Jay Cohen believes he knows what went wrong in Michael Hope's life.
Hope, 56, sits in his home in the San Gabriel Valley and tries to use his brain, an effort of tortuous frustration for a former quick-thinking business executive. Not only does he suffer from constant muscle pain throughout his body, but also from the anguish of short-term memory loss and the inability to command words in simple conversation. When he finally gives up on the word he is trying to think of and attempts a substitute, he has forgotten not only what he has been trying to say, but what the entire conversation was about.
The reason for his Job-like travails? Not a dread disease or an exotic virus from Africa. After years of tests and consultations with doctors, chemists and others, Hope believes he suffers from overdoses of the drug Lipitor, the top-selling prescription drug in America today and a member of the family of drugs--called statins--that are hailed as lifesavers for reducing cholesterol.
Hope took the drug for four years. The dosage was just 10 milligrams per day, the standard dose recommended by the pharmaceutical company. So what's the problem?
The standard dose is the problem, says Cohen, an activist physician and author who has picked a fight with the powerful pharmaceutical industry. Lipitor should have been available in doses of 5 milligrams or even 2.5 milligrams, Cohen says, but he doesn't believe the problem is confined to Lipitor. It also is true for many prescription medicines today, Cohen argues in "Over Dose," his 2001 book that points fingers at people in the medical profession. Standard doses are damaging lives and are linked to the deaths of thousands of Americans each year, he says. Precise numbers aren't known, but Cohen cites a 1998 article in the Journal of the American Medical Assn. that said prescription drugs cause more than 2.2 million severe medical reactions in hospitals and could kill more than 100,000 people a year.
"We have a huge problem with side effects, year after year, decade after decade," Cohen says. "Every family is affected by it. I don't know how many people have told me that their parents didn't die of disease; they died of drugs. The problem is solvable if we just pay attention to it."
Jay Cohen is slight and bookish, a 58-year-old single father who looks like an accountant, not an agitator. His fashionable rustic home blends into a Del Mar hillside and rests on some of the most expensive dirt in California. Prominent among the large light-filled rooms is a study that is book-deep and organized, pointing to a systematic fellow who might develop a rash if his glasses weren't where he left them.
The uncommon breadth of the man is apparent as he proudly shows off his garden, with its splashes of color that would flatter a Costa Rica travel brochure. When he endured his own severe medical afflictions that effectively ended his medical practice in the 1990s, he turned horticulture into therapy and taught himself about tropical plants.
To Cohen, pharmacology is like collecting baseball cards: He does it for fun. However, his dedication is the glitter-eyed intensity of a door-to-door evangelist.
It all started with Prozac. When the drug was introduced in the U.S. in 1988, it held the promise of a new era of depression management--at a starting dose of 20 milligrams. Cohen and many other physicians started using it as a welcome tool to help angst-ridden patients, prescribing it in the recommended strength. But then, several of Cohen's patients started crawling the walls.
The loud-bang imprint on Cohen's mind was from a female patient in her early 30s who suffered from mild chronic depression. "I gave her the recommended dose," he says. "In three days she was psychotic--totally psychotic. But when I stopped the drug, she recovered in a few days." So Cohen lowered her dose, eventually to 5 milligrams, and she did fine. He also lowered dosages for other patients, in some cases by having them dissolve the pill in liquid and drink it over three or four days. It worked, and they got better.
Seeking to understand the experience, Cohen found data that showed Prozac to be effective in much lower doses even before it was released at 20 milligrams. "I found research that shocked me. I thought, 'Wait a minute! If you don't give me the information to do my job right, how can I protect my patients?' I took that very personally."
Life soon got even more personal when, in 1990, he was attacked by a rare vascular disease known as erythromelalgia, and also an autoimmune connective-tissue disease. He spent years immobilized by grinding pain that accompanied every movement. It was impossible for him to walk without tendons from hip to shoulder pleading to stop. In his treatment, he discovered just how personal drug therapy could get. "I tried scores of medications for these illnesses and had many instances where the standard doses were much too strong." So he relied on the lessons learned from Prozac--"to start low, go slow."
Since he could no longer practice medicine, he applied himself to correcting the harm he had observed. He learned to use software that allowed him to voice-activate his computer, and he spent the next decade turning out reams of published material on patient-oriented subjects, including his own disease, on which he became one of the world's few experts. He also has published articles on alternative treatments, especially on the use of magnesium. His research is not the test-tube variety, but mainly consists of delving into dusty, often-ignored medical studies and patient experiences, which when taken together can turn the arcane into the obvious.
Maybe because his illnesses reminded him that the human body is always running downhill, Cohen became purpose-driven; one of the lucky who had found the job he was born to do: "I was fortunate as a child--and I don't say this arrogantly--to be a mathematics prodigy. So this came easy to me, and I found it challenging. I always had a natural interest in pharmacology and seriously considered specializing in it, but I was afraid I'd end up working for a drug company in New Jersey and having to wear a tie every day."
