Topamax for Alcoholism: A Closer Look

Epilepsy drug gains ground, draws fire as newest anti-craving pill

A drug for seizure disorders and migraines continues to show promise as an anti-craving drug for alcoholism, the third leading cause of death in America, the Journal of the American Medical Association (JAMA) reported in its current issue.

371 male and female alcoholics between the ages of 18 and 65 took part in the study. The subjects received either topiramate or a placebo. Over 14 weeks, patients taking topiramate showed a significantly higher rate of abstinence for 28 consecutive days or more. (Rates of abstinence increased slightly in the placebo group as well. Both groups received some psychological counseling.)

Topamax is currently only approved by the Food and Drug Administration (FDA) for use against seizures and migraine. The controversial practice of “off-label” prescribing—using a drug for indications that are not formally approved by the FDA—has become so common that Johnson & Johnson (JNJ) said it had no plans to seek formal approval for the use of Topamax as a medicine for addiction.

In an editorial accompanying the study, published in the October 10 issue of JAMA, Mark Willenbring of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) wrote: “We now have very high-quality evidence that shows efficacy. The medical world doesn’t wait for the indication. Topamax is a drug that many physicians have used and many patients have had an experience with because of its use in migraines.”

In addition, Topamax is already prescribed off-label in some cases for depression and Post Traumatic Stress Disorder, according to reports.

At present, there four medications legally available by prescription for alcoholism: disulfiram (Antabuse), SSRIs (off-label), naltrexone (Revia and Vivitrol), and acamprosate, the latest FDA-approved entry. Acamprosate binds to both GABA and glutamate receptors. Acamprosate, marketed in the U.S. as Campral, has been widely used in Europe on problem drinkers.

Dr. Bankole Johnson, chairman of Psychiatry and Neurobehavioral Sciences at the University of Virginia, told Bloomberg News that Topamax does everything researchers want to see in a pharmaceutical treatment for alcoholism: “First, it reduces your craving for alcohol; second, it reduces the amount of withdrawal symptoms you get when you start reducing alcohol; and third, it reduces the potential for you to relapse after you go down to a low level of drinking or zero drinking.”

According to Forbes.com, “The drug isn’t cheap—it costs about $1,000 for three months, according to Johnson. “And, patients, don’t see benefits for two to four weeks.”

Moreover, Topiramate is not without serious side effects for some users, including vision problems, difficulty remembering words, and a tingling in the arms and legs known as parasthesia.

The study was funded by Ortho-McNeil-Janssen, the subsidiary of Johnson & Johnson that produces and markets Topamax. Citing this and other alleged irregularities, Public Citizen’s Sidney Wolfe, Director of the Health Research Group, sent a stinging letter to the FDA demanding that the agency “stop the illegal and dangerous promotional campaign by Ortho-McNeil-Janssen-funded researchers for the unapproved use of Topamax (topiramate) for treating alcoholics.”

And to make things even more interesting, drug developer Mylan (MYL) received FDA approval last month for a generic form of Topamax, seeking a share of the estimated $50 million in annual sales the drug currently enjoys.

Like Campral, Topamax causes changes in the GABA and glutamate systems, which in turn affect dopamine and serotonin function. Acamprosate, like topiramate, harkens back to earlier work on GABA transmission in alcoholism. Both drugs attack the craving and relapse dilemma by stimulating GABA, the inhibitory transmitter that is the target of benzodiazepines like Valium, Xanax and Klonopin. However, Campral is not sedating. There is no buzz, no psychoactive effect, and no evidence of abuse potential whatsoever. Major side effects of acamprosate include gastrointestinal cramps and diarrhea. In addition, Campral may also “restore receptor tone” in the hyperactivated glutamate system of the alcoholic, specifically in the nucleus accumbens.

In a dozen clinical trials conducted in Europe, involving thousands of alcohol abusers, 50 per cent of acamprosate users maintained sobriety for three months without relapse, compared to 39 per cent of the placebo group. (The distressingly low numbers are testimony to the fierce mechanism of relapse.)

Topamax shows a similar mechanism of action. Earlier, researchers from the University of Texas conducted topiramate studies at the South Texas Addiction Research and Technology Center, later published in Lancet. Alcoholic patients achieved a rate of continuous abstinence six times higher than those in a placebo group did. They also reported fewer cravings, compared to a placebo group.

