Experts hope cutting-edge treatments will block the need and end the drive for the ‘rush’
PHOTOS BY JON NASO/THE STAR-LEDGER
Caption: In a Baltimore detox program using buprenorphine, heroin addicts, as part of their counseling, listen to a “love letter” from their addictions.
One morning more than a quarter of a century ago, scientists Alan Cowan and John Lewis folded themselves into a small observation box at an industrial laboratory outside London. Fingers crossed, they peered through a hazy one-way mirror at three patas monkeys playing in a room.
For weeks, the monkeys had been injected three times daily with an experimental painkiller and opiate called RX 6029-M. Now, the animals had been injected with another drug, naloxone, which normally provokes instantaneous withdrawal in subjects taking opiates.
Over the next hour, Cowan, a pharmacologist, and Lewis, a chemist, waited for the classic signs of drug withdrawal – sweating, nausea, itching, agitation. With every other compound they had tried, that’s what had happened. This time, nothing adverse happened. This was one strange drug, they agreed. On that day, a quixotic quest to find the best use for the mystery drug RX 6029-M, now known as buprenorphine, was born.
A few years later, it would take a pioneering addiction researcher, Donald Jasinski of Johns Hopkins University School of Medicine, to make the leap in logic that buprenorphine might be a potent treatment for heroin addiction. His research showed that it blocks heroin from connecting with the pleasure receptors in the brain, eliminating the high that junkies crave.
Once Jasinski realized that this odd opiate wasn’t addictive, the idea stirred other brain researchers to turn to pharmacology manuals in hopes of designing other drug treatments.
An examination of the kinds of drugs now in the development stage – ones to treat heroin and cocaine addiction, to combat alcoholism and to vaccinate people against nicotine addiction – illustrates the progress that is being made by scientists in finding so-called cures for addiction.
Buprenorphine has been edging its way toward U.S. government approval ever since the British researchers discovered its unusual powers.
Its backers – scientists, drug policy wonks, government officials and industry executives – say buprenorphine is one of the most effective treatment options for heroin addicts.
“From a scientific point of view, there is no question in anyone’s mind that buprenorphine is going to be useful,” said Martin Adler, director of the Center for Substance Abuse Research at Temple University’s School of Medicine in Philadelphia, noting that the drug has been approved as a treatment for heroin addiction in more than a dozen other countries. “We’re way behind the world on this one.”
Fears by governmental anti-drug authorities that buprenorphine could turn into another problem street drug and that it could unseat the prevalent treatment, methadone, has slowed its advance, officials said.
“Buprenorphine is important both in terms of what it means for addicts and what it means for the larger field of addiction research,” said Jasinski, the physician-scientist credited with first seeing buprenorphine’s potential. Many patients who have gone through detoxification and more extended treatments at his Bayview clinic in Baltimore have been helped by the drug.
Since the 1930s, government scientists had been searching for pain medications that were not as addictive as morphine, like codeine.
Cowan and Lewis, the scientists who had been spying on the monkeys, were the first to realize that buprenorphine was a new kind of powerful, nonaddictive painkiller, mimicking morphine in some ways and not in others. There was more to this drug, they said, than met the eye.
Jasinski suggested in a 1977 paper that a painkiller that did not produce a high, did not produce withdrawal and did not dangerously suppress respiration might be useful in treating heroin addicts. The drug merited study, he said.
His idea ignited a bitter argument among addiction and drug policy experts in industry and government circles over what to do about the enigmatic compound and whether it needed to be strongly regulated as a controlled dangerous substance, dispensed in clinics with intense government oversight like methadone.
Those divisions led to further delays.
While the addiction uses were being studied, executives at Cowan and Lewis’ firm, Reckitt & Colman, a British household products company, looked for more traditional uses. In 1981, they won approval from the U.S. Food and Drug Administration for buprenorphine to be used as an analgesic for post-operative pain.
Efforts to develop the drug as a substance abuse treatment continued to stall. Meanwhile, scientists at the federal National Institute for Drug Abuse approached Reckitt officials in 1990 about sponsoring clinical trials for the drug, even offering to share the costs.
Charles O’Keefe, a former drug policy official in the Carter administration who now heads Reckitt’s pharmaceutical division, agreed. “It was a very difficult decision for the company to make,” O’Keefe said, explaining that developing addiction drugs is not a popular choice for a pharmaceutical firm. “We made it not on the basis of the bottom line but because it was the right thing to do.”
The firm, now known as Reckitt Benckiser, is best known for producing Woolite, Lysol and French’s mustard. Its American headquarters is in Wayne.
Buprenorphine, unlike methadone, is not addictive, blunts the effects of withdrawal and provides a feeling of well-being, although not euphoria. The result is that people who are on buprenorphine are able to stop taking heroin and, gradually, stop taking buprenorphine as well. “I would never have been able to kick heroin without buprenorphine,” said Odis Rivers, 52, who took buprenorphine for a year, kicking a 28-year heroin habit. “It’s probably why I’m alive today. It took away all those rough, hard feelings.”
