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Drug Overdosing: How to Avoid Medication
Side Effects
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" (AMA 1994).
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. Indications are that about
10% of people are highly sensitive to medications. This is called 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 of medication 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. This is called 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.
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 drug company dosage guidelines uncritically, 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 are 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"
(Grady 1999).
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.
| Table 1: Medical experts agree
that individual variation is common and matching doses to patients
is essential. |
| Goth's Medical Pharmacology (Clark et al. 1992) |
"Many adverse reactions probably arise from failure to tailor
the dosage of drugs to widely different individual needs." |
| Goodman and Gilman's The Pharmacological Basis of Therapeutics
(Gilman et al. 1990) |
"Therapists of every type have long recognized that individual
patients show wide variability in response to the same drug or treatment
method." |
| Hazards of Medication (Martin 1978) |
"The ultimate hazard is variability of patient response." |
| American Medical Association Drug Evaluations (AMA 1994) |
"Almost all drugs cause reasonably predictable toxic reactions
when given in excessive doses." |
| British Medical Journal (Herxheimer 2001) |
"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." |
| Pharmacoepidemiology and Drug Safety (Heerdink et al. 2002)
|
"Optimal drug therapy requires appropriate dosing in order
to obtain the desired therapeutic effects at minimum risk." |
| Variability in Drug Therapy--A Sandoz Workshop (Rowland
et al. 1985) |
"Even if we try to forget, we are constantly reminded, by
one experience or another, that patients differ in their responses
to drugs." |
| Goth's Medical Pharmacology (Clark et al. 1992) |
"Biologic variation in drug effect is an important reason to
individualize dosage and adjust treatment to the requirements of a
given patient." |
| Paracelsus (1493-1541): (Gilman et al. 1990) |
"All substances are poisons; there is none which is not a
poison. The right dose differentiates a poison and a remedy."
("Principles of Toxicology and Treatment of Poisoning"). |
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.
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% (Wernicke et al. 1988). 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 (Physicians' Desk Reference 2003). 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.
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.
| 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.
|
| J. Clin. Psychopharmacol. (Schatzberg et al. 1987) |
"Clinically, we have observed fluoxetine (Prozac) to be effective
over a wide range with many patients requiring very low dosages..." |
| Psychopharmacol. Bull. (Wernicke et al. 1988) |
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." |
| J Clin. Psychiatry (Salzman 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." |
| J Clin. Psychiatry (Schatzberg 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]." |
| J Clin. Psychiatry (Cain 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." |
| J Clin. Psychiatry (Louie et al. 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." |
| Conn's Current Therapy (Rakel 1993) |
"Many patients respond to the starting dose of 20 mg per day,
but a substantial proportion need lower doses (e.g., 2.5 to 10/day)" |
| N. Engl. J. Med. (Gram 1994) |
"The results of three dose-effect studies... [demonstrated
that] a dose of 5 mg per day was effective as any of the higher doses."
|
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 said. "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 we 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 (NCEP 2001). Ten milligrams 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 (Nowrocki
et al. 1995; Wolffenbuttel et al. 1998; Bakker-Arkema et al. 1997; Cilla
et al. 1996). Dr. Graveline required a 25% reduction in LDL-C and should
have been started at 2.5 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
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" (Roberts 1997). 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
(Physicians' Desk Reference 2003). 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"
(Sinatra 2002). 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).
| 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. |
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
(Bristol-Myers Squibb 2000). 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
(FDA 2000). This isn't surprising; some people get much better LDL-C reductions
than the averages in the PDR.
|