The downside to Topiramate may prove to be side effects. The NIAAA’s Raye Z. Litten, chief of treatment research, believes that the drug may ultimately be a strong player. “On the other hand,” he cautions, “Topiramate appears to have more severe side-effects than naltrexone and acamprosate.” Litten argues that greater efforts at testing are needed.

The National Institutes of Health (NIH) estimated that it would be sponsoring more than 30 new clinical trials of drugs for alcoholism in the next few years. The JAMA editorial, “Medications to Treat Alcohol Dependence,” concludes that the pace of development for alcoholism drugs in increasing. “A solid understanding of the neurobiology of alcohol addiction is providing the framework for multiple avenues of further medication development.”

OxyContin Back in Court

Kentucky goes after makers of “hillbilly heroin”

The attorney general for the state of Kentucky filed a lawsuit last week against Purdue Pharma L.P., makers of OxyContin, seeking to recover damages related to widespread addiction to the painkiller commonly known as “hillbilly heroin.”

Brought to widespread attention by Rush Limbaugh’s well-publicized addiction, OxyContin is a prescription narcotic for which a thriving black market has been established. It did not take drug users long to discover that OxyContin could also be ground up and either snorted or injected for a heroin-style high. Hundreds of deaths have been attributed to the street use of this Schedule II narcotic. Kentucky state officials say the social costs associated with fighting addiction have increased dramatically since the drug’s introduction. Others states are prepared to make the same argument.

Oxycontin racked up sales of $2 billion for the year ended August 2005. At least two companies, Pain Therapeutics (PTIE) and Alpharma, (ALO) are aiming at the market for more abuse-proof versions of OxyContin. “The big issue,” writes The Motley Fool’s Brian Lawler, “is whether insurers and government health programs will be willing to pay the premium price for an abuse-resistant drug.”

Oxycodone, as the drug is known medically, is a semi-synthetic derivative of thebaine, an alkaloid found in opium. It was developed in Germany in the early years of the 20th Century as a morphine substitute. Today, oxycodone is used extensively and very effectively for pain relief in terminal cancer patients. The Food and Drug Administration (FDA) approved the used of OxyContin in a time-release version in 2004.

Purdue Pharma said it will contest the lawsuit, which charges fraud, conspiracy and negligence--but the company recently settled other litigation with West Virginia and the U.S. Department of Justice for $685 million in cases alleging illegal marketing and promotion of the drug. U.S Attorney John Brownlee of the Western District of Virginia said that company sales reps falsely implied that OxyContin had less potential for addiction and abuse than similar prescription narcotics. Several other states were parties to those complaints, in which Purdue Pharma officials pled guilty last year to charges of misleading the public. Several states have taken a similar approach toward Merck, the manufacturers of Vioxx.

The Kentucky attorney general’s office said OxyContin addiction was so widespread that officials in Pike County were forced to build a $5.6 addition to the county jail to cope with increased convictions for oxycodone addiction. “It’s ironic that those who manufacture a drug that is meant to ease the pain of those suffering from debilitating diseases… have in fact inflicted so much pain by being deceptive and greedy,” said Country Judge-Executive Wayne Rutherford.

With the plethora of state lawsuits brought on behalf of Medicaid programs and law-enforcement agencies against OxyContin, “I think we have the answer as to whether government health programs will cover the costs of these abuse-resistant drugs,” Lawler concludes. “Count this as one less hurdle for Pain Therapeutics, Alpharma, and the other developers of these abuse-resistant compounds."

Defining Alcoholism

How much is too much?

Alcohol consumption lies on a spectrum, from nondrinkers on one end to patients dying of alcohol-related liver disease on the other. Novelist Jim Harrison once claimed that his ambition was to be a “problem drinker,” rather than an alcoholic.

How do we make the distinction?

Professor George Vaillant of Harvard felt obliged to study that question, an inclination that resulted in his 1983 landmark work, The Natural History of Alcoholism, revised in 1995.

