Take Two And Cross Your Fingers

[Guest guest]

Take Two And Cross Your FingersAmericans swallow close to 1 billion prescription drugs a year . . . for conditions they weren't designed to treat. Some call it smart medicine. Others? A huge gambleBy: Bill Gifford, Photographs by: Manno

Napier still doesn't know what made him go down to the basement that day 3 years ago. Was it the pain, he wonders, or was it the pill?

He had always been athletic, competing in the Highland Games, a traditional ish athletic festival that includes hammer throwing, stone lifting, and "haggis hurling," all performed while wearing a kilt. But as he entered his 30s, his back began to betray him, perhaps due to a motorcycle crash in his 20s. He went through two surgeries, numerous cortisone injections, and bottle after bottle of prescription painkillers. But nothing worked very well.

The pain was so bad he had to quit his job as a diesel mechanic. He couldn't even play with his daughter for more than a few minutes before he'd have to rest. Despite it all, he stayed positive: "Pain is inevitable," he would say, "but misery is optional."

Then one day he came home in a black mood. He told his wife to leave the house--take their daughter and go to the store, or wherever--and he stalked down to the basement. That was where he kept his rifle. He heard the front door slam and thought he was alone.

But then he heard something from upstairs: his daughter, screaming. She was refusing to leave. "She knew what was happening," Napier says now. He put the gun down and lay there on the basement floor, crying.

Not long afterward, Napier saw a TV commercial about a drug linked to severe depression and suicide attempts. He perked up at the name: Neurontin.

A year earlier, his doctor had put him on Neurontin, an epilepsy drug that some physicians also prescribed for nerve pain. The commercial gave a lawyer's telephone number, and Napier dialed it.

Napier's doctor did nothing illegal: Once a medication is approved by the FDA, your physician is allowed to dispense it as he or she sees fit. This makes a certain amount of sense. To gain FDA approval, a drug company must prove that its product is both safe and effective--a process that can take several years, tens of millions of dollars, and multiple major studies. If, after all that energy and expense, the FDA says a medication can safely treat condition X, why not let doctors prescribe it to try to remedy Y and Z, too?

When a drug is used this way--that is, for something other than what's listed in the package insert--it's called an off-label use. The classic off-label drug is minoxidil, which began life in the 1970s as Loniten, a pill for treating high blood pressure. Patients taking Loniten began reporting an unusual side effect: hair growth. It wasn't long before some ingenious pharmacist began crushing Loniten pills and dissolving them in a solution that balding men could then rub onto their scalps. Minoxidil is now a baldness treatment named Rogaine, available at your local CVS for $25.

If there's a lesson here, it's that drugs generally work across a wide range of body systems, often in ways even their makers don't understand. For example, another class of blood-pressure-lowering medications, known as beta-blockers, have been used off-label for years to quell stage fright. That's logical, since beta-blockers work by lowering the heart rate. Older SSRI-class antidepressants such as Zoloft and Prozac can help control premature ejaculation. The antianxiety medication Xanax has been found to relieve irritable-bowel syndrome, of all things. Ritalin is used to combat fatigue. And so on.

These kinds of off-label uses are so common they're routine. Exact figures are difficult to pin down, but most sources estimate that one in four prescriptions in the United States is written for an off-label purpose. With total annual U.S. prescriptions over 3.6 billion, that works out to almost 1 billion off-label prescriptions in 2005. It's a staggering number of scripts, and some would say evidence of how essential off-label drugs are for treating patients--and for advancing the art of medicine.

"Where do we get leads for new and exciting uses for drugs?" asks J. McCaffrey III, R.Ph., Ph.D., director of the center for pharmaceutical marketing and management at the University of Mississippi. "Physicians provide many of them."

Nor do these accidental pioneers seem to have any qualms about acting without the official imprimatur of the FDA. Some even see off-label prescribing as a matter of upholding their Hippocratic oath. "In many cases, you would be negligent to wait for the FDA before treating someone with a drug that you know will work," says Bransfield, M.D., a board-certified psychiatrist in Red Bank, New Jersey, who often relies on off-label drugs to help the patients in his practice. "When something receives formal approval, it's often very much after the fact, and everybody's known about it for years."

