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LE Magazine March 2003

Medications side effects

Exceptions

There are some drugs for which the low-dose approach does not apply. For example, antibiotics, antifungal and anticancer drugs should be used at full doses. These drugs are not targeting you, but invaders that can be made stronger if inadequate doses are used.

The elderly

"The overall incidence of adverse drugs reactions in the elderly is two to three times that found in young adults," states the New England Journal of Medicine.38 Although people over age 60 comprise 19% of the population, they account for 39% of all hospitalizations and 51% of all deaths related to medication reactions.39

Seniors metabolize drugs more slowly than younger people, so they are frequently more sensitive to their effects. That's why gerontologists recommend extra caution in treating seniors and starting with low doses (Table 6). Yet, for scores of top-selling drugs, drug company guidelines tell doctors to use the same strong doses for young and old. Even when we know that blood levels of drugs rise much higher in seniors, doctors are told to ignore this fact and prescribe the same doses.

For example, Allegra® blood levels rise 99% higher in seniors versus younger adults. Claritin® rises 50% higher. Blood levels of top-selling antihypertensives Zestril® and Prinivil® rise 100% higher. Blood levels of Prilosec® and Nexium® are higher in the elderly. Yet, the recommended doses of all these drugs are the same for young and old.7

The Celebrex® package insert tells us "the incidence of adverse experiences tended to be higher in elderly patients." Yet no dosage adjustment is recommended. Blood levels of Lipitor®, Zocor® and Mevacor® rise higher in seniors.40 In fact, the Lipitor® package insert tells of "a greater degree of LDL-lowering at any dose in the elderly patient population compared to younger adults."7 So seniors should need less Lipitor®, but they are dosed the same as younger people. Could this be why so many reports of cognitive and memory problems in older people taking statins are being reported?

The FDA itself states, "There is evidence that older adults tend to be more sensitive to drugs than younger adults, due to their generally slower metabolisms and organ functions. The old adage, 'Start low and go slow,' applies especially to the elderly."41 Yet the FDA keeps approving drugs at identical doses for young and old. Perhaps this explains why 9% of all hospital admissions for seniors are related to side effects from standard doses of prescription drugs.42

Women

In summer 2002, two studies caused alarm by revealing increased risks of cancer and heart disease with Premarin® and Prempro®, the top-selling hormone replacement therapies (HRT) for menopausal women.43,44 The dose of estrogens in these drugs: 0.625 mg. But we've known for years that lower doses of Premarin® (0.3 mg) and other estrogens are often effective and cause fewer risks.45-48 Might these doses be safe enough today? Quite possibly, but the studies ignored this obvious question, leaving women in the lurch.

The studies also didn't mention that from 1964 through 1999, the recommended dose of Premarin® for hot flashes was 1.25 mg. How much cancer did this double dose cause? Why was such a strong dose approved in the first place? These questions weren't answered.

A similar pattern was seen with birth control pills. The hormone doses in the first pills were 300% to 1000% higher than in today's pills,49-52 yet it took decades-and hundreds of women's lives-before high-dose pills were withdrawn and replaced with today's lower doses.

Similar problems are seen with other medications. A study of ibuprofen for menstrual pain showed that 44% of women did just fine with the 200 mg over-the-counter dose, but the researchers still recommended 400 mg for all women.53 Studies of cholesterol-lowering drugs show that many women respond to lower doses,54-57 but they are routinely prescribed the same doses as men.