Dr. Vaillant was the motive force behind the Harvard Medical School’s Study of Adult Development, which began in 1940. The study was divided into three groups: the middle-class College sample, the so-called “Core City Longitudinal Study”, and a later group, the Clinic sample, comprised solely of people who had been admitted to a clinic for detoxification, and the only one of the three groups that included women.

So what did George Vaillant discover in the longest formal study of drinking behavior ever undertaken in the United States? One of the first observations Vaillant drove home was that the amount of alcohol consumed is NOT a reliable indicator of alcoholism. Not only is “amount of alcohol ingested” an unreliable predictor of alcoholic drinking—so is “frequency of intoxication.” Both attributes, Vaillant found, proved to be very poor “discriminators” when it came to distinguishing alcoholics from “problem” drinkers.

So, if how much you drink, and how often you drink, are not reliably predictive of alcoholism, what, IS a reasonable predictor? The key item on Vaillant’s questionnaires turned out to be: “Admits problem controlling alcohol use.”

Vaillant showed that “multiple alcohol-related problems result not from ingesting large amounts of alcohol but from being unable consistently to control when, where, and how much alcohol is consumed.” Alcoholism, Vaillant concluded, is “defined by the number, not by the specificity, of alcohol-related problems.”

This insight dovetailed neatly with the definition of alcoholism the National Council on Alcoholism had adopted way back in 1976: “The person with alcoholism cannot consistently predict on any drinking occasion the duration of the episode or the quantity that will be consumed.”

For George Vaillant and other pioneers of the disease model, the conceptual view had shifted long ago: “As with coronary heart disease, we must learn to regard alcoholism as both disease and behavior disorder.” Genetic loading, says Vaillant, “is an important predictor of whether an individual develops alcoholism,” while a difficult childhood environment “is an important predictor of when an individual loses control of alcohol.”

Based on his lifelong study, Vaillant discloses that chronic alcoholics are involved in at least half of all vehicle accident deaths, which comes as no surprise. Half of all emergency room patients with severe multiple fractures are alcoholics, and alcoholics are six times as costly to keep when hospitalized, says Vaillant. Alcoholics—22 million of them in the U.S. alone, by a recent federal estimate—commit suicide far more often than non-alcoholics do. 10 to 30 per cent of all suicides may be alcoholics, according to statistics cited by Vaillant. And this does not include suicides by people addicted to drugs other than alcohol.

“Progressive” alcoholics—those who never abstain or go through periods of stable social drinking—were twice as likely to smoke two packs of cigarettes a day, compared to other drinkers. Indeed, alcoholics almost never stop smoking. Vaillant believes that heavy drinking acidifies the urine in a way that increases the urinary excretion of nicotine. Hence, there is a need to smoke more while you are drinking more, lest blood nicotine levels fall below the comfort range.

And along with cigarettes, says Vaillant, comes depression: “Like smoking and alcohol abuse, depression is associated with premature mortality; and if alcoholics were three times as likely to be dead, they were also three times as likely to be depressed.” Depressed men and women, then, drink more, smoke more, and take more drugs than non-depressed people. It is never hard to anticipate the chorus of complaint that such reasoning elicits. Everybody has emotional vicissitudes, but not everybody resorts to abusing drugs. Everybody gets the blues, but not everybody drowns them in drink. With courage and discipline, people can resist the easy notion of a whiskey, neat, for every problem.

To combat that notion, Vaillant also documents the dismal stats concerning “treated” alcoholism: “For short periods, middle-class individuals respond well to treatment in the medical model, but that response may be short-lived and reflect premorbid variables rather than the efficacy of specific treatment.” It turns out that if you simply control for two “premorbid” variables—marriage and employment—you can account for most of the difference. Alcoholics who are solidly married and have jobs fare better in treatment. But even they don’t always do very good for very long.

(Image courtesy of Medline Plus-National Library of Medicine)

Nicotine Addiction in the U.K.

Study group urges harm reduction strategy for heavy smokers

Britain's Royal College of Physicians (RCP) called upon the government to treat cigarette smoking like any other drug addiction, and faulted its members for failing to offer sufficient help to heavy smokers trying to kick the habit.

Because of that failure, the Academy called for greater access to nicotine substitution products, and the development of safer and more effective nicotine delivery systems for smokers who cannot quit.

