Medications side effects 
By Life Extension, March 2003.

Re-posted April 23, 2016. Disclaimer The information presented here is for informative and educational purposes only and is not intended as curative or prescriptive advice.

This article illustrates with examples how the medical system prescribes medications that cause side-effects in patients. The examples are detailed and use medical terms.

imagePrescription drugs help millions of people. Still, most people don't like taking drugs, although many of us ultimately need to. So how can you get the treatment you need while minimizing the risks?

Mainstream medicine's record on preventing medication side effects is poor. A 1998 article in the Journal of the American Medical Association (JAMA) defined the scope of the problem: 106,000 deaths and 2,000,000 severe reactions from medications annually in U.S. hospitals, making side effects the fourth leading cause of death in America.1 These numbers aren't new. The side effect problem has continued for decades and persists unrecognized by many doctors and authorities.

But patients understand. Patients' first concern about medications is safety. They know intuitively that, as a leading drug reference states, "Any drug, no matter how trivial its therapeutic actions, has the potential to do harm." 2

 How can you maximize safety while getting the treatment you need?  There are ways, ways in accordance with scientific principles and proven by medical studies, yet routinely ignored by drug companies, the FDA and doctors.

The first key to avoiding side effects

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Jay Cohen, M.D.Associate Professor, Dept of Family and Preventative Medicine (Voluntary), University of California, San Diego

Side effects occur because most drugs aren't specific in their actions. We may call a drug an "anti-inflammatory" or "antidepressant," but medications don't just go to the cells involved in these problems. They go to most of the cells of our bodies, which can provoke undesirable effects. Thus, an anti-inflammatory may reduce your joint pain, but it may also cause stomach bleeding, kidney failure or anxiety. An antidepressant can improve mood but can also cause insomnia, nausea, weight gain or diminished sex drive.

Most of these unintended effects-side effects-are dose-related. You see the same phenomenon every day with alcohol and coffee. In moderate amounts, they cause few problems. But at excessive doses, coffee causes edginess and insomnia, and alcohol impairs thinking and coordination.

It's the same with medications. Indeed, in the 1998 JAMA study cited at the beginning of this article, 76.2% of all side effects were dose-related. Melmon and Morrelli's Clinical Pharmacology places the number at 75% to 85%. 3 I believe the number is higher, because many drug interactions are also dose-related. When people take multiple drugs, higher doses cause more adverse interactions than lower doses. Whatever the actual number, the first key to avoiding side effects is this:

Most side effects are dose-related. Hence, the problem isn't the drug itself, but a dose that's too strong for you.

Thus, the best way to avoid side effects is to use the lowest dose that works. Excessive dosing merely increases risks.

The second key: individual variation

Why do side effects occur in some people but not in others? Because people vary tremendously in their sensitivities to medications, just as they do to alcohol and coffee.

The American Medical Association states that the difference in people's response to a specific drug can vary "4- to 40-fold." 4 With such variability, it isn't surprising that some people can drink a pot of coffee without problems while others can't handle a cup. Similarly, it isn't surprising that some people need 80 mg of the antidepressant Prozac® or the cholesterol-lowering drug Lipitor®, while others need just 2.5 mg.

Individual variation with medications isn't the exception; it's the rule

The basis of individual variation is well known. People differ greatly in how they absorb, metabolize and eliminate drugs. The new science of pharmacogenetics has revealed wide variations in the efficiency of people's liver enzymes in processing drugs. People also differ in the sensitivity of their tissues to medication effects. These factors change with age, and many people become more sensitive as they get older.

Some people are sensitive from the start. My sense is that about 10% of people are highly sensitive to medications. I call this a general medication sensitivity. Some doctors dismiss such patients, but these people are real enough. Often they are "poor metabolizers" with inefficient liver enzymes that are genetically determined. With standard doses, they develop high blood levels that provoke side effects. Such people need exceedingly low doses.

Because of the great variability between people, it is essential for drug doses to be tailored to each person's needs. I call this precision prescribing. Doctors already practice this with a few drugs-digoxin, insulin, thyroid drugs-but not with most drugs. Many drugs are prescribed one-size-fits-all or at doses that are identical for young and old, big and small, healthy or taking six other drugs at the same time. The failure to match drug doses to individual needs underlies the high incidence of side effects.

TABLE 1: MEDICAL EXPERTS AGREE THAT INDIVIDUAL VARIATION IS COMMON AND MATCHING DOSES TO PATIENTS IS ESSENTIAL.

Goth's Medical Pharmacology: "Many adverse reactions probably arise from failure to tailor the dosage of drugs to widely different individual needs."1
Goodman and Gilman's The Pharmacological Basis of Therapeutics: "Therapists of every type have long recognized that individual patients show wide variability in response to the same drug or treatment method."2
Hazards of Medication: "The ultimate hazard is variability of patient response."3
American Medical Association Drug Evaluations: "Almost all drugs cause reasonably predictable toxic reactions when given in excessive doses."4
BMJ (British Medical Journal): "Many drugs have been introduced at doses that later were found to be too high; and usually years have passed, with unnecessary toxicity, before action was taken."5
Pharmacoepidemiology and Drug Safety: "Optimal drug therapy requires appropriate dosing in order to obtain the desired therapeutic effects at minimum risk."6
Variability In Drug Therapy-A Sandoz Workshop: "Even if we try to forget, we are constantly reminded, by one experience or another, that patients differ in their responses to drugs."7
Goth's Medical Pharmacology: "Biologic variation in drug effect is an important reason to individualize dosage and adjust treatment to the requirements of a given patient."1
Paracelsus (1493-1541): "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."2

References for Table 1 at the end.

  Creating a side effect epidemic 

Drug companies and the FDA routinely ignore the wide differences in people's drug tolerances and the fact that most side effects are dose-related. Doctors, accepting uncritically drug company dosage guidelines, don't think twice about prescribing the same doses of powerful drugs to young and old, big and small, healthy and frail. They ignore patients with long histories of medication reactions. Cookbook dosing is the rule, and an epidemic of side effects is the result.

Even when studies show that half and quarter doses are effective, the data is ignored and dosing is one-size-fits-all. Even when studies show that women or the elderly respond to lower doses, they get the same higher doses as younger, larger men. Something is very wrong when Shaquille O'Neal, Ally McBeal and Grandma Moses are getting the exact same doses of potent drugs, yet this is exactly how many drugs are prescribed.

"To think that the same dose will do the same thing to all patients is absurd," says Dr. Raymond Woosley, Vice President of Health Services at the University of Arizona. "Patients need to be titrated, starting with the lowest possible dose that could have the desired effect."5

Experts everywhere agree with him (Table 1), but that's not how it's done today. The side effect epidemic isn't caused by a few bad drugs, but by bad dosing methods with many drugs.

Listening to Prozac®

When I began treating patients in 1970, I quickly noticed how differently people responded to medications and began adjusting doses accordingly. Although this occurred with every drug I used, I didn't realize the depth of the problem until Prozac® arrived in 1988.

As I did with all new drugs, I waited awhile before prescribing Prozac®. New drugs, like new model cars, often manifest unexpected problems. But I heard only good things about Prozac®, so I began prescribing it. I saw two distinct patterns. Half of my patients did extremely well. Prozac® was clearly a breakthrough drug, far better than any earlier antidepressant.