Still, off-label prescribing comes with undeniable risks. Once your physician departs from FDA guidelines, he--and you, the patient--may be sailing into a foggy sea, with little solid research to guide the way. Very often, off-label drug uses are supported only by very small, uncontrolled studies--or, worse, by anecdotal physician experience. In fact, a new study in the Archives of Internal Medicine reveals that nearly 75 percent of the drugs prescribed off-label in 2001 had "little or no scientific support" for their use. One of the worst offenders was gabapentin. The researchers singled out gabapentin for the disturbing disparity between how often it was used off-label (83 percent of gabapentin prescriptions written--more than any other drug) and how few of those prescriptions were backed up by sound science (just 17 percent). Gabapentin's brand name: Neurontin.

"Off-label drug prescriptions without scientific data aren't necessarily dangerous situations," says Randall Stafford, M.D., Ph.D., the lead study author and an associate professor of medicine at Stanford University. "But there are situations in which our knowledge is really limited, and that creates the potential for safety issues."

And that risk, argue other experts, raises ethical issues. "Off-label use, to a large extent, is medical experimentation on patients," says Maxwell Mehlman, J.D., a professor of law and bioethics at Case Western Reserve University. "Yet it's conducted without any of the protections of human experimentation. How does a doctor know it's safe and effective without a large, comprehensive study? They're essentially just trying it out."

Often, doctors turn to off-label drugs as a last resort. This is what happened to Bill , a 51-year-old sales manager who had suffered from frequent severe headaches since his teens. Over the years, he had tried everything: He gobbled aspirin and Tylenol to control the pain, and gave up headache triggers like alcohol and caffeine. He used Frova, Imitrex, and Depakote, all drugs commonly prescribed for migraines. He even tried Neurontin, which was thought (at one point) to have some beneficial effect. None of it worked. His worst headaches, he says, "were showstoppers."

He ended up at the Atlanta clinic of E. DeRossett, M.D., Ph.D., who ran through everything she could think of and finally prescribed Botox injections, every 3 months. With each course of treatment, 's condition steadily improved. "I'm lucky," he says. "My doctor was a real problem solver."

Botox, or botulinum toxin, is of course best known for reducing wrinkles in aging Hollywood actors. But in the mid-1990s, a surgeon also noticed that his patients reported fewer migraines. "Current theories suggest that Botox prevents the release of pain neuro-transmitters and inhibits inflammation," says Dr. DeRossett. Allergan, the maker of Botox, is now running trials aimed at winning approval as a headache treatment.

In this regard, Allergan is unique. Drug companies have few incentives to pursue additional approval in the United States, since by the time the required studies are finished, their marketing exclusivity (typically 3 to 10 years) could be close to expiring. The situation is slightly better in Europe, where drug makers who apply for a new usage receive a patent extension of a year or more.

If Allergan hopes to recoup its investment before generics jump into the fray, it'll have to begin a marketing barrage the instant FDA approval is granted. Until then, you won't see a single ad touting Botox as a migraine medicine. "A company cannot promote an off-label use of a product," says FDA spokeswoman Alvey. On one level, this is a good rule: Manufacturers can only make claims they've proven beyond a whiff of scientific doubt.

Go to the next page to read how the FDA's rules have affected off-prescribing...

But government rules have also blocked the flow of useful information to doctors--and, ultimately, to you. This is what happened with the most widely used medication of all: the humble aspirin. In 1988, scientists discovered that a low daily dose of aspirin helped prevent heart attacks. When aspirin makers started promoting this lifesaving finding, the FDA cracked down. Preventing heart attack was an "unapproved use" of aspirin, said the FDA (which also regulates over-the-counter drugs). By the time aspirin was finally approved for preventing heart attacks in 1998, an estimated 50,000 to 100,000 Americans had died because they didn't know about the benefit, according to the American Heart Association.