Rivers, who now lives in Baltimore, took buprenorphine as part of a nationwide clinical trial at Wayne State University in his hometown of Detroit. For the past two years, he has been attending weekly Narcotics Anonymous meetings.
When it goes on the market, buprenorphine will be taken in pill form under the tongue. Now under review by the Food and Drug Administration, it has been altered to contain naloxone, the withdrawal-producing drug. If addicts take the pill under the tongue like they’re supposed to, naloxone won’t have any effect. If they try to inject the compound, naloxone will make them sick.
Company executives expect the inclusion of naloxone will appease government authorities worried that street addicts will grind up the buprenorphine pill and shoot it up.
Physicians who have been treating addicts with buprenorphine in experimental trials report that beyond showing great effect, the medication is drawing a new kind of heroin addict, one from the upper and middle classes, normally loath to be seen at a methadone clinic.
Unlike methadone, which can only be dispensed at clinics, buprenorphine, if approved by the FDA, may legally be prescribed in a doctor’s office. Congress in 2000 amended the 1914 Harrison Narcotics Act to allow physicians to directly prescribe an opiate. To do so, physicians must receive special training. Organizations offering the seminars, such as the American Psychiatric Association, have reported that the sessions have been standing-room-only.
“It’s the most exciting time ever in the field,” said Paul Casadonte, director of substance abuse treatment programs at the Manhattan Veterans Administration Hospital in New York. Many of his patients who have participated in the experimental clinical trials on buprenorphine are actors, writers, lawyers and stockbrokers. They are anxious, he said, for the drug to be approved so they can continue to take it and stay clean.
Like heroin addiction, alcohol abuse has baffled researchers seeking to find medications to thwart its assault upon the brain.
Donald Elbel, a Texas rancher, considers himself lucky. In 1999, after decades of uncontrolled drinking, Elbel spotted an ad in a local newspaper suggesting he could get help from a brain researcher. At the University of Texas Health Science Center in San Antonio, he met neuroscientist Bankole Johnson, who told him: “You’ll never drink again.”
Elbel was enrolled in a clinical trial testing the drug ondansetron in treating alcoholics like him who started drinking in their teens. Johnson, it appears, was right: Elbel has not had a drop of the stuff since.
His family regards his resurrection as a miracle, he said. “I was on the road to hell,” said Elbel, 47. “I thought God had turned his back on me. I was wrong.”
Long deterred from his dream of being a NASCAR racing driver, Elbel is fixing up an old Camaro and is looking for sponsors. “That’s his dream and I’m going to encourage it with every lick of what I’ve got,” said Joanne Elbel, his wife of 20 years.
According to Johnson’s hypothesis, ondansetron, which is already on the market as an anti-nausea medication for cancer patients, corrects an imbalance in a brain chemical called serotonin in some drinkers, taking away the urge to drink.
Other drugs are being studied for alcoholism. While not a cure-all, naltrexone, sold as Revia, has been found in studies to be effective in preventing single drinks from triggering binges. It reduces craving, scientists said.
Scientists working in a federal study called COMBINE are investigating whether a combination of Revia and Campral, also known as acamprosate, can help addicts to stop drinking.
Naltrexone and Campral seem to be useful in reducing craving and preventing relapses, said Barbara McCrady, director of the clinical division of the Center of Alcohol Studies at Rutgers University in Piscataway.
Naltrexone works by jamming up the brains opiate receptors, blocking pleasure signals. In studies of alcoholics taking naltrexone who were trying to stop drinking, “if they drank, they did not drink as much,” McCrady said.
The California biotech Drug Abuse Sciences also is developing Naltrexone Depot, a form of the drug that is injected but lasts for weeks, designed to overcome alcoholics resistance to taking a daily pill.
Acamprosate, marketed in the United States by Forest Laboratories in New York and under review by the FDA, seems to increase the chances, at least in those motivated to stop drinking, that they wont drink at all, McCrady said.
FDA officials declined to approve the drug for alcohol treatment in July, contrary to industry expectations. Though clinical trials in Europe showed the drugs effectiveness, an American clinical trial produced less convincing data. Company officials were asked to redesign the trial and try again.
Several scientists are seeking to close the gap between their research into addicts brains and treatment for one of the banes of America – cocaine addiction. Cocaine is the second most commonly abused drug after marijuana. There is currently no FDA-approved treatment.
Cocaine, a natural substance found in coca leaves, has a powerful grip on users. Monkeys given unlimited access to the substance have been shown to binge, giving up sleep and any other activity until they die.
