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LE Magazine March 2003

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Medications side effects

The FDA's role

In November 2002, I spoke at the FDA. I met many scientists concerned about these dose issues, but also some who weren't. Overall, the FDA has not pushed the drug industry to provide better dose studies or a range of doses to match patients' differences.

TABLE 8: EIGHT OF THE 11 DRUGS WITHDRAWN BY THE FDA*

SINCE JANUARY 1997 POSED GREATER RISKS FOR WOMEN

Drug Date Usage Date Approved Withdrawn Risk
Pondimin® (Fenfluramine)
Appetite Suppressant
6/14/73 9/15/97 Heart Valve Disease
Redux® (Dexfenfluramine)
Appetite Suppressant 4/29/96
9/15/97 Heart Valve Disease
Seldane® (Terfenadine)
Antihistamine
5/8/85
2/27/98
Cardiac Arrhythmias
Posicor® (Mibefradil)
Cardiovascular Drug
6/20/97
6/8/98
Low Heart Rate in Elderly, Multiple Drug Interactions
Hismanal® (Astemizole)
Antihistamine
12/19/88
6/18/99
Cardiac Arrhythmias
Rezulin® (Troglitazone)
Diabetes 1/29/97
3/21/00
Liver Failure
Propulsid® (Cisapride)
Gastrointestinal
7/29/93
7/14/00
Cardiac Arrhythmias
Lotronex®** (Alosetron)
Gastrointestinal
2/9/00
11/28/00
Impaired Intestinal Blood Flow

* Baycol®, withdrawn in 8/01, may also have affected women more.

** Lotronex® has been re-introduced at a lower starting dose.

Adapted from: Heinrich, J, Director. Health Care-Public Health Issues, United States General Accounting Office. "Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women." Letter to Senators Harkin, Snowe, Mikulski. GAO-01-286R Drugs Withdrawn from Market, Jan. 19, 2001.

The FDA's decisions about drug doses have been criticized even from within the FDA itself. Based on his recent study showing that dozens of drugs ultimately require dosage reductions years after approval, FDA officer James Cross stated in September 2002, "We've seen a lot of situations where drugs are approved by the FDA and subsequent important information about their optimal dose is not determined until afterward."71

Even if the FDA wanted to push the matter, could it? The pharmaceutical industry has the biggest lobby in Washington and is a top contributor to elected officials. With Congress pressuring the FDA to approve drugs faster and faster over the past decade, and the new commissioner vowing to speed approvals even more, the FDA isn't likely to reject drugs for better dose studies. "Making sure the dosages that are used best serve the patients should be near the top of the agenda for regulators and the prescribing community," Dr. Herxheimer insists. "Right now this item seems to be nowhere on the agenda."72

Consequences of a flawed system

The failure of the system is revealed by disaster after disaster. "Discovery of new dangers of drugs after marketing is common," a 1998 study in JAMA declared. "Overall, 51% of approved drugs have serious adverse effects not detected prior to approval."73

Another study disclosed that 20% of all new drugs ultimately require a new "black box" warning, indicating serious or fatal reactions. The study noted: "Serious adverse drug reactions commonly emerge after FDA approval. The safety of new agents cannot be known with certainty until a drug has been on the market for many years."74

How can long-term side effects be minimized? By using the lowest, safest doses. For example, the jury is still out on the long-term safety of statin drugs, but already serious nerve injuries are being reported. A 2002 study found that "people who had taken statins were 4 to 14 times more likely to develop" peripheral nerve injuries (tingling, numbness, shooting or electrical pain, muscle weakness).75 These reactions occur in one in 2,000 users of statin drugs per year. With 35 million Americans projected to take statins, that's 17,500 cases of peripheral neuropathies each year. Discontinuation doesn't always bring reversal. Most important, the risk is cumulative: the higher the dose, the greater the risk.

Doctors and the drug industry

Some doctors are terrific. Some aren't. But even good doctors often don't have all of the information you'd like in order to make good dose decisions.
Doctors ultimately decide which drugs are successful, so doctors are in a position to demand better drug information, a wider range of drug doses to fit patients and better information about non-drug alternatives. Doctors can play a pivotal role, but so far they haven't demanded anything. Many doctors aren't even aware that a problem exists.