On paper, the FDA still prohibits off-label drug promotion in any form. But in reality, its rules are easily evaded by pharmaceutical sales reps. In 2000, a federal court found that the FDA rules infringed on drug companies' right to free speech. So while regulations still prohibit off-label promotion to the public, companies are allowed to distribute studies to doctors, as long as the studies have been published in a peer-reviewed journal. What's more, doctors can discuss off-label uses with other doctors--something that often occurs at medical conferences. The result, says a Washington, D.C., lawyer who represents drug manufacturers and wishes to go unnamed, is that "the FDA has ceased to be a factor with regard to unapproved uses."

But even before this shift, the temptation for drug companies to pad their profits by influencing prescribing patterns was huge: Off-label sales can turn a humdrum drug into a billion-dollar blockbuster, which is what happened to Neurontin.

The FDA approved Neurontin in late 1993, for use in conjunction with another medicine to treat a narrow class of epilepsy seizures. And while it did fairly well in its early years, Neurontin was far from a home run.

At the time, Parke- needed a profitable drug, in part to help fund two other product launches. Two Neurontin competitors--Depakote and Tegretol--were already being used off-label for bipolar disorder and for pain. Parke- considered seeking FDA approval for those indications as well, but decided against it. According to court documents, conducting large studies was deemed too expensive, and Neurontin's patent protection was set to expire in 1998.

Instead, beginning in the mid-1990s, Parke- began aggressively marketing Neurontin for off-label uses--illegally, say government prosecutors. During this time, Parke- began funding small studies designed to demonstrate how Neurontin could treat bipolar disorder, anxiety, depression, and pain, among other conditions. Because sales reps were not allowed to discuss off-label uses with doctors, the company hired "medical liaisons," physicians paid as much as $250,000 to talk up off-label uses of Neurontin to other doctors. "When we get out there, we need to kick some ass on Neurontin," a sales manager exhorted the liaisons in a voice mail. "We want to sell Neurontin on pain."

Even though Neurontin hadn't been approved for pain, bipolar disorder, or anything besides seizures, the marketing campaign worked brilliantly, and a minor epilepsy drug grew into a monster. In 2002, Pfizer (which had bought Warner-Lambert, which had bought Parke-) sold $2.1 billion worth of Neurontin. Ironically, Neurontin was never the treatment of choice for epilepsy, according to Columbia University neurologist Karceski, M.D., because it had to be taken three or four times daily, rather than once or twice, like other meds. But doctors kept prescribing it at a terrific pace for almost everything else; by 2002, nearly 94 percent of Neurontin prescriptions were off-label.

Neurontin's long reign ended soon afterward, in May 2004, when Pfizer pleaded guilty to two felony charges of illegal drug promotion and paid $430 million in fines and damages. The Neurontin sales force had the last laugh, however: That same year, Pfizer moved $2.6 billion worth of Neurontin.

Go to the next page to read about how Neurontin affected Bill Young....

Bill Young wasn't laughing. and unlike Napier, he didn't put the gun down.

When Young, a 54-year-old insurance appraiser in upstate New York, started taking Neurontin for his bipolar disorder in 2001, his doctor assured him that he was getting "state- of-the-art treatment." The only problem was that the medicine made him feel bad: listless, numb, detached. He called his doctor's office, only to be told to increase his dosage. Young ignored that advice but kept taking the Neurontin; he knew how bad things could become if he didn't take any medication.

As it turned out, his doctor was off base. A clinical trial published in Bipolar Disorders in 2000 showed that Neurontin was no better than a placebo at treating bipolar disorder. And although that study was funded by Parke-, Young's doctor didn't seem to have read it--or the research tying Neurontin to depression and suicidal thoughts.

And so, after nearly a year on Neurontin, Young went to his basement, took out a shotgun, put the barrel in his mouth, and pulled the trigger.

Miraculously, he missed: The gun jumped, and the shotgun blast blew out his right cheek instead of his brain. "I didn't think about it, didn't plan it; it just happened," he says. "I'm very lucky." Three years and several plastic surgeries later, he says, "that whole period in my life is a blur."

Like Napier, Bill Young is suing Pfizer, and he is extremely wary about taking any off-label drugs--which is understandable, but also wrongheaded. "We don't want to throw out all off-label prescribing; some of it is beneficial," says Dr. Stafford. "But we need to be more alert to situations in which there may not be sufficient scientific evidence."