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But the other half of my patients had side effects, some severe. One woman became so agitated it incapacitated her. Another became completely psychotic after just three Prozac® doses. The problem? The recommended, one-size-fits-all initial dose, 20 mg, was too strong. I would have started patients with lower doses, but Prozac® was marketed in only one size, a 20 mg capsule. After these reactions occurred, I had patients open the capsules, mix the powder in juice and start lower. Most did fine at 5 mg to 10 mg daily, and the severe, dose-related reactions ceased.

Meanwhile, troubled by the reactions I saw, I searched the medical literature for explanations. I found more than I anticipated. A study published before Prozac's® approval showed that just 5 mg helped 54% of patients, while 20 mg-the recommended dose-helped 64%.6 In other words, quadrupling the dose only improved efficacy 10%. To me, this meant that 5 mg was a reasonable starting dose, yet doctors were told to start everyone at 20 mg, even the 54% who needed only 5 mg! I was shocked and appalled.

Meanwhile, other doctors began reporting severe reactions to Prozac® and that lower doses worked better (Table 2). Yet today, the standard starting dose of Prozac® remains 20 mg, and there's still scant information in the package insert or Physicians' Desk Reference (PDR) about the effectiveness of the 5 mg dose.7 Prozac® and other selective serotonin reuptake inhibitors (SSRIs) continue to cause high incidences of dose-related side effects such as headaches, nausea, weight gain, irritability, sexual dysfunctions (impaired orgasm, reduced libido), low energy, dry mouth and tremor. Insomnia or anxiety occur frequently, too, which doctors handle not by reducing the dose, but by adding a dependency-causing sleep or anxiety remedy.

TABLE 2: LOW-DOSE PROZAC®

Studies before and shortly after Prozac's® approval
revealed that 5 mg, one-quarter the standard 20 mg initial dose,
was highly effective and less toxic for many people.

Journal of Clinical Psychopharmacology, 1987: "Clinically, we have observed fluoxetine (Prozac®) to be effective over a wide range with many patients requiring very low dosages...."1
Psychopharmacology Bulletin 1998: 5 mg helped 54% with major depression; 20 mg helped 64%. Fewer adverse effects with the 5 mg dose. Conclusion: "No lower limit for an effective dose of this potent serotonin uptake inhibitor has been demonstrated in moderately depressed outpatients."2
Journal of Clinical Psychiatry 1990: "A single daily dose of 20 mg may overmedicate some older depressed patients. Experienced geriatric clinicians sometimes advise older patients to open the capsule and sprinkle small amounts of fluoxetine in a flavored beverage such as orange juice. Alternatively, the contents of an entire capsule may be dissolved in a beverage, but only a part (such as one quarter or one half) is consumed each day."3
Journal of Clinical Psychiatry 1991: "Today, it is clear, however, that the precept of pushing the depressed patient quickly to a high dosage of antidepressant medication is not the optimal strategy for serotonergic agents. `Start low and stay low' may be the new watchword, particularly with... compounds such as fluoxetine [Prozac®]."4
Journal of Clinical Psychiatry, 1992: "In the 5 mg, 20 mg, and 40 mg fixed-dose study, there were no differences in effectiveness between the active treatment groups, all of which were superior to placebo. Side effect dropouts increased significantly with dosage....With endpoint analysis, numerically, 5 mg/day outperformed 40 mg/day which outperformed 20 mg/day...These data point to 5 mg/day as optimal, although there is no evidence that doses below 5 mg/day are not equally effective."5
Journal of Clinical Psychiatry, 1993: "We conclude that starting fluoxetine at doses lower than 20 mg is a useful strategy because of the substantial fraction of patients who cannot tolerate a 20-mg dose but appear to benefit from lower doses.... Patients often benefitted clinically from treatment at lower doses, and failure to tolerate 20 mg/day of fluoxetine should not be taken as evidence that the agent cannot be used efficaciously in these patients."6
Conn's Current Therapy, 1993: "Many patients resond to the starting dose of 20 mg per day, but a substantial proportion need lower doses (e.g., 2.5 to 10/day)...."7
New England Journal "The results of three dose-effect studies... [demonstrated that] a dose of 5 mg per day was as of Medicine, 1994: effective as any of the higher doses."8

References for Table 2 at the end.

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Dosage problems with other antidepressants
Doctors follow the guidelines in the drug company-written PDR. The PDR still advises 75 mg initially for Elavil® (amitriptyline), yet 10 mg or 25 mg is frequently enough for mild depressions or pain syndromes. Effexor® is recommended at 75 mg, but 37.5 mg or 50 mg often is enough initially. Zoloft® is recommended at 50 mg, but 25 mg works well for many mild depressions. Serzone is recommended at 100 mg twice-daily, but 50 mg once or twice daily is usually plenty initially.

Similar strategies apply to Paxil®, Wellbutrin®, Celexa®, Norpramin®, Pamelor®, imipramine, doxepin and just about every other antidepressant. "The sales representatives for most antidepressants are now giving out sample packs starting with half-strength doses," Dr. Anthony Weisenberger, a top psychopharmacologist, recently told me. "They lose so many sales because patients get side effects and quit treatment, the drug companies have finally caught on that the dose makes a big difference."

Why is this happening with drug after drug? One reason is that the standard doses of antidepressants are based on studies of major depression-a severe disorder that requires strong treatment. In contrast, the great majority of office patients with depression have mild disorders. Yet, no distinction is made about treating mild and severe disorders in the dosage guidelines of most antidepressants, so doctors prescribe the same doses to everyone.

Drugs for elevated cholesterol and C-reactive protein

The statins-Lipitor®, Zocor®, Pravachol®, Mevacor®, Lescol®-were the best-selling group of drugs in America in 2001. There's no doubt that statins help millions by reducing heart attacks, strokes and overall cardiac mortality. But statins harm thousands, perhaps millions more, often unnecessarily.

Duane Graveline's first dose of Lipitor® caused amnesia "so severe that I landed in the emergency room of a hospital near my Vermont home. I didn't remember any of it." Dr. Graveline, a retired family doctor, flight surgeon and astronaut (www.spacedoc.net), was perplexed. After all, he wasn't usually sensitive to medications, and he'd taken only 10 mg, the lowest dose recommended and marketed by the manufacturer.

Yet, 10 mg of Lipitor® is very strong, much stronger than many people need. It was much stronger than Dr. Graveline needed, because he needed only 2.5 mg of Lipitor®-75% less medication than he got. How do I know? Experts advise doctors to select statin doses based on the reduction in LDL-C (the bad, low density lipoprotein-cholesterol) that each person needs.8 10 mg of Lipitor® reduces LDL-C 39%, a strong response needed by cardiac patients and people with severely elevated cholesterol.

But most people with high cholesterol have mild-to-moderate elevations and no cardiac history, and they require only 20% to 30% reductions in LDL-C. This can be attained with only 2.5 mg or 5 mg of Lipitor®.9-12 Dr. Graveline required a 25% reduction in LDL-C and should have been started at 2.5 mg mg. Yet, there's no information about 2.5 or 5 mg of Lipitor® in the package insert or PDR and no pills in these doses, so doctors start everyone at 10 mg, or even 20 mg or 40 mg.

Excessive statin doses, unnecessary side effects

TABLE 3: THE POTENCY OF DIFFERENT STATIN DRUGS

The initial dose is generally based on the amount of LDL reduction required. However, these numbers are averages, and you may get a larger or smaller response than listed. Statin therapy should always be combined with a heart healthy diet.