Even though Cohen's health is improving, he has no intention of returning to medical practice as we think of it. "Doing this is where I'm needed," he says of his current work. Recently he formed a nonprofit corporation called the Center for the Prevention of Medication Side Effects through which he will continue to track drugs whose recommended doses he believes are too high.
Over the years, in addition to writing his book, Cohen has lectured at medical schools and health-care conferences, and he has written ceaselessly on the dangers and misuse of prescription drugs. Yet he has drawn little heat from the establishment, in part because the Journal of the American Medical Assn. and other respected publications have favorably reviewed his work.
In the Nov. 6, 2002, issue of JAMA, a reviewer said, "Jay Cohen, MD, long a thorn in the industry's side, has written a highly readable, user-friendly, and well-researched account of a serious clinical issue plaguing the everyday practice of medicine. The problem is over-medication."
Robert Ehrlich is head of DTC Perspectives Inc., a New Jersey pharmaceutical publishing company. He formerly was vice president of consumer marketing for Parke-Davis, the company that developed Lipitor. He says pharmaceuticals limit dosages to the ones that fit the needs of most patients. "Otherwise, a multiplicity of choices would be confusing for patients and too time-consuming for doctors."
Has Cohen overstated his case? "If the problem is serious side effects, probably. I think his basic premise is fair. I think he's right that they should offer lower doses; I don't think he's right that there's a big risk to society in the doses they do offer." A potential risk of Cohen's theory, he says, is that if doses are too small to be effective, then patients might stop taking medications.
Jim Dickinson, publisher of "Dickinson's FDA Webview," a watchdog publication in Camp Hill, Pa., known for being evenhanded, has watched Cohen's work closely. "I think everybody agrees he's right. It's obvious to everybody that the ax he's got to grind is not for anything but a noble cause."
The "cause" Dickinson refers to is eliminating a practice followed in the drug-approval process whereby companies submit drugs at higher dosages than they need to be. "When they do that, they're playing Russian roulette with the patient," Dickinson says. By opposing those practices, he explains, Cohen "has had a very beneficial effect. I commend him."
The process starts to go wrong, Cohen says, the moment the idea of a new drug is developed by a pharmaceutical company. To gain FDA approval, the company must demonstrate that the drug works against whatever ailment it targets. They do not have to show that it is better than existing similar drugs, but only that it is more effective than a placebo, which is another name for a fake pill. Consequently, Cohen says, it behooves the company to put its new drug through clinical trials at a strong enough dosage so as to take no chances that the FDA will find it insufficiently effective. And since the FDA can only approve dose levels that the company submits, the frequent result is that a recommended dosage of, say, 10 milligrams is put on the market rather than maybe 5 milligrams, which might better serve many people who can't tolerant the higher amount.
Dr. Karen Lasser of Cambridge Hospital and Harvard Medical School says that in the pre-market trials, drug companies usually recruit younger, healthier people for their studies. "The patient who ultimately takes the drug may be elderly and on 10 other medications, but those patients tend to be excluded from the trials," thus the dosage being tested may be far too strong for eventual users.
Even if the drug company later goes back to the FDA and seeks authorization for a lower level, the original dosage already may have sunk in with physicians. Pharmacologist Joe Graedon, author of "The People's Pharmacy," agrees that it is not unusual for drug companies to select a high dose based on early research. "It's a fast way to get [FDA] approval. The name of the game is to get your drug on the market as soon as possible, even though it may not be the proper strength for a diverse population. Sometimes they will come back later and apply for other doses. However, physicians get in the habit of prescribing the original dose."
The whole drug-marketing game, Cohen says, is to make sure that a new drug can be shown to outperform competitive drugs already available, and the way to get results fast is to make the dosage strong, as in, "Gee, doctor, I've only been on the drug three days and already I feel a difference. Thanks."
He says that pharmaceutical companies will research a drug in variable doses, and when they find the one they consider most marketable, they drop all other findings. Then they publish the preferred result in medical journals, hand it to doctors and advertise it widely.
"When you're designing your own studies, you can prove almost anything you want," Cohen says. "Companies have learned that if you want a doctor to switch from, say, Motrin to Bextra, you've got to be able to give a reason--it works better, it's stronger, it helps more people. They've got to find an edge, so you use a stronger dose, you get a better result, but you also get side effects, but they don't worry about that." That's why you see so many ads on TV for new drugs, he says. The companies want you, the patient, to go into your doctor's office and ask about it, thus greatly increasing the chances of having it prescribed.
And if the dose is strong enough, the bang will be quick and dramatic, even though trouble may arise down the line. Patients love those quick results, and doctors know it, Cohen says. Rather than patiently inch the dosage up to just what the patient needs, the doctor--who already relies on drug companies for guidance--will prescribe a higher dosage that will bring surefire results, but sometimes much more in the form of side effects, some mild, some serious. Of a very common side effect, Cohen says, "If it's someone else's diarrhea, it's no big deal, but if it's yours, it's a big deal."
