical industry had surpassed the federal government’s National Institutes of Health as the world’s principal source of biomedical research and development funding. One of the stiffest challenges facing managed health care in the future will be the matter of evaluating the effectiveness of medications for addiction.

Fighting fire with fire brings scientists face to face with the problems posed by the blood-brain barrier, that superfine mesh of cells that protects the brain from unwelcome molecular intruders. Bacteriologists discovered the barrier more than two centuries ago, when they learned that dyes injected into the body stained all the organs except the brain. Normally, the capillary-rich barrier of cells is so densely packed that the only way to penetrate the tight junctions between them is by means of special transporter molecules. These specialized molecules act as chauffeurs for the amino acids, hormones, and other compounds that must pass regularly and consistently into the brain. These transporter molecules can be fussy about riders, and the only way around that is to use molecules so tiny that they are measured in units of atomic mass called “Daltons.”

Knowing this, biochemists have worked toward discovering extremely small molecules, and this is partly why so few effective psychoactive drugs come along. While scientists have had some luck with small-molecule approaches to treating epilepsy, schizophrenia, and certain mood disorders, there is no reason to assume a small molecule can always be found to fit the bill.

Current work centers on tricking existing transporter molecules into ferrying artificial cargos into the brain. Pills that easily penetrate the blood-brain barrier are rare, special, and capable of causing a host of problematic side effects. If Zyban demonstrated that there were good reasons to be hopeful about future anti-craving drugs, then the diet drugs Redux and “fen-phen” demonstrated to critics of the drug industry what seemed to be a reversion to type—unsafe drugs released to the public without sufficient attention to dangerous side effects. Eli Lilly’s earlier caution about moving forward with serotonin boosting drugs as anti-obesity medications—as anti-craving drugs for food addicts--soon came to look like a wise decision.

--Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

Related posts:

Chantix and Suicide
What is Drug Craving?
Naloxone and "Receptorology"
Topamax for Alcoholism: A Closer Look

Digg!
Related Posts Plugin for WordPress, Blogger...