TABLE 9: WHY DON'T DRUG COMPANIES PRODUCE DOSES THAT FIT INDIVIDUALS?
1. COST:
Good dose studies cost a little more.
2. TIME:
Good dose studies take a little more time, placing a company at a disadvantage versus its less diligent competitors.
3. UNREPRESENTATIVE POPULATIONS:
Women and seniors are often underrepresented in dose studies. A 2001 GAO analysis found that 78% of subjects in dose trials are male.
4. STUDY DESIGINS:
Drug companies prefer to study serious disorders because they are more stable and measurable. Serious disorders usually require potent doses. When marketed, these same doses are often prescribed for milder disorders that don't usually require such potent doses.
5. LESS INVENTORY:
Fewer doses cost less to manufacture.
6. EFFECTIVE ADVERTISING:
Higher doses produce higher efficacy rates, which makes great advertising that influences doctors.
7. EFFECTIVE MARKETING:
Simplicity sells. Doctors like one-size-fits-all drugs because they
are easy and quick to use.
8. WEAK FDA REGULATIONS:
FDA definitions of "effective and safe" do not ensure that the
lowest, safest doses are marketed.
9:FDA ANALYSIS: Fearing long delays if a drug is denied, drug companies use
strong doses to ensure that the efficacy passes FDA analysis.
10. NO PUBLIC PRESSURE: The public isn't aware of the side effect epidemic or that most
side effects are dose-related, so it doesn't demand change.
11. NO ACCOUNTABILITY: The drug industry isn't required to pay the billions for the extra
doctors' visits, prescriptions, ER visits and hospitalizations from dose-related side effects.
12. BASIC ECONOMICS: With record profits and weak regulation, the drug industry has
little incentive to change.

"There is an informational void about pharmaceuticals in the training of most doctors, despite the importance of the prescription in medical care," stated Harvard physician Jerry Avorn. "Most of those who have looked thoughtfully at this process have been appalled at its inadequacy."76

The result is that doctor's knowledge of medications is less than ideal, which is directly linked to the high rate of side effects. "Much of the morbidity and mortality currently associated with drug therapy is due to well-recognized adverse effects and reflects our inability as health professionals to implement current knowledge fully," Dr. Alastair Wood, Vice Chancellor of Medical Affairs at Vanderbilt, wrote in 1998.77

In my experience, specialists are usually more knowledgeable about drugs that general physicians, but many specialists don't even understand the importance of precision prescribing. One heart specialist told me, "Most doctors don't think about dose-response. They think you either get side effects or you don't." Dr. Herxheimer agrees: "Clinicians rarely think critically about the dose-response relations of the drugs they use."72

Marlene had a serious reaction to Lipitor®, so her doctor switched her to Zocor®. When another reaction occurred, he switched her to Pravachol®. After another reaction, she quit treatment.

"If a medication doesn't work or causes side effects," a pharmacist told me years ago, "most physicians just switch from one to another, then another, then another, until they either find a drug that works, or they or the patient give up. Very few physicians go to the trouble of adjusting drug dosages to fit their patients. Most don't deviate from the drug companies' recommendations."

Marlene was 64 and obviously sensitive to statin drugs, but the doctor never considered simply reducing the dose. Why? I asked Dr. Woosley, who develops medical training programs. "Only about fifteen of the medical schools today teach formal courses in clinical pharmacology, which is the discipline that emphasizes individual variability in response to drugs. This small effort will never counter the overwhelming message from the drug industry that one dosage is all that is needed and everyone will respond nicely without side effects."

The result is that most doctors accept drug company information uncritically. They assume that the drug companies and the FDA have chosen doses carefully and that the recommended doses are right for everyone. They accept incomplete side-effect lists in the PDR as the final word, even when published studies repeatedly say otherwise.

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Most doctors get their drug information from the drug company-written PDR, the 80,000 drug representatives dispatched to doctors offices, the drug advertising that fills medical journals, drug company-designed studies and drug company-underwritten conferences. Many doctors don't hesitate to accept $500 stipends and fancy dinners to receive drug company-paid presentations. One concerned doctor wrote to the New England Journal of Medicine: "The conflicts are obvious to everyone in the field. Who hasn't sat through a company-sponsored presentation by a well-known colleague without squirming a little at the obvious bias in the discussion?"78 A doctor visiting from Germany, appalled at the overt willingness of doctors to accept drug company goodies, wrote to JAMA, "In the long run this behavior will undermine the respect and trust of physicians and the standing of the entire medical profession."79

Dr. Marcia Angell, former Editor-in-Chief of the New England Journal of Medicine, chided doctors, "It is well to remember that the costs of the industry-sponsored trips, meals, gifts, conferences, symposiums and honorariums, consulting fees, and research grants are simply added to the prices of drugs and devices."80 But many doctors eagerly accept these freebies. As one doctor wrote to me, "Physicians as a group have an amazing capacity to rationalize their own greed."

