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Life Extension Magazine

LE Magazine March 2003

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Medications side effects

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Prescription 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.

Continued on Page 2 of 6

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