Cohen also believes that drug companies exert far too much influence on the drugs doctors choose for treatment. He says physicians must bear part of that blame simply because they often lack basic knowledge of pharmacology and instead fall back on what drug company salespeople advise: "The standard medical school requirement is for one course in pharmacology in the second year, before the student has seen even one patient. That's it! One course. When a physician enters practice, he is at the mercy of drug companies." Most doctors, he says, get about 95% of their information from drug companies--sales reps, seminars, advertising and samples. Even the book they use, the "Physician's Desk Reference," is written by the drug companies.
Others agree. Lasser says, "The reason many doctors go to pharmaceutical companies for drug information is that it's easier: The drug reps are there, they're smiling, they're paying for lunch and handing out free samples."
The free samples are a particular problem, Cohen says. "Why are doctors given samples to hand out?" Cohen asks. "When you're trying to get your drug positioned in the market, how do you do that? You advertise the hell out of it. You get doctors who will speak positively about it. You give them stipends for going to seminars in nice places with golf courses. And then there are those free samples. It's a freebie, and when the doctor gives it to a patient, the patient says, 'Gee, thanks.' "
As an example, Cohen compares Nexium, the new stomach-acid controller, to Prilosec, which is virtually identical and for which a generic is available for a price about 10 times less. But once a patient tries Nexium and is doing well, he's not going to want to switch, Cohen says. "Every dollar that goes into these 'me-too' drugs that are virtually the same as existing drugs is a dollar that is bled out of the health-care system. Drug companies are looking for their profits and will squeeze it every way they can."
Cohen is talking to the Democratic Club of Solana Beach, an affluent suburb of Del Mar. The audience of 20 or so are Birkenstock-shod McGovern types who kept the faith. Cohen has been talking for more than an hour, and aging bladders notwithstanding, the audience hangs on every word. This guy is smart, a believer, articulate in a professorial way, and he's talking about something even more important than Bush's tax cut: their health and the drugs that repose, even as he speaks, in pillboxes in each of their bathrooms. His points are as known to him as his name, and he glides through them:
* About 75% to 85% of all side effects are dose-related, which means the drug might be fine, but the dose might be wrong for you. Doses must be individualized, which means that in most cases, the doctor should start you on the lowest dosage and gradually increase it to its desirable level. "Doctors are giving the same dose of a powerful anti-inflammatory to Shaquille O'Neal for his arthritic toe as to Ally McBeal for her tennis elbow, and that's insane. Vets or farmers will tell you that they adjust doses for the size of animals, so why don't we do it for people?"
* One danger of overdosing is that many patients will simply stop taking drugs because of unacceptable side effects. How many people have died of heart attacks because they couldn't tolerate the medications that might have kept them alive?
* Twenty percent of drugs on the market underwent dosage changes after their introduction. Eighty percent of those were reductions.
* Ultimately, drugs are a business. Doctors and scientists don't call the final shots, marketers do.
* When severe side effects occur, most doctors just switch medications. Instead, why don't they try reducing dosages?
In a later conversation, Cohen is asked to name the drug groups he believes are most frequently prescribed at excessive doses. He begins with the caveat that they are all good drugs when used properly, but then ticks off four:
* The statins, particularly Lipitor, Zocor and Crestor; the standard starting doses are too strong for the millions of users with mild-to-moderate elevated cholesterol.
* Antidepressants, particularly in the same family as Prozac, Zoloft, Paxil, Celexa and Effexor. These drugs are notorious for causing many side effects such as agitation, insomnia, weight gain and sexual dysfunctions. These are all dose-related.
* Anti-inflammatories, especially Celebrex and Bextra. Celebrex is the top seller and Bextra is the newest fast-selling one. Both are very strong. Both are one-size-fits-all for their primary use, osteoarthritis. Celebrex is recommended by the manufacturer at 200 milligrams, and Bextra at 10 milligrams. The data show, however, that half doses of each are highly effective. Anti-inflammatory drugs cause more injury and death than any other group of drugs. Every medical authority urges the use of the lowest effective doses of these drugs, but with Celebrex and Bextra, the lowest, safest effective doses aren't available.
* Premarin and Prempro, which are hormones for menopause. Recent studies have linked these drugs to cancer, causing havoc for menopausal women. The untold story is that the estrogen dose that was studied, 0.625 milligrams, was actually half of the recommended dose, 1.25 milligrams, that was urged on women from 1964 through 1999. How much harm did the higher dose cause? No one knows.
Although Cohen realizes how daunting it is for a patient to confront a doctor, he believes patients must become more assertive about drug treatment. And, increasingly, they have more resources to do so as solid information written for the laity proliferates on the Internet and elsewhere.
"First, patients must tell their doctors if they've had past problems with side effects, and then insist they would rather start with the lowest effective dose of a drug," Cohen says. "Doctors hear a lot of dumb questions, but they're also trained to respond to the informed patient who insists on being the guardian of his or her own health."