Medication
Average LDL Reduction
Lescol® (fluvastatin)
20 mg 22%
40 mg 25%
80 mg 36%

Lipitor® (atorvastatin)
2.5 mg 20-25%
5 mg 27-29%
10 mg 39%
20 mg 43%
40 mg 50%
80 mg 60%

Mevacor® (lovastatin)
10 mg 21%
20 mg 27%
40 mg 32%
80 mg 40%

Pravachol® (pravastatin)
10 mg 22%
20 mg 32%
40 mg 34%

Zocor® (simvastatin)
5 mg 26%
10 mg 30%
20 mg 38%
40 mg 41%
80 mg 47%

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

Dr. Graveline received 400% more medication than he needed and got a major dose-related side effect because of it. This is a common story. Cognitive and memory problems, sometimes severe and long lasting, occur far more often with statins than doctors recognize. Muscle pain and abdominal discomfort occur frequently. All of these are dose-related.

Liver disorders occur in 1% of patients taking statins. With statins now recommended for 35 million Americans, that's 350,000 people with liver problems, which include liver toxicity and, rarely, death. Dr. W.C. Roberts, the Editor-in-Chief of the American Journal of Cardiology, states, "With each doubling of the dose, the frequency of liver enzyme elevations also doubles."13 Liver enzyme elevations signify liver injury. So if you get 10 mg of Lipitor® when you only need 2.5 mg, your risk of liver injury is also quadrupled.

Lipitor® is the best-selling drug In America. In 2001, patients filled more than 57 million prescriptions for Lipitor®, and sales are skyrocketing. Zocor®, the third best-selling drug, presents the same dose problems as Lipitor®. Zocor's® standard starting dose, 20 mg, reduces LDL-C 38%. Many people need only 10 mg or even 5 mg, which reduce LDL-C 30% and 26%, respectively.7 If the standard doses of such widely advertised, top-selling drugs, are so strong, how can we rely on the standard doses of any drug?

More is not always better with medications. Some people do need strong statins. Often, however, a milder drug that works is preferable to a potent one. "Pravachol® is the statin drug I prescribe most often because it is the weakest of the bunch," Dr. Stephen Sinatra writes. "We don't need to prescribe large doses of these statins to get results."14 People with mild cholesterol elevations usually don't need high potency doses of Lipitor® and Zocor®, but doctors prescribe them anyway even when milder statins-Pravachol®, Mevacor®, Lescol®-would do (Table 3).

Even with the latter drugs, lower doses work for millions of people. A study conducted by the manufacturer of Pravachol® showed that just 10 mg was sufficient for 83% of people with moderate cholesterol elevations.15 Four studies by Mevacor's® manufacturer showed that just 10 mg, with diet counseling, reduced cholesterol satisfactorily in 69% to 75% of subjects. Indeed, the LDL-C of 17% to 26% of subjects dropped below 100 mg/dl, the level sought for people with cardiac disease. This isn't surprising; some people get much better LDL-C reductions than the averages in the PDR.

Treating elevated C-reactive protein

Half of all cardiac deaths occur in people with normal cholesterol levels. Something else is going on. New studies suggest that elevated C-reactive protein (CRP), a test for internal inflammation, may be as important an indicator of cardiovascular risk as cholesterol levels, because inflammation in artery walls plays an important role in the development of atherosclerosis.17

Mainstream doctors are already prescribing statins to people with elevated C-reactive protein (CRP) levels, often at doses that are unnecessarily high. Meanwhile, other, safer methods such as omega-3 oils, which are known to reduce inflammation and cardiac risk,18,19 are being overlooked.

Drugs for high blood pressure

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Fifty million Americans have high blood pressure (hypertension), and 90% of us will ultimately develop this potentially deadly disease as we age. Hypertension is a particularly vicious disease, a silent destroyer of blood vessels that causes heart attacks, strokes, kidney disease, peripheral vascular diseases and erectile dysfunctions in men. Much of this is preventable with treatment. Yet half of the people starting treatment for hypertension quit within a year. Most do not last 90 days. Why? Medication side effects.

Wendy reacted to one antihypertensive drug after another. Her side effects were dose-related, usually occurring with the first doses, a sure sign of excessive dosing. Wendy knew her hypertension posed a serious threat because relatives had died prematurely from hypertension-related strokes. Wendy was motivated, but side effects made treatment impossible. "I don't know what I'm going to do," she told me.

Experts acknowledge the problem: "Often, the cure is perceived as being worse than the disease, and when this is the case, the patient is unlikely to remain [in] treatment."20

People get worn down by side effects such as dizziness, weakness, drowsiness, fatigue, diarrhea, muscle cramps and sexual impairments, and give up. Doctors often dismiss so-called "minor" side effects, but minor reactions drive millions from needed treatment-with dire consequences. There's a better solution.

Lower doses recommended by experts

TABLE 4: LOWER INITIAL DOSES OF
ANTIHYPERTENSIVE DRUGS

ACE INHIBITORS PDR PROVEN LOSER
DOSE
Accupril® (quinapril): 10 mg 5 mg
Altace® (ramipril): 2.5 mg 1.25 mg
Capoten® (captopril): 50-75 mg 25 mg
Prinivil®, Zestril® (lisinopril): 10 mg 5 mg

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)
Cozaar® (losartan): 50 mg 25 mg

BETA BLOCKERS
Inderal® (propanolol): 80 mg 40 mg
Kerlone® (betaxolol): 10 mg 5 mg
Levatol® (penbutolol): 20 mg 10 mg
Lopressor® (Metoprolol): 100 mg 50 mg
Sectral® (acebutolol): 400 mg 200 mg
Tenormin® (atenolol): 50 mg 25 mg
Zebeta® (bisoprolol): 5 mg 2.5 mg

CALCIUM ANTAGONISTS (BLOCKERS)
Calan®, Isoptin®, Verelan® (verapamil): 120-180 mg 90 mg
Cardizem®, Dilacor® (diltiazem): 180-240 mg 120 mg
Norvasc® (amlodipine): 5 mg 2.5 mg
Plendil® (felodipine): 5 mg 2.5 mg

DIURETICS
Demadex® (torsemide): 10 mg 5 mg
Edecrin® (ethacrynic acid): 50 mg 25 mg
HCTZ® (Hydrochlorothiazide): 25 mg 12.5 mg
Lasix® (Furosemide): 80 mg 40 mg
*Spironolactone®: 50 mg 25 mg
Thalitone® (Chlorthalidone): 15 mg 12.5 mg
*Triamterene®: 200 mg 25 mg

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

And from: Cohen, JS. Adverse Drug Effects, Compliance, and the Initial Doses of Antihypertensive Drugs Recommended by the Joint National Committee (JNC) Vs. the Physicians' Desk Reference. Archives of Internal Medicine 2001;161:880-85.

Because most side effects with antihypertensive drugs are dose-related, experts recommend starting with the very lowest effective doses. But what are they? Most doctors turn to the PDR, but the PDR's doses often aren't the lowest. In an analysis I published in the Archives of Internal Medicine in 2001, I found that for 23 of 40 top-selling antihypertensive drugs, the initial doses recommended by the drug companies in the PDR were much higher than recommended by the Joint National Committee-the national board of medical experts on hypertension. 21

For example, the manufacturer's initial dose for Norvasc, the fifth most prescribed drug in the U.S. in 2001, is 5 mg. The experts recommend 2.5 mg, 50% less medication. The manufacturer of Capoten (captopril) recommends 50 mg to 75 mg/day initially, 100% to 600% more than the 12.5 mg to 25 mg recommended by experts.