Side effects with antihypertensive drugs occur more often in women,58,59 which, according to the American Journal of the Medical Sciences, "could be due to the fact that women are treated with antihypertensives using the dosage and schedule established with men, even though it is well known that body size, fat distribution and coronary artery size differ in women and men."59

Not all women require lower doses, but many do, especially small women. Why aren't doses developed for them? A 2001 report of the U.S. General Accounting Office found not only that women are underrepresented in the dose studies, but even when dose differences are identified, they usually aren't reflected in the final dosage guidelines.60 A 2001 report by the National Academy of Sciences recommended additional attention to differences between men and women in diseases and treatments.61 The panel's report added that medical researchers often view men as the norm while underreporting rather than highlighting sex differences. Commenting on this report, Dr. Woosley added that many drug studies he sees "don't consider sex differences at all."62

Is this important? In the U.S., 55% of women versus 37% of men take a prescription drug daily.63 And of the 11 drugs withdrawn in recent years, eight (maybe nine) affected women more than men (Table 8)

Entrenched problems with the medical-pharmaceutical complex

"It's long been known that for individual subjects the dosage listed on a drug label is not necessarily the right one," Dr. Carl Peck, the highly respected director of Georgetown's Center of Drug Development Science and a former division director at the FDA, stated in September 2002.64 This is a chilling, and accurate, comment. Yet, the medical-pharmaceutical complex-drug companies, FDA and mainstream doctors-maintain that our medications are as safe as possible. Clearly, this isn't the case.

I compare the situation to the automobile industry in 1960, when auto executives insisted that our cars were as safe as possible. Then we learned that safety could be greatly enhanced with seat belts, air bags, bumpers that didn't fall off, side panels that didn't cave in, dashboards not made of metal, gas tanks positioned more safely, and other improvements. Similarly, there's much that can be done to increase drug safety and end the side-effect epidemic now, and it begins with identifying and marketing the lowest, safest doses of all drugs.

Problems in drug industry research

Why isn't this done now? Why aren't drug doses designed to fit individuals and to prevent side effects? Don't drug manufacturers care?

They do care. "More and more senior executives are concerned that so many patients are dropping out of therapy prematurely," declared DTC [Direct to Consumer] In Perspective magazine declared in 2002. "So many are asking, "What can I do to increase patient retention?"65 Each year, patients driven from treatment by side effects cost the drug industry billions in sales.

Yet, many economic factors keep the system from changing (Table 9). Drug companies are profit-driven entities, so marketing issues weigh very heavily. Manufacturers feel great pressure to keep costs down while hastening new drugs to market. And drug companies aren't held responsible for the huge costs of dose-related side effects to the healthcare system. The result is that marketing issues frequently outweigh medical science in drug company decisions.

Indeed, marketing influences affect science so severely that even the medical journals, which depend on drug company advertising, rebelled against them. In September 2001, Reuters Health reported: "Seeking to curb the growing influence exerted by drug firms over research findings, the world's top medical journals announced steps on how to prevent firms that fund studies from manipulating results to favor their drugs and bury studies that are unfavorable.66 The editors of JAMA, Lancet, the New England Journal of Medicine and ten others declared: "We are concerned that the current environment in which some clinical research is [conducted] may threaten medical objectivity...The use of clinical trials primarily for marketing makes a mockery of clinical investigation...."67 The journals implemented new guidelines to ensure the integrity of clinical studies, but a year later few medical schools had adopted them.68

Drug marketing is geared toward doctors' preferences, and doctors like drugs that can be dosed simply and quickly. No time is required to match doses to individual patients if drugs are one-size-fits-all. Expediency sells.

So does pumped-up effectiveness. Strong doses produce higher efficacy numbers, which are essential for introducing a new drug into a competitive market. Dr. Thomas Bodenheimer of the University of California, San Francisco, reported: "Drug company studies are often done in younger, healthier populations-providing better rates of effectiveness and fewer adverse reactions-than those who will actually receive the drug."69

Dr. Alexander Herxheimer, Professor Emeritus at the Cochrane Center in Britain, concurred in Lancet. "For quick market penetration, a drug must be simple to use and effective in the greatest number of people. Drugs are often introduced at a dose that will be effective in around 90% of the target population, because this helps market penetration. The 25% of patients who are most sensitive to the drug get much more than they need."70 With nearly 100 million Americans taking a prescription drug daily, that's 25 million people.

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