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Drug Overdosing: How to Avoid Medication Side Effects

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 (Ridker et al. 2002).

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 (Carroll et al. 2002; GISSI-Prevenzione Investigators 1999), are being overlooked.

DRUGS FOR HIGH BLOOD PRESSURE

• Lower Doses

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" (Elliott et al. 2000). People get worn down by side effects such as dizziness, weakness, drowsiness, fatigue, diarrhea, muscle cramps, and sexual impairments, and they 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
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. An analysis published in the Archives of Internal Medicine in 2001 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 (Cohen 2001).

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."

Note: When it comes to antihypertensive drugs, some patients are not taking them frequently enough to maintain continuous blood pressure control. Many antihypertensives 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 antihypertensive drug is not wearing off and endangering the arterial system.)

ANTI-INFLAMMATORY DRUGS

• Motrin and Voltaren
• Celebrex and Bextra

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" (Wolfe et al. 1999). 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 overdosing 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 (Chalmers 1969; Brooks et al. 1970; Thompson et al. 1970; Hingorani 1970). 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 (Durrigl et al. 1975; Mutru et al. 1978; Ciccolunghi et al. 1978, 1979).

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 an 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 (Bensen et al. 1999). 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 (Hall 2001).

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 (Azarbal et al. 2000). 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 starting with a half dose is suggested, especially in middle-age men (Cohen 2000), 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 reported to 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.

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 (Slatton et al. 1997).

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 (Reuters Health 2002). 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 (Associated Press 2001). 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.