Cocaine was placed under extreme legal restrictions in the Harrison Narcotic Act of 1914. Used as a powerful local anesthetic in the early 20th century, it was replaced by its synthetic cousins, Novocain and lidocaine, which deaden local nerves but do not enter the brain as readily.
Cocaine overstimulates brain receptors for dopamine and serotonin, scientists believe, and, over the long term, decreases the number of those receptors. This, they say, causes the depression that follows withdrawal. Sometimes the damage cant be reversed, allowing relapses after long periods of abstinence.
Stephen Dewey, a 42-year-old brain scientist at Brookhaven National Laboratory on the eastern tip of Long Island, has spent more than a decade looking at the brain images of drug addicts. The images are so dramatic and the brain changes so graphically clear that he often shows them to schoolchildren as part of an anti-drug speech.
One night in 1991, he had a thought Vigabatrin, a drug prescribed in Europe for symptoms of epilepsy, might be useful to treat cocaine addiction.
Drugs of abuse elevate levels of dopamine, a chemical messenger in the brain. Vigabatrin controls another brain chemical, GVG, which flips the “off” switch for dopamine. Vigabatrin would elevate GVG (gamma-vinyl gammaminobutyric acid). GVG would shut off dopamine. Addicts, he reasoned, would no longer feel the craving caused by dopamine. As an added plus, vigabatrin was not addictive.
In experiments conducted in his laboratory, rats trained to take cocaine rejected the drug when they were given vigabatrin.
Dewey and executives at Catalyst Pharmaceutical Partners of Coral Gables, Fla., have been meeting with FDA officials over the summer to set up clinical trials with human subjects. “Im very hopeful,” Dewey said.
In Connecticut, Thomas Kosten, professor of psychiatry at Yale School of Medicine, has been working to develop another cocaine treatment – this time, a vaccine.
Immunologic Pharmaceutical Corp., a California biotech startup, developed the vaccine and first approached Kosten in April 1998 to do human studies. The next year, the company sold the vaccine to Cantab Pharmaceuticals plc, a British concern. When Cantab executives sold the rights to the vaccine the next year to Xenova Group plc during a merger, Kosten found himself with his third partner.
The vaccine has been advancing ever so slowly through the various regulatory hurdles that make up the U.S. drug approval process, based on data provided by trials supervised by Kosten.
The vaccine works by binding the cocaine to antibodies on entering the bloodstream, preventing the cocaine from crossing the blood-brain barrier and blocking the euphoric rush caused by the substance.
The vaccine, Kosten said, would be most effective for those drug abusers who are motivated to stop using cocaine. It is possible that someone intent on getting high can override the vaccines binding action by taking more cocaine.
Currently in Phase II of FDA-approved trials, the drug has been tested on eight patients. Six of them reported using cocaine once or twice during six months of follow-up treatment. Two other patients used co caine on a regular basis during that period.
“These are very good results for people who use co caine,” Kosten said. He hopes to enroll a total of 150 patients in the trial over the next few years.
Elizabeth Greetham, chief executive officer of Drug Abuse Sciences, the eight-year-old California biotech firm also working on a drug for alcoholics, said her company also is developing a cocaine vaccine but is waiting to see what happens with the rival product.
“Were waiting to see how it does, sort of as a test case,” Greetham said. “If it does well, then well go ahead. We think weve got better chemistry – a more effective mousetrap, if you will.”
When cigarette smokers inhale, they hold the smoke in their lungs before exhaling. Very quickly, the smoke, like a ghost moving through a wall, crosses through the partition between the air sac in the lung and the blood rushing by. From there it is carried quickly to the brain, where it moves out of the capillary network into brain tissue and finds its destination the nicotinic acetylcholine receptors. The process takes seconds.
Each puff produces a spike of satisfaction in the brain, reinforcing the smoking behavior. Though its complete method of action in the brain is not fully known, it is clear that nicotine creates high levels of dopamine in the brain, like other addictive substances.
Nicotine is metabolized quickly, meaning that the smoker in a few hours will possess only residual levels. Smoking again will bring relief from that withdrawal discomfort.
Scientists at Nabi Pharmaceuticals of Rockville, Md., have started early trials in humans to test whether a tobacco vaccine works to ward off addiction to smoking. The vaccine encourages the human body to make antibodies that will soak up nicotine like a sponge before it reaches the brain.
“By reducing the amount of nicotine available to stimulate the brains pleasure centers, an immunized tobacco user would theoretically receive no positive reinforcement from nicotine use,” said Robert Naso, a vice president at Nabi.
For many, stopping smoking could be the key to renewed enjoyment of life. “I can play my saxophone again,” said Steve Ryden, a Somerville management consultant who quit smoking in May after seeking treatment at a state-sponsored tobacco treatment center in New Brunswick. “It means a lot.”
Copyright © 2002 The Star-Ledger. All rights reserved. Reprinted with permission.