The Academy’s report, "Harm Reduction in Nicotine Addiction: Helping People Who Can’t Quit," called for a sweeping overhaul of the country’s nicotine marketing structure "so that harm reduction strategies are in place."

The report’s principle suggestion: "Change nicotine product regulation to make it easier to produce and market medicinal nicotine products."

Jean King, Cancer Research UK's director of tobacco control, said the report highlighted the "stark fact" that cigarettes are freely available, while medicinal nicotine products are heavily regulated.

The report also calls for continued development of new forms of “user-friendly medicinal nicotine substitutes,” as well as relief from burdensome regulations that impede the marketing of new nicotine alternatives—chewing gums, nasal sprays, and patches.

“Smokers smoke because they are addicted to nicotine,” said Professor John Britton, chair of the Academy’s Tobacco Advisory group. “There are millions of smokers who can’t quit, or else are unlikely to quit, and those people need nicotine products that can satisfy their addiction without killing them.”

This methadone-style approach to nicotine addiction is sure to prove controversial. Will it save lives, or will it simply keep nicotine addicts from getting clean? Reuters reports that some British scientists are concerned that an emphasis on cigarette substitution products is at odds with a policy of helping people completely break their addiction to nicotine—which the Royal Academy maintains is still their primary focus.

Shining New Light on Addiction

SAD phototherapy may help with alcoholism

It’s that time of the year again.

For many people, autumn is a bracing and enjoyable time of the year. But for an unlucky minority of people, the advent of seasonal affective disorder, or SAD, is only, and literally, a matter of time. Since the autumnal equinox at 9.51 a.m. GMT on September 23, when daytime lost its annual circadian struggle with nighttime, the amount of daily sunlight slowly but surely diminishes by as much as several minutes a day. And for a few months, it will only get worse. For dwellers in the northern latitudes, the long dark has begun.

To be precise, seasonal affective disorder is not typically considered to be a separate or unique disorder, but rather a symptom of unipolar or general depression, the “garden-variety” form of depression. Both general depression and its seasonal variant involve symptoms such as lethargy, weight gain, carbohydrate craving, oversleeping and joylessness.

The addition of strong light in certain frequencies—a form of phototherapy—helps some people combat this seasonal form of depression. The so-called SAD lights have become a fixture in homes, offices, and mail-order catalogs. The evidence for effectiveness is somewhat controversial, but generally accepted.

Recently, Science magazine has spotlighted work being done on other conditions that may respond to SAD phototherapy. Citing the work of Alfred Lewy and Thomas Wehr at the National Institute of Mental Health (NIMH), who showed that phototherapy worked by decreasing the production of melatonin through a complicated set of reactions leading to an increase in blood levels of serotonin, the article summarizes the evidence showing that many people suffering from either seasonal depression or general depression benefited from spending 30 minutes each morning sitting three feet away from bright white fluorescent lighting--light banks very much like the indoor “grow lights” people often purchase for their house plants.

However unorthodox it may sound, recent studies strongly suggest that phototherapy might also aid people suffering from bipolar disorder, commonly called “manic-depression.” This is a striking possibility, since bipolar depression is distinct from general depression, and rarely responds to the same therapies and medications used for that condition.

This development has led researchers to wonder whether other mental or behavioral disorders partially mediated by fluctuations in serotonin might also respond to light therapy. Last year, writing in the American Family Physician, Stephen J. Lurie and coworkers pointed out that “SAD is associated with serotonergic dysregulation and… may overlap with other diagnoses that share similar mechanisms.”

One diagnosis that shares similar mechanisms is alcoholism. The neurological connection between alcoholism and major depression is well documented by now, and involves serotonin, among other neurotransmitters and neurotransporters that ferry molecules around the brain and the rest of the central nervous system. Brain imaging studies of alcoholics do indeed show a marked reduction in serotonin transporter availability in cases of accompanying depression.

According to Lurie, a summary of recent research findings reveals that “some patients with alcoholism may be self-medicating an underlying depression with alcohol or manifesting a seasonal pattern to alcohol-induced depression.” Such patterns also show genetic underpinnings—SAD often runs in families with a strong history of alcoholism and general depression. All of this, the paper states, “may be related to serotonergic functioning.”