Some doctors are rightfully concerned, but not near enough. "Many physicians have grown accustomed to industry-subsidized education and now resist paying even modest amounts to attend classes" offered by unbiased medical centers, the Wall Street Journal reported recently.81

Yet, if you bring your own ideas about drugs and doses to your doctor, don't expect a warm reception. Many doctors get defensive, even hostile, when patients question their methods. If there's any area that defines doctors, it's their ability to prescribe drugs. They are the experts, and too often they choose to defend their turf rather than expand their minds.

"Doctors don't like to be challenged," a pharmacist wrote to me. "One doctor was prescribing Paxil® well above the highest recommended dosage. When I asked him about it, he said, "Are you a doctor? Who are you to be telling me what to do!"

Indeed, some doctors have difficulty admitting even common side effects listed in the PDR. Being defensive doesn't strengthen doctor-patient relationships. More and more, doctors are perceived as pill pushers and as defenders of the medical-pharmaceutical machine instead of their own patients.

This perception is enhanced when drug companies can so easily convince doctors to prescribe new drugs even when older, better-known drugs are equally effective. For years, the FDA has warned doctors against using new drugs unless a patient has a specific need. Dr. Janet Woodcock, Director of the FDA Center for Drug Evaluation and Research, has stated, "The sad truth is that, even after all the clinical development that occurs with every drug and even after drugs have been approved for a time, we only have a crude idea of what they do in people."82 With the FDA approving drugs faster than ever, the American public is frequently the world's first population to try out new drugs.

Yet, doctors repeatedly make new drugs bestsellers within months. Drug reps fill doctors' cabinets with "free" samples, knowing that if patients do well on them, they won't want to switch. Drug advertising seizes upon any difference, no matter how trivial, to sway doctors to prescribe expensive new drugs with no track records, and doctors readily oblige. You'd think that after recent disasters with Baycol®, Rezulin®, Lotronex®, Duract®, Redux® and Fen-Phen®, doctors would learn, but they keep prescribing new drugs like Clarinex®, Nexium® and Bextra® at greater risk and cost. These repeated problems compelled Drs. Marcia Angell and Arnold Relman, another former Editor of the New England Journal of Medicine, to warn, "Few Americans appreciate the full scope and consequences of the pharmaceutical industry's hold on our health care system."83

One healthcare observer wrote to me: "The root cause is the physician, his lack of knowledge or intellectual curiosity. The pharmaceutical companies are trying to make a buck anyway they can, and it is up to the physician to have the fortitude to resist." He has a point. Doctors can't have it both ways. They can't be objective advisors to patients while being so reliant on drug company data and accepting of drug company influences.

Such reliance explains why people today make more visits to alternative practitioners than mainstream doctors. It explains why mainstream doctors remain largely unaware of proven-effective alternatives like omega-3 oils for reducing inflammation and sudden cardiac death, policosanol and inositol hexanicotinate for reducing cholesterol, or the importance of coenzyme Q10 for people taking statins. It explains why mainstream doctors continued to make Premarin®, with its conjugated horse estrogens, a top-seller for decades although many types of human estrogens (estradiol, estriol) were available.

It explains why, despite hundreds of studies in medical journals, most doctors don't know anything about magnesium's essential role for normal blood vessel functioning or that 80% of westerners are deficient in magnesium. By balancing calcium, magnesium is a safer, natural, much less expensive way to help reduce blood pressure than the prescription calcium blockers for which doctors write $4 billion in prescriptions each year, yet few mainstream doctors know about it.

Without drug-company backing, vital information about lower drug doses and non-drug alternatives can take years or decades to permeate mainstream medicine. That's why I wrote Over Dose: The Case Against The Drug Companies, to expose the problems in the medical-pharmaceutical complex while providing low-dose and other important self-help information to patients and doctors. That's why, despite its revelations about the drug industry and mainstream medicine, the Journal of the American Medical Association, Publishers Weekly, Booklist, Mensa Bulletin and everyone else-have strongly recommended the book (see reviews at www.amazon.com).

To begin bridging the information gap in mainstream medicine, I'm also launching a free electronic newsletter and a series of inexpensive booklets with evidence-based information for patients and their doctors. You can sign up for my upcoming newsletter or obtain my first booklets (Magnesium for High Blood Pressure and Magnesium for Migraine Headaches) at www.MedicationSense..com. If we are to improve our medical care and end the side effect epidemic, we have to make all doctors integrative practitioners. To do so, we have to develop new mechanisms for getting good drug and non-drug information to mainstream doctors.