It's also important that your doctor communicate with you, adds Muzina, M.D., head of psychiatry at the Cleveland Clinic. "When your doctor prescribes something off-label, ask him to review what you can expect--good and bad. And if it sounds like more bad than good, you might want to discuss other options. If he doesn't tell you that, then think about finding a new doctor."

Bill Young, it goes without saying, has a new doctor.

Multipurpose Meds

Seven overachieving drugs for men and whether they're worth taking off-label

DRUG: Cardura XL (doxazosin)

FDA-APPROVED INDICATIONS: Enlarged prostate and high blood pressure

OFF-LABEL INDICATIONS: Kidney stones

BIGGEST DANGER* Priapism (a painful, long-lasting erection), which is a rare side effect

OFF-LABEL EVIDENCE Research published in the journal Hospital Pharmacy found it to be beneficial as a kidney-stone killer.

DRUG: Prozac, Zoloft, Paxil (fluoxetine, sertraline, paroxetine)

FDA-APPROVED INDICATIONS Obsessive-compulsive disorder, anxiety, depression, and panic disorder

OFF-LABEL INDICATIONS Premature ejaculation

BIGGEST DANGER* Manic episodes or seizures in very rare cases

OFF-LABEL EVIDENCE A study review from the Netherlands showed SSRIs to be the most effective treatment for a hair trigger.

DRUG: Parlodel (bromocriptine)

FDA-APPROVED INDICATIONS Parkinson's disease and pituitary tumors

OFF-LABEL INDICATIONS Male infertility

BIGGEST DANGER* Very rarely, a severe headache followed by a seizure, stroke, or possible heart attack

OFF-LABEL EVIDENCE Are you among the 5 percent of men whose infertility is caused by hyperprolactinemia? In that case, consider taking it.

DRUG: Wellbutrin, Zyban (bupropion)

FDA-APPROVED INDICATIONS Depression and smoking cessation

OFF-LABEL INDICATIONS Chronic neuropathic pain

BIGGEST DANGER* A seizure in up to 4 out of 1,000 patients

OFF-LABEL EVIDENCE University of Arizona research shows that it can help erase the ache.

DRUG: Desyrel (trazodone)

FDA-APPROVED INDICATIONS Depression

OFF-LABEL INDICATIONS Insomnia

BIGGEST DANGER* Irregular heartbeat in heart-disease sufferers

OFF-LABEL EVIDENCE A University of Chicago study review determined that the science is sketchy and the side effects are serious.

Your Drug Money

How to arm wrestle your insurance into covering an off-label treatment.

Insurance companies are masterful at squirming out of unconventional claims, such as those for off-label drugs. Still, an initial "Declined" doesn't mean you pay the bill for your pills. "Sometimes simply having your doctor call can get you coverage," says Christin Engelhardt, of the Health Assistance Partnership, an organization that aids in health-insurance negotiations for consumers. No luck? Follow this plan for getting them to fork it over.

Keep written records. Hold on to your "Explanation of Benefits" document and any claim-related correspondence. If the insurer calls, ask for a follow-up in writing. You're looking for evidence that they think the off-label use lacks scientific support. If so, your doctor can appeal with research.

Call expert witnesses. Ask everyone involved in your care--from doctors to nurses to physical therapists--to attest to how your condition has been improved (or cured) by the off-label drug. "The more letters, the better," says Engelhardt.

Mark your calendar. Insurance companies usually specify a time frame during which you can file an appeal, and you must hit that deadline, or the fight will be over before it's begun. In fact, use certified mail to provide a record that has legal weight.

Make persistence pay off. Many appeals are eventually approved if the patient can manage to stay the course, says Engelhardt. Use every possible step in the appeals process, and if all else fails, involve your state insurance department. Go to naic.org for a nationwide list.

http://www.menshealth.com/cda/article.do?site=MensHealth & channel=fitness & category=motivation & conitem=220ab148afd48010VgnVCM100000cfe793cd____ & page=0 & pageLocation=true 2006 RODALE INC. ALL rights reserved

Regards, Vergelpowerusa dot org