When Tenormin (atenolol) was introduced in 1976, the one-size-fits-all dose was 100 mg. It wasn't until 1980 that a 50 mg dose was available and until 1989 that 25 mg was produced. The manufacturer still recommends 50 mg initially, 100% higher than the 25 mg recommended by the national board.

The manufacturer of Lasix® (furosemide), a commonly prescribed diuretic, recommends 80 mg initially; the national board, 40 mg. The top-selling diuretic hydrochlorothiazide (HCTZ) was recommended at 100 mg initially, but this dose caused serious metabolic problems that affected millions. Yet, it took decades for manufacturers to lower the dose to 25 mg, still 100% higher than the 12.5 mg experts recommend today.

Similar over-dosing is seen with top-sellers Zestril®, Prinivil®, Altace®, Inderal® (propanolol), Cardura®, Cozaar®, and many others (Table 4). Is it any wonder why so many people quit treatment?

Some savvy doctors recognize that starting with the lowest dose not only reduces risks, but allows people time to improve their diets, lose weight, start exercising and learn stress reduction or meditation. These methods not only lower blood pressure, but can reduce the amount of medication you need. As one specialist put it, "With blood pressure, it's easy to overshoot the mark. That's why I always start low and give people time to make other changes. Very often, their blood vessels relax over a period of time and you wind up ultimately needing less medication. When I start with standard doses, we spend the rest of our lives combating side effects."

(Editor's note: When it comes to anti-hypertensive drugs, some patients are not taking them frequently enough to maintain continuous blood pressure control. Many anti-hypertensives are sold in "one-per-day" dosing units, but some people need to take these drugs in two divided doses to achieve all-day blood pressure control. Optimal control of hypertension requires blood pressure checks throughout the day. This is the only way to make sure the anti-hypertensive drug is not wearing off and endangering the arterial system.)

Anti-inflammatory drugs

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In package inserts and PDR descriptions of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Motrin®, Voltaren®, Celebrex® and Vioxx®, the FDA specifically requires drug companies to tell doctors to use "the lowest dose for each patient." Why? Because gastrointestinal hemorrhaging and kidney damage from NSAIDs have caused more than 16,000 deaths and 100,000 hospitalizations annually. In 1999, the New England Journal of Medicine reported that NSAIDs were the 15th leading cause of death in the U.S.: "Yet these toxic effects remain largely a 'silent epidemic,' with many physicians and most patients unaware of the magnitude of the problem."22 And they are unaware that these reactions can occur without any warning signs.

These and other NSAIDs side effects are dose-related, yet doctors and patients often aren't informed about the very lowest effective doses, so over-dosing is common.

Motrin® and Voltaren®

When Motrin® (ibuprofen) was introduced in America in 1974, the lowest dose was 300 mg and the most prescribed dose was (and still is) 400 mg. Yet, studies had already proven that 200 mg was effective for osteoarthritis (degenerative arthritis) and rheumatoid arthritis.23-26 Yet, low-dose Motrin® wasn't available for 10 years until over-the-counter Motrin® arrived in 1984. Most doctors still don't know about its effectiveness and instead usually prescribe 400 mg when half as much will do.

The standard dosage of Voltaren® (diclofenac) for osteoarthritis is 50 mg twice or three times daily. Yet, studies before Voltaren's® approval showed that 25 mg three times daily is enough for many patients.27-30

Celebrex® and Bextra®

Dosing with new drugs like Celebrex® and Bextra® is even worse. Both drugs are one-size-fits-all for osteoarthritis, their most common use. This means that the identical amount is prescribed to football players with injury-induced arthritis and to osteoarthritic 90 year-olds weighing 95 pounds and taking nine other drugs.

The standard dose of Celebrex® for osteoarthritis is 100 mg twice-daily. A Mayo Clinic study showed that 50 mg twice-daily works for many people with severe osteoarthritis. Moreover, compared with higher doses, the 50 mg dose not only caused fewer side effects, but wasn't associated with kidney problems.31 Starting at this lower, safer dose would make sense, but the package insert and PDR don't say a word about it, and the smallest Celebrex® pill is a 100 mg capsule. Bextra was effective at half (5 mg) and quarter (2.5 mg) doses in early studies, but this was ignored and only 10 mg is offered for osteoarthritis.

Other drugs

A half dose of the antihistamine Allegra® is effective, but because the drug is one-size-fits-all and the pill is a capsule, a half dose is difficult to get. Half doses of Claritin®, especially Claritin-D®, work for some people, but for others even full-dose Claritin® isn't enough. In fact, the FDA wanted Claritin® produced at 20 mg, but this dose could cause sedation, which would hamper advertising. So doctors and patients are stuck with a one-size-fits-all 10 mg dose that is inadequate for as many as 50% of patients.32

Half doses of Zantac®, Axid® and Pepcid® were proven effective long before they were first marketed in the 1980s. It was only a decade later, when the drugs were marketed over-the-counter, that lower doses became available. Until then, people with mild heartburn got the same strong doses as people with bleeding ulcers.

Prilosec® is effective at a half dose of 10 mg, but there's scant information about it in the PDR, so doctors rarely prescribe it. Over-the-counter 10 mg Prilosec will finally allow people to take a lower, safer dose for mild conditions.


Viagra® has been linked with more than 500 deaths and 1,500 heart attacks, strokes and other vascular events.33 The manufacturer and FDA blame this on patients' age, health or sexual activity, but many deaths have occurred in men with no major medical problems and before they even had sex. Suspicion remains that Viagra® may affect blood pressure or cause a cardiac arrhythmia in rare individuals. The standard starting dose is 50 mg for all men ages 18 to 65, but I've suggested starting with a half dose, especially in middle-age men,34 the group in which many reactions have occurred. A half dose works for some men; if it isn't enough, it can be easily increased.

Lotronex® generated a controversy that did not have to happen. Lotronex® is effective for irritable bowel syndrome, a nasty disorder that limits people's lives, but the condition isn't an emergency requiring immediate powerful dosing. Yet, Lotronex was released one-size-fits-all, and after causing hospitalizations and deaths, was withdrawn. As I told the FDA, one-size-fits-all drugs tie doctors' hands by keeping them from matching doses to patients' needs or reducing doses when side effects emerge. Belatedly, after unnecessary harm and a public furor, Lotronex® was re-released in 2002-at a half dose.

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Dosage is key with the widely used heart drug digoxin because excessive doses can cause cardiac arrhythmias. For years, the recommended starting dose was 0.25 mg. However, a half dose works. A 1997 study showed that 0.125 mg of digoxin improved congestive heart failure, whereas higher doses produced diminishing improvement and greater toxicity.35

Sleep medicines such as Ambien® and Halcion® (triazolam) are often effective at half doses. Halcion® is another drug released at excessive doses that, after undue harm, widespread controversy, and being banned in many countries, had its dose lowered.

The neuroleptic Risperdal® was marketed in 1993 at 2 mg/day, which was rapidly increased to 6 mg within three days. Doctors quickly learned-from patients' adverse reactions-that these doses were excessive, and the manufacturer now recommends 1 mg the first day, increasing to 3 mg in three days. That's 50% less medication. Still, doctors start some patients at 0.25 mg or 0.5 mg. Similar patterns have occurred with Haldol® and other drugs.

Because Xenical®, a weight-loss drug, works by blocking fat absorption, it can cause embarrassing side effects. Dosage is key, yet whether you are slightly overweight or massively obese, whether you eat a little or a lot, you get the same dose of one-size-fits-all Xenical®: 120 mg three-times-a-day. A half dose was proven effective in studies, but the manufacturer does not market it.