What you can do

If you are doing well on a medication, that's good. That's the goal: receiving benefit without side effects. But if medications are causing problems, or if the next time you need a medication you want to minimize the risk, you need to inform yourself about the lowest, safest doses. Do not reduce doses without your doctor's guidance. Undertreatment can have serious medical consequences.

Hopefully, you have a doctor who recognizes the importance of precision prescribing. Some do. Following my 1999 article in Newsweek,84 one doctor wrote to me, "I have always found that patients do well on low, 'subtherapeutic' doses, which are not just placebos." Another wrote, "As a physician who is a patient with a chronic illness, I can tell you from my vast experience that the doses in the PDR are often way off."

If your doctor, like most doctors, isn't aware of the low-dose alternatives, what can you do? Inform yourself. The day when you could rely on doctors to provide all of the important drug information is long gone. Doctors have less time than ever to read medical journals or to search the medical literature. You can access it yourself at www.PubMed.org, established by the National Institutes of Health. People spend a lot of time researching an auto or stereo purchase; they need to do the same for their own bodies.

You have a right to be informed

The American Medical Association's Code of Medical Ethics states:
"The patient's right of self-decision can be effectively exercised only if the patient possesses enough information to enable an intelligent choice."85 What is "enough information?" Surely, if a lower dose is effective, you have a right to know about it. If you are prescribed a standard dose of a drug without being told about an effective lower dose, you haven't received informed consent. If the standard dose has done major harm, you may have grounds to sue.

Higher doses are certainly appropriate sometimes. Emergencies and acute situations demand immediate relief. However, 90% of office visits aren't for acute problems, but for minor or chronic conditions. There's time to match doses to individuals. There's time to start with a lower, safer dose and then to adjust upward, if necessary. You are paying the bill and taking the risk, so you have a right to be fully informed about the options.
The low-dose method is especially fitting for:

Older people
Small people
People with multiple medical conditions
People taking multiple medications
People with histories of medication sensitivities
People wanting to minimize costs
People wanting to minimize risks

The "start low, go slow" approach may take a little more time initially, but it saves a lot of time (and money) in the long run. Some people will get surprisingly good results with a low dose and never need higher doses. Some won't, and the dose will need to be increased. Even then, they are assured that they are getting exactly what their bodies need.

Not everyone opts for the low-dose approach. Some people know that they aren't sensitive to medications. With such people, starting with standard doses is valid. Indeed, some people seem resistant to drugs and require very high doses. The key is to match the dose with the person. Ultimately it doesn't matter whether you need a low dose or a high dose-what matters is that you get the right dose for you.

CURRENT BOOKS/BOOKLETS BY DR. COHEN

Over Dose: The Case Against The Drug Companies. Prescription Drugs, Side Effects, and Your Health. Tarcher/Putnam, New York: October 2001.

Magnesium For High Blood Pressure (Hypertension): The Complete Guide To Using Magnesium To Help Prevent and Treat High Blood Pressure Naturally. Del Mar, CA: 2002. Books available at: www.medalternatives.com

Magnesium for Migraine and Cluster Headaches: The Complete Guide To Using Magnesium To Prevent and Treat Migraines and Cluster Headaches Naturally. Del Mar, CA: 2002. Books available at: www.medalternatives.com

Doing so requires good dose information and a range of drug doses. If anything, the drug industry is providing less of each. The irony is that other industries not only recognize the differences among people, they capitalize on it. They produce cars, clothes, cosmetics and all kinds of commodities in vast arrays to match individual sizes and needs. But with its monopolistic patents and sway over doctors, the drug industry can do what it likes and charge what it wants.

In 2001, 3.2 billion prescriptions were filled in America-12 prescriptions for each man, woman, and child. Forty-six percent of adult Americans take a prescription drug every day. Each year, drug sales increase 25%.86 And medication side effects remain a top killer. How can we restore sanity to this system? It will have to begin with you.

You are paying the bill and taking the risk, so you have a right to ask questions and to request better information. You have a right to ask your doctor why he's selecting a specific drug at a specific dose. Are there lower doses that work? What is his source of information? We must require doctors to explain their decisions, to think about their choices, and to consider other sources of information.

Most people don't like taking medication. If they must take it, they want to use as little as possible. When I offered the low-dose approach to patients, most opted for it, side effects dropped dramatically, success rates climbed, patients were pleased and so was I. Most side effects are avoidable. The side effect epidemic can be halted. And everybody wins. But the current system is entrenched, so change is going to have to begin with us.

Continued on Page 6 of 6

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