Dr. Leo Sher of the Department of Psychiatry at Columbia University believes that “Family and molecular genetic studies suggest that there may be a genetic link between seasonality and alcoholism.” In an article for the January 2004 issue of Comprehensive Psychiatry, Sher writes:

“The fact that SAD and alcoholism may be comorbid [occur together] shows the importance of a thorough diagnostic interview. Both mental health and drug and alcohol professionals should be provided with education to assist with appropriate identification, management and referral of patients presenting with comorbid alcoholism and SAD.”

For alcoholics who also suffer from seasonal affective disorder, a therapy regimen that includes exposure to bright lights in the morning could do more than boost their moods. It might also help them drink less. Much more research is needed, but the possibility that SAD phototherapy might help curb alcohol cravings or prevent relapse is a hypothesis worthy of further investigation.

Sources:

Bhattacharjee, Yudhijit, “Is Internal Timing Key to Mental Health?” Science, 317 14 September 2007. (Subscription).

“Alcohol and Seasonal Affective Disorder.” Comprehensive Psychiatry.

“Serotonergic dysfunction, negative mood states, and response to alcohol.” Alcoholism, Clinical and Experimental Research.

"Circadian Phase Variation in Bipolar I Disorder." Chronobiology International

"Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression." Journal of Clinical Psychiatry.

“Seasonal Affective Disorder.” American Family Physician

“Shedding Some Light on Bipolar Disorder.” Living the Scientific Life (Scientist, Interrupted).

Bulimia as Food Addiction

Serotonin-mediated brain activity drives the binge-and-purge cycle

Bulimia, the binge-and-purge disorder that tends to afflict young women, seems especially linked to serotonin abnormalities. Bulimics gorge themselves and then induce vomiting--a debilitating cycle that often leads to severe health consequences.

Richard and Judith Wurtman, of the Massachusetts Institute of Technology (MIT) identified a subset of bulimics who binge severely and almost exclusively on high-carbohydrate foods. These bulimics tended to be mildly obese, severely depressed--and came from families with a strong history of alcohol abuse. Other researchers have reported that a significant number of bulimics are themselves abusers of alcohol and other drugs. What is being suggested is that carbohydrate-craving obesity and bulimia may turn out to be two additional forms of drug addiction. They may be variations on the addictive theme, and the underlying cause may be the same--irregularities in the reward system neurotransmitters.

For women whose bodies do not regulate the production of serotonin successfully, bulimia is one of the possible symptoms that can result from this condition. Unlike anorexia, its “partner” disorder, bulimia resembles addiction in several important ways. There is a definite “high,” which comes with the purging, and which has no analogue in anorexia. (Recall that serotonin is involved in smooth muscle functions, like vomiting and bowel movements.)

Bulimia’s impact on the brain’s reward center also seems to be quite direct, judging by the high relapse rates of bulimics. As further evidence, studies were performed by Walter Kaye and colleagues at the University of Pittsburgh Medical Center, where PET scans were taken of women who were former bulimics, and compared to a set of PET scans from healthy, age-matched women. The ex-bulimics showed a marked decrease in serotonin binding at the 5HT receptors, and studies by Kaye and others offer evidence that alterations in the brain’s serotonin pathways often persist after recovery from bulimia, and may represent permanent changes in brain chemistry.

The idea that serotonin disturbances are at the root of bulimia continues to make sense. Moreover, preliminary studies of female twins have bolstered the basic hypothesis, by showing evidence of a possible genetic predisposition toward bulimia.

Serotonin and Dopamine: A Primer

The Molecules of Reward

Serotonin and dopamine are part of a group of compounds called biogenic amines. In addition to serotonin and dopamine, the amines include noradrenaline, acetylcholine, and histamine. This class of chemical messengers is produced, in turn, from basic amino acids like tyrosine, tryptophan, and choline. The amines are of great interest, because both mood-altering drugs and addictive drugs show a very straightforward affinity for receptors sites designed for endogenous amines.