Zyban®, widely advertised for smoking cessation, is started at 150 mg, then doubled to 300 mg in three days, but even at this strong dose long-term cessation rates aren't impressive. Some people taking Zyban® can tolerate only 150 mg, and others tolerate even less. In 2001, British regulators issued warnings about seizures with Zyban® at the standard dosage.36 To obtain lower doses, some doctors prescribe Wellbutrin®, an antidepressant that's identical to Zyban® but comes in lower doses.

In 2001, users of inhaled steroids for asthma or allergies learned that these drugs had been discovered to cause bone loss. "The message really is, we need to use inhaled corticosteroids at the lowest doses that we can," Dr. Elliott Israel told the San Diego Union-Tribune.37 But why weren't they doing so from the start?

The list goes on and on (Table 5). Repeated discoveries of dose-related toxicities years after people have started medications is not satisfactory. We know that most side effects are dose-related, which means that many are preventable by defining the lowest, safest doses initially, not years or decades later after problems inevitably emerge or drugs go over-the-counter.

TABLE 5: LOWER, SAFER, EFFECTIVE DOSES FOR 36 OTHER FREQUENTLY PRESCRIBED DRUGS THAT YOU WON'T FIND IN THE PDR OR MOST OTHER DRUG REFERENCES

Even if a drug isn't listed here, a lower dose may still work. Many drugs are never tested at lower doses or the research isn't published, but a lower initial dose may be appropriate in some situations. Work with your doctor. Do not change doses without medical direction; undertreatment can be harmful.

MEDICATION DRUG COMPANY INITAL DOSAGE EFFECTIVE, LOWER DOSAGE
ALLEGRA® (FEXOFENADINE) 60 mg twice-daily 20 mg three-times-a-day, or 40 mg twice-daily1
AMBIEN® (ZOLPIDEM) 10 mg 5 or 7.5 mg at bedtime2
AXID® (NIZATIDINE) 150 mg twice-daily 25-75 mg twice-daily or 300 mg at bedtime 100 mg at bedtime3
CELEBREX® (CELECOXIB) 100 mg twice-daily 50 mg twice-daily
COLCHICINE® 0.6 mg twice-daily 0.3 mg twice-daily
CYTOTEC® (MISOPROSTOL) 200 mcg 50 or 100 mcg four-times-a-day four-times-a-day4
DALMANE® (FLURAZEPAM) 30 mg at bedtime 15 mg at bedtime5
DESYREL® (TRAZODONE) 150 mg/day 25-100 mg/day6
EFFEXOR® (VENLAFAXINE) 75 mg/day 37.5 or 50 mg/day7
ELAVIL® (AMITRIPTYLINE) 50-75 mg/day 10-25 mg/day8
ESTRACE® (ORAL ESTRADIOL) 1-2 mg/day 0.5 mg/day9
ESTRADERM® (TRANSDERMAL ESTRADIOL) 0.05-0.1 mg/day 0.02-0.025 mg/day10
ESTRATAB® (ESTERIFIED ESTROGENS) 1.25 mg/day 0.3-0.625 mg/day11
LIPITOR® (ATORVASTATIN) 10 mg/day 2.5 or 5 mg/day
MEVACOR® (LOVASTATIN) 20 mg/day 10 mg/day
MOTRIN® (IBUPROFEN) 300-400 mg three- 200 mg three- or four-times-a-day times-a-day
NORPRAMIN® (DESIPRAMINE) 100 mg/day* 10 or 25 mg/day
PAMELOR® (NORTRIPTYLINE) 50-75 mg/day 10 or 25 mg/day12
PEPCID® (FAMOTIDINE) 20 mg twice-daily 10 mg twice-daily or or 40 mg at bedtime 20 mg at bedtime13
PRAVACHOL® (PRAVASTATIN) 10-20 mg/day 5-10 mg/day
PREMARIN® (CONJUGATED ESTROGENS),for vasomotor symptoms or osteoporosis: 0.625 mg/day 0.3 mg/day
PRILOSEC® (OMEPRAZOLE) 20 mg/day 10 mg/day14
PROZAC® (FLUOXETINE) 20 mg/day 2.5, 5, or 10 mg/day
RISPERDAL® (RISPERIDONE) 1-2 mg/day 0.5 mg/day15
SERZONE® (NEFAZODONE) 100 mg twice-daily 50 mg once or twice daily 16,17
SINEQUAN® (DOXEPIN) 75 mg/day 10, 25, or 50 mg/day18
TAGAMET® (CIMETIDINE) 800 mg at bedtime 400 mg at bedtime
TOFRANIL® (IMIPRAMINE) 75 mg/day 10-25 mg/day19
VASOTEC® (ENALAPRIL) 5 mg/day 2.5 mg/day**20
VOLTAREN® (DICLOFENAC) 50 mg two-, three-,or four-times-a-day 25 mg three- times-a-day
WELLBUTRIN® (BUPROPION) 100 mg twice-daily 50 mg twice-daily21
XENICAL® (ORLISTAT) 120 mg 3 times daily 60 mg 3 times daily22
ZANTAC® (RANITIDINE) 150 mg twice-daily 100 mg twice-daily 23 or 300 mg at bedtime
ZOCOR® (SIMVASTATIN) 10-20 mg/day 2.5, 5, or 10 mg/day24,25
ZOFRAN® (ONDANSETRON) 8 mg twice-daily 1-4 mg three-times-a-day26
ZOLOFT® (SETRALINE)
50 mg/day 25 mg/day

* The manufacturer recommends starting with a lower dose, but doesn't specify.
** The manufacturer does recommend 2.5 mg for people on a diuretic, but this lower initial dose may also be useful for small, elderly, or other people.

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

References for Table 5 at the end.

 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

TABLE 6: LOWER MEDICATION DOSES FOR OLDER PEOPLE

Experts consistently recommend lower doses for seniors.

Journal of the American Geriatrics Society, 1999: "Choosing the correct dose of a drug therapy is critical when prescribing for older people because adverse effects are often dose-related. The conventional wisdom has been to start low and go slow.''1
Goth's Medical Phatmacology "In general the best approach is to start with lower doses and to increase dosage slowly and in small increments."2
Public Citizen's Worst Pills, Best Pills II, 1993: "If drug therapy is indicated, in most cases it is safer to start with the dose which is lower than the usual adult dose."3
Drug Safety, 1990: "Starting doses can often be reduced in the elderly."4
FDA Consumer Magazine, 1997: "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."5
Archives of Internal Medicine, 1986: "The elderly are especially sensitive to both the intended pharmacologic effects of drugs and their undesirable adverse reactions."6
BMJ (British Medical Journal), 1997: "If drug treatment is necessary, the lowest feasible dose of the drug should be used."7
United States Pharmacopeia, Drug Information, 1994: "Some clinicians recommend that geriatric patients, especially those 70 years of age or older, be given one-half of the usual adult dose initially."8
Australian Family Physician, 1992: Article title, "Rational drug therapy in the elderly, or, How not to poison your elderly patients." Recommends: "The starting dose should be lower than that recommended for younger adults; the maximum tolerated dose may well be lower than for younger individuals." "Select the minimum dose of the safest medication.... Start low and go slow."9

References for Table 6 at the end.

Women

TABLE 7: WHICH HORMONES ARE NATURAL?

Premarin® is advertised as "natural," because it's derived from horses. For decades, doctors continued making Premarin® a best-seller while truly human-identical hormones were available.

ESTROGENS Type Of Estrogen Identical To Human Estrogens
Drug Company Products
PREMARIN® (0.3, 0.625, 0.9, 1.25, 2.5 mg) Equilin,
Estrogens and Estrone
No
Yes
ESTRATAB® (0.3, 0.625, 1.25, 2.5 mg) Equilin and Estrone No
Yes
OGEN®, ORTHO-EST® (0.75, 1.5, 3, 6 mg) Estropipate No
ESTINYL® (0.02, 0.05 mg) Ethinyl Estradiol No
ESTRACE® (0.05, 1, 2 mg) Estradiol (Oral) Yes
ESTRADERM®, CLIMARA® 0.05 and 0.1 mg/day Estradiol Yes (Transdermal) Yes
Compounding Pharmacy Products*
NATURAL ESTRIOL Estriol: 1, 2 mg twice-daily Estriol Yes
TRIPLE NATURAL ESTROGEN 80% Estriol, 10% Estradiol, 10% Estrone
(0.625, 1.25, 2.5, or 5 mg twice-daily)
All 3 Estrogens Yes
DUAL NATURAL ESTROGEN 80% Estriol, 20% (0.625, 1.25, 2.5, 5 mg twice-daily) Estradiol Estriol/Estradiol Yes
PROGESTERONES
Drug Company Products
MEDROXYPROGESTERONE Provera, others: 2.5, 5, 10 mg   No
Compounding Pharmacy Products
NATURAL MICRONIZED PROGESTERONE Progesterone: 50, 100, 200 mg twice-daily   Yes
PROGESTERONES
Drug Company Products
CONJUGATED ESTROGENS & MEDROXYPROGESTERONE Prempro, Premphase: Premarin 0.625 mg and Provera 2.5, 5 mg   No
Compounding Pharmacy Products
MIXTURES OF THE ABOVE NATURAL ESTROGENS AND PROGESTERONES ARE INDIVIDUALIZED   Yes

*Not generally available in regular pharmacies. These non-patented products are made by compounding pharmacies, which upon receiving physicians' orders, will mail prescriptions to patients. These products are not generally available in regular pharmacies. For a compounding pharmacy near you, call the Professional Compounding Centers of America, 800-331-2498.

** Although a combination pill is slightly more convenient, a wider choice of hormones and more precise dosing can be accomplished with separate estrogen and progesterone products.

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

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.

image

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.

 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."

 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.

image

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.

References:

Life Extension Magazine, March, 2003. LE Magazine

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6. Wernicke, JF, Dunlop, SR, Dornseif, BE, Bosomworth, JC, Humbert, M. Low-dose fluoxetine therapy for depression. Psychopharmacology Bulletin 1988; 24(1):183-188.

7. Physicians' Desk Reference, 57th Edition. Montvale, N.J.: Medical Economics Company, 2003.

8. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285(19):2486-97.

9. Nowrocki, J, Weiss, S, et al. Reduction in LDL Cholesterol by 25% to 60% in Patients with Primary Hypercholesterolemia by Atorvastatin, a New HMG-Co-A Reductase Inhibitor. Arteriosclerosis, Thrombosis, and Vascular Biology 1995;15:678-682.

10. Wolffenbuttel, BH, Mahla, G, Muller, D, et al. Efficacy and safety of a new cholesterol synthesis inhibitor, atorvastatin, in comparison with simvastatin and pravastatin, in subjects with hypercholesterolemia. Netherlands Journal of Medicine 1998;52(4):131-7.

11. Bakker-Arkema, RG, Best, J, Fayyad, R, et al. A brief review paper of the efficacy and safety of atorvastatin in early clinical trials. Atherosclerosis 1997;131(1):17-23.

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21. Cohen, JS. Adverse drug effects, compliance, and the initial doses of antihypertensive drugs recommended by the Joint National Committee vs. the Physicians' Desk Reference. Archives of Internal Medicine 2001;161:880-85.

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29. Ciccolunghi, SN, Chaudri, HA, Schubiger, BI. The value and results of long-term studies with diclofenac sodium (Voltarol). Rheumatology and Rehabilitation 1979;(suppl2):100-115.

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31. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib: a randomized controlled trial. Mayo Clinic Proceedings 1999;74(11):1095-105.

32. Hall, SS. Claritin and Schering-Plough: a Prescription for Profit. New York Times, Mar. 11, 2001:www.nytimes.com.

33. Azarbal, B, Mirocha, J, Shah, PK, Cercek, B, Kaul, S. Adverse Cardiovascular Events Associated with the Use of Viagra. Journal of the American College of Cardiology 2000;35(SupplA):553A-554A. Abstract.

34. Cohen, JS. Should Patients Be Given a Low Test Dose of sildenafil (Viagra) Initially? Drug Safety 2000;23:1-10.

35. Digitalis: More Is Not Necessarily Better. Journal Of The American College Of Cardiology 1997;29:1206-13.

36. 57 Deaths in Britain associated with Zyban. Reuters Health, Jan. 10, 2002:www.reuters.com.

37. Associated Press. Inhaled steroids for asthma cause bone loss, study finds. San Diego Union-Tribune, Thurs., Sept. 27, 2001:A-14.

38. Recchia, AG, Shear, NH. Organization And Function Of An Adverse Drug Reaction Clinic. Journal Of Clinical Psychiatry, 1994; 34:68-79.

39. Smucker, WD, Kontak, JR. Adverse drug reactions causing hospital admission in an elderly population: experience with a decision algorithm. Journal of the American Board of Family Practice 1990;3(2):105-9.

40. Cheng H, Rogers JD, Sweany AE, et al. Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin. Pharmaceutical Research 1992;9:1629-1633.

41. Williams, RD. Medications and older adults. FDA Consumer Magazine, Sept.-Oct. 1997.

42. Montamat, SC, Cusack, BJ, Vestal, RE. Management of drug therapy in the elderly. New England Journal of Medicine 1989;321(5):303-9.

43. Writing Group for the Women's Health Initiative. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. JAMA 2002;288:321-333.

44. Lacey, JV, Mink, PJ, Lubin, JH, Sherman, ME, Troisi, R, Hartge, P, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341.

45. Ettinger B. Personal perspective on low-dosage estrogen therapy for postmenopausal women. Menopause, 1999; 6(3):273-6.

46. Weinstein L. Efficacy of a continuous estrogen-progestin regimen in the menopausal patient. Obstetrics and Gynecology 1987;69(6):929-32.

47. Greendale, GA, Reboussin, BA, Hogan, P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstetrics and Gynecology 1998;92(6):982-8.

48. McNagny, SE. Prescribing Hormone Replacement Therapy for Menopausal Symptoms. Annals of Internal Medicine, 1999;131:605-16.

49. Snider S. The Pill: 30 Years of Safety Concerns. U.S. Food and Drug Administration, Dec. 1990;www.fda.gov/bbs/topics/CONSUMER/CON00027.html. Checked: Mar. 9, 2002.

50. Marks L. "Not just a statistic": The history of USA and UK policy over thrombotic disease and the oral contraceptive pill, 1960s-1970s. Social Science and Medicine 1999;49:1139-1155.

51. Vessey MP, Inman WH. Speculations about mortality trends from venous thromboembolic disease in England and Wales and their relation to the pattern of oral contraceptive usage. Obstetrics and Gynecology in the British Commonwealth 1973;80:562-566.

52. Bottiger LE, Boman G, Eklund G, Westerholm B. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980;1:1097-1101.

53. Shapiro, SS, Diem, K. The effects of ibuprofen in the treatment of dysmenorrhea. Current Therapeutic Research 1981;30(3):327-334.