Addictive drugs have molecules that are the right shape for the amine receptors. Drugs like LSD and Ecstasy target serotonin systems. Serotonin systems control feeding and sleeping behaviors in living creatures from slugs to chimps. Serotonin, also known as 5-HT, occurs in nuts, fruit, and snake venom. It is found in the intestinal walls, large blood vessels, and the central nervous system of most vertebrates. The body normally synthesizes 5-hydroxytryptamine, as serotonin is formally known, from tryptophan in the diet.

Thus far, no other substance found the central nervous system has as many diverse receptor actions as 5-HT. The average adult has only about 10 milligrams of serotonin in his or her body. It is involved, to one degree or another, in appetite, sleep, mood, memory, learning, endocrine regulation, smooth muscle contractions, migraine headaches, motility of the GI tract, blood platelet homeostasis, so on. Serotonin also plays a large role in initiating and shaping certain kinds of behavior, especially behaviors of a sexual or hallucinatory nature. In animal models, lower serotonin levels correlate with higher levels of violence.

A receptor-selective agent like Sumatriptan, a popular migraine medication, works by binding selectively to a serotonin receptor subtype involved in arterial circulation and dilation. The difference between serotonin-active drugs like sumatriptan, and similarly serotonin-active drugs LSD or Ecstasy, is that the former locks exclusively into these “5-HT1” receptors, and nowhere else. The ergot alkaloids are all over the serotonin system, causing general surges of their own.

Psychedelic drugs like LSD and Ecstasy (chemically known as indoleamines) and mescaline (phenethylamines) make up the two major classes of hallucinatory drugs. They are both partial agonists at 5-HT receptors, boosting serotonin particularly in the cerebral cortex and the locus coeruleus. There is also some enhancement of glutamine activity as well. Other 5-HT agonists, like ondansetron (trade name Zofran), do not have that effect. Ondansetron helps block the nausea of chemotherapy by blocking serotonin activity in the GI tract. Vomiting is a serotonin-mediated reflex. In this case, it is the 5-HT3 receptor subtype that is of note. Ondansetron’s selective affinity for that subtype makes it a useful anti-emetic.

Dopamine, like serotonin appears to be strongly involved in mediating craving-- drug hunger, as well as real hunger. This yields a partial answer to one of addiction’s mysteries: Why would a drug addict, an alcoholic, continue to use when the adverse effects of continued use have long ago swamped whatever euphoric sense of well being, or even just plain normalcy, that once was obtained through the drug? One answer might be that dopamine causes human beings to pay attention to stimuli that are potentially rewarding. Even in the absence of any possibility of reward--on a desert island, in a rehab clinic--dopamine dysregulation could kindle episodes of fierce craving, because such episodes had led in the past to a renewed ingestion of the drug in question-- all the fiercer, these cravings, this drug hunger, whenever the addict was exposed to direct cues, like seeing the drug, or being in places where the addict had used before.

Scientists have managed to record a rise in dopamine levels in lab rats simply by cueing the rats to anticipate a pleasurable event--food, sex, sweet drinks. For example, you could condition the rats to a ringing bell before dinner, and soon the rats would be showing elevated dopamine levels at the sound of the bell only--with no reward at all. Anticipation of reward was all it took. Or you could give one of the male rats a good close look at a suitable female through a mesh panel, and the male rat’s dopamine levels would surge, presumably in anticipation of possible carnal pleasures, and dopamine levels would spike even higher, of course, once the divider was removed.

Serotonin/dopamine dysfunctions cause physical discomfort, anxiety, and panic--what a renowned neuropharmacologist has termed “spiraling distress”—which continues to occur even in the complete absence of the addictive drug. Take the drug away, and the brain begins its complex and minutely ordered repertoire of compensatory effects--unpleasant sensations as read out by the addict.

Finding a way to override serotonin- and dopamine-mediated mid-brain commands is one of the keys to recovery from addiction. One of the aims of a biological understanding of addiction is to tease out the mechanisms by which the reinforcing effects of addictive drugs become transformed into long-term adaptive changes in certain areas of the brain. “Why are we so surprised that when you take a poison a thousand times, it makes some changes in your head?” wondered James Halikas, who was co-director of the chemical dependency treatment program at the University of Minnesota during the crack heyday of the late 1980s and early 1990s. “It makes sense that poisons change things.”

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