54. Wierzbicki AS, Lumb PJ, Chik G, Crook MA. High-density lipoprotein cholesterol and triglyceride response with simvastatin versus atorvastatin in familial hypercholesterolemia. American Journal of Cardiology 2000;86:547-549.

55. Ose L, Luurila O, Eriksson J, Olsson A, Lithell H, Widgren B. Efficacy and safety of cerivastatin, 0.2 mg and 0.4 mg, in patients with primary hypercholesterolaemia: A multinational, randomised, double-blind study. Cerivastatin Study Group. Current Medical Research and Opinion 1999,15:228-240.

56. Peters TK, Muratti EN, Mehra M. Efficacy and safety of fluvastatin in women with primary hypercholesterolaemia. Drugs. 1994;47(Suppl2):64-72.

57. Leitersdorf E. Gender-related response to fluvastatin in patients with heterozygous familial hypercholesterolaemia. Drugs. 1994;47(Suppl 2):54-58.

58. Lewis CE. Characteristics and treatment of hypertension in women: a review of the literature. American Journal of the Medical Sciences 1996;311(4):193-9.

59. Israili, ZH, Hall, WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Annals of Internal Medicine 1992;117(3):234-42.

60. Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement. Report to Congressional Requesters. US General Accounting Office, GAO-01-754, July 6, 2001:www.fda.gov/womens/informat.html.

61. Exploring the Biological Contributions to Human Health: Does Sex Matter? Wizemann, TM, Pardue, ML, Editors, Committee on Understanding the Biology of Sex and Gender Differences, Board on Health Sciences Policy, Institute of Medicine, National Academy of Sciences, National Academy Press, 2001.

62. Kritz, FL. Mars and Venus and Drugs: Sex Differences Create Extra Risks for Women. Washington Post, Feb. 20, 2001:T7.

63. Bowman, L. 51% Of U.S. Adults Take 2 Pills or More a Day, Survey Reports (Scripps Howard News Service). San Diego Union-Tribune, Jan. 17, 2001:A8.

64. Zuger, A. Caution: That dose may be too high. New York Times, September 17, 2002:nytimes.com.

65. Dorothy L. Smith, DTC Perspectives, Jan.-Feb. 2002.

66. Reuters Health. Medical Journals Act to Limit Drug Firms' Influence. Reuters, Sept. 10, 2001:www.reuters.com.

67. Davidoff, F, DeAngelis, CD, Drazen, JM, Hoey, J, Hojgaard, L, Horton, R, et al. Sponsorship, Authorship, and Accountability. New England Journal of Medicine, Sept. 13, 2001;345(11):825-27.

68. Schulman, KA, Seils, DM, Timbie, JW, Sugarman, J, et al. A national survey of provisions in clinical-trial agreements between medical schools and industry sponsors. New England Journal of Medicine 2002;347:1335-41.

69. Bodenheimer, T. Uneasy Alliance -- Clinical Investigators and the Pharmaceutical Industry. New England Journal of Medicine 2000;342:1539-44.

70. Herxheimer A. How much drug in the tablet? Lancet 1991;337:346-8.

71. Zuger, A. Caution: That dose may be too high. New York Times, September 17, 2002:nytimes.com.

72. Herxheimer, A. Dosage needs systematic and critical review. BMJ 2001;323.

73. Moore, TJ, Psaty, BM, Furberg, CD. Time to act on drug safety. JAMA 1998;279(19):1571-3.

74. Lasser, KE, Alan, PD, Woolhandler, SJ, Himmelstein, DU, Wolfe, SM, Bor, DH. Timing of New Black Box Warnings and Withdrawals for Prescription Medications. JAMA 2002;287:2215-2220.

75. Gaist, D, Jeppesen, U, Andersen, M, et al. Statins and the risk of polyneuropathy: a case-control study. Neurology 2002;58:1333-1337.

76. Avorn, J. The prescription as final common pathway. International Journal of Technology Assessment in Health Care 1995:11(3):384-90).

77. Wood, AJJ, Stein, CM, Woosley, R. Making Medicines Safer: the Need for An Independent Drug Safety Board. New England Journal of Medicine 1998;339:1851-54.

78. Young, SA. Is Academic Medicine for Sale? New England Journal of Medicine 2000;343:508.

79. Vollmann, J. Gifts to physicians from the pharmaceutical industry. JAMA 2000;283:2656-8.

80. Angell, M. Is Academic Medicine for Sale? New England Journal of Medicine 2000;342:1516-18:

81. Hensley, S. When doctors go to class, industry often foots the bill. Wall Street Journal, Dec. 4, 2002:A1.

82. Cimons, M. Scientists Study Gender Gap in Drug Responses. Los Angeles Times, Sun. June 6, 1999: A-1,8-9.

83. Angell, M, Relman, AS. Prescription for Profit. The Washington Post, June 20, 2001:A27.
84. Cohen, JS. The One-Size Dose Does Not Fit All: Look beyond the guidelines of drug manufacturers. Newsweek, Dec. 6, 1999:92.

85. American Medical Association Council on Ethical and Judicial Affairs. Code of Medical Ethics. 1998-1999 Edition. American Medical Association, Chicago, IL.

86. Top 10 Drugs of 2001. Pharmacy Times, Apr. 2002;68(4):10-15.


References for Table 1:

1. Clark, WG, Brater, DC, Johnson, AR. Goth's Medical Pharmacology. 13th Edition. St. Louis: The C.V. Mosby Company, 1992.

2. Gilman, AG, Rall, TW, Nies, AS, Taylor, P. Goodman and Gilman's The Pharmacological Basis of Therapeutics. New York: Pergammon Press, 1990 and 1996.

3. Martin, E.W. Hazards of Medication: A Manual on Drug Interactions, Contraindications, and Adverse Reactions with Other Prescribing and Drug Information. 2nd edition. Philadelphia: J.B. Lippincott Company, 1978.

4. American Medical Association. AMA Drug Evaluations, Annual 1994. Chicago: American Medical Association, 1994.

5. Herxheimer, A. Dosage needs systematic and critical review. BMJ 2001;323.

6. Heerdink, ER, Urquhart, J, Leufkens, HG. Changes in prescribed drug doses after market introduction. Pharmacoepidemiology and Drug Safety 2002;11:447-453.

7. Rowland, M, Sheiner, L, Steimer, J. Variability In Drug Therapy: Description, Estimation, And Control. A Sandoz Workshop. New York: Raven Press, New York, 1985.


References for Table 2:

1. Schatzberg AF, Dessain E, O'Neil P, Katz DL, Cole JO. Recent studies on selective serotonergic antidepressants: trazodone, fluoxetine, and fluvoxamine. Journal of Clinical Psychopharmacology 1987;7(6):44S-49S.

2. Wernicke, JF, Dunlop, SR, Dornseif, BE, Bosomworth, JC, Humbert, M. Low-dose fluoxetine therapy for depression. Psychopharmacology Bulletin 1988; 24(1):183-188.

3. Salzman C. Practical considerations in the pharmacologic treatment of depression in the elderly. Journal of Clinical Psychiatry 1990;59(1 Suppl):40-43.

4. Schatzberg AF. Dosing strategies for antidepressant agents. Journal of Clinical Psychiatry 1991:52(5suppl):14-20.

5. Cain, JW. Poor response to fluoxetine: underlying depression, serotonergic overstimulation, or a "therapeutic window"? Journal of Clinical Psychiatry 1992;53(8):272-277.

6. Louie, AK, Lewis, TB, Lannon, MD. Use of low-dose fluoxetine in major depression and panic disorder. Journal of Clinical Psychiatry 1993;54(1):435-438.

7. Rakel, RE. Conn's Current Therapy. Philadelphia: W.B. Saunders Company, 1993.

8. Gram, LF. Fluoxetine-review article. New England Journal of Medicine 1994;331:1354-61.


References for Table 5:

1. Tinkelman D, Falliers M, Bronsky E, et al. Efficacy and safety of fexofenadine in fall seasonal allergic rhinitis. Journal of Allergy and Clinical Immunology, 1996;97(1):1009.

2. Merlotti L, Roehrs T, Koshorek G, Zorick F, Lamphere J, Roth T. The dose effects of zolpidem on the sleep of healthy normals. Journal of Clinical Psychopharmacology 1989;9:9-14.

3. Cloud, ML, Offen, WW, Matsumoto, C. Healing and subsequent recurrence of duodenal ulcer in a clinical trial comparing nizatidine 300-mg and 100-mg evening doses and placebo in the treatment of active duodenal ulcer. Current Therapeutics and Research, Clinical Experience 1989;45(3):359-367.

4. Cohen MM, Clark L, Armstrong L, D'Souza J. Reduction of aspirin-induced fecal blood loss with low-dose misoprostol tablets in man. Digestive Diseases and Sciences, 1985;30(7):605-11.

5. Salkind MR, Silverstone T. A clinical and psychometric evaluation of flurazepam. British Journal of Clinical Pharmacology 1975;2:223-226.

6. Schatzberg AF, Dessain E, O'Neil P, Katz DL, Cole JO. Recent studies on selective serotonergic antidepressants: trazodone, fluoxetine, and fluvoxamine. Journal of Clinical Psychopharmacology 1987;7:44S-49S.

7. Mendels J, Johnston R, Mattes J, Riesenberg R. Efficacy and safety of b.i.d. doses of venlafaxine in a dose-response study. Psychopharmacology Bulletin 1993;29:169-174.

8. Roy, D, Dawling, S. Application of an individually predicted dosage of amitriptyline to the treatment of depression. International Clinical Psychopharmacology 1987;2:307-315.

9. Ettinger, B. Personal perspective on low-dosage estrogen therapy for postmenopausal women. Menopause, 1999; 6(3):273-6.

10. De Aloysio, D, Rovati, LC, Giacovelli, G, Setnikar, I, Bottiglioni, F. Efficacy on climacteric symptoms and safety of low dose estradiol transdermal matrix patches. Arzneimittel-Forschung 2000;50(3):293-300.

11. American Society of Hospital Pharmacists. American Hospital Formulary Service, Drug Information 1999. Gerald K. McEvoy, Editor. Bethesda: 1999.

12. Schatzberg AF. Dosing strategies for antidepressant agents. Journal of Clinical Psychiatry. 1991:52(Suppl5):14-20. Sjoqvist F, Bertilsson L. Clinical pharmacology of antidepressant drugs: Pharmacogenetics. Advances in Biochemistry and Psychopharmacology 1984,39:359-372.

13. Savarino, V, Mela, GS, Zentilin, P, Bonifacino, G, Moretti, M, et al. Low bedtime doses of H2-receptor antagonists for acute treatment of duodenal ulcers. Digestive Diseases and Sciences 1989;34(7):1043-46.

14. Lauritsen, K, Andersen, BN, Laursen, LS, Hansen, J, Havelund, T, Eriksen, J, et al. Omeprazole 20 mg three days a week and 10 mg daily in prevention of duodenal ulcer relapse; double-blind comparative trial. Gastroenterology 1991;100(3):663-9.

15. Rainer, MK, Masching, AJ, Ertl, MG, Kraxberger, E, Haushofer, M. Effect of risperidone on behavioral and psychological symptoms and cognitive function in dementia. Journal of Clinical Psychiatry 2001;62:894-900.

16. Elliott RL, Shillcutt SD. Using newer antidepressants in the medically ill: An update. Primary Psychiatry. 1996;3:42-56.

17. Rickels K, Schweizer E, Clary C, Fox I, Weise C. Nefazodone and imipramine in major depression: A placebo-controlled trial. British Journal of Psychiatry. 1994;164:802-805.

18. McCue R. Using tricyclic antidepressants in the elderly. Clinical Geriatric Medicine 1992;8:323-334.

19. Preskorn S. Pharmacokinetics of antidepressants: Why and how they are relevant to treatment. Journal of Clinical Psychiatry. 1993;54(suppl 9):14-34.

20. The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Archives of Internal Medicine 1993;153:154-183.

21. Kirksey DF, Harto-Truax N. Private practice evaluation of the safety and efficacy of bupropion in depressed outpatients. Journal of Clinical Psychiatry. 1983;44:143-147.

22. Rossner S; Sjostrom L; Noack R; Meinders AE; Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obesity Research 2000;8:49-61.52.

23. Dobrilla, G, Barbara, L, Bianchi-Porro, G, Felder, M, Mazzacca, G, et al. Placebo Controlled Studies with Ranitidine in Duodenal Ulcer. Scandinavian Journal of Gastroenterology 1981;69(suppl):103-4.

24. Steinhagen-Thiessen E. Comparative efficacy and tolerability of 5 and 10 mg simvastatin and 10 mg pravastatin in moderate primary hypercholesterolemia. Simvastatin Pravastatin European Study Group. Cardiology, 1994, 85(3-4):244-54.

25. Tuomilehto J; Guimaraes AC; Kettner H; Lithell H; Pitkanen M; et al. Dose-response of simvastatin in primary hypercholesterolemia. Journal of Cardiovascular Pharmacology, 1994; 24(6):941-9.

26. Beck TM, Ciociola AA, Jones SE, et al. Efficacy of oral ondansetron in the prevention of emesis in outpatients receiving cyclophosphamide-based chemotherapy. Annals of Internal Medicine 1993;118:407-413.


References for Table 6:

1. Rochon, PA, Anderson, GM, Tu, JV, et al. Age- and gender-related use of low-dose drug therapy: the need to manufacture low-dose therapy and evaluate the minimum effective dose. Journal of the American Geriatrics Society, 1999 47(8):954-9.

2. Clark, WG, Brater, DC, Johnson, AR. Goth's Medical Pharmacology. 13th Edition. St. Louis: The C.V. Mosby Company, 1992.

3. Wolfe, SM, Hope, RE. Worst Pills, Best Pills II: The Older Adult's Guide to Avoiding Drug-Induced Death or Illness. Washington, D.C.: Public Citizen's Health Research Group, 1993.

4. Brawn, LA, Castleden, CM. Adverse drug reactions. An overview of special considerations in the management of the elderly patient. Drug Safety 1990;5(6):421-35.

5. Williams, RD. Medications and older adults. FDA Consumer Magazine, Sept.-Oct. 1997.

6. Everitt, DE, Avorn, J. Drug prescribing for the elderly. Archives of Internal Medicine 1986;146(12):2393-6.

7. Rochon, PA, Gurwitz, JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ 1997;315(7115):1096-9.

8. United States Pharmacopeia, Drug Information (USP DI): Drug Information for the Health Care Professional. Taunton, MA: Rand McNally, 1994.

9. Gibian T. Rational drug therapy in the elderly, or, how not to poison your elderly patients. Australian Family Physician 1992;21(12):1755-60.