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By Jay Cohen, M.D.
Part 1 of 2
Chapter 1: The Race To
the Bottom
Over
Dose: The Case Against the Drug Companies: Prescription Drugs, Side Effects,
and Your Health
I was in my recliner, headset
on, writing this book when the telephone rang.
"Dr. Cohen, my name is
Alex. I'm sorry to bother you, but I need to speak to you about problems
I'm having with my medication."
I don't get many calls. After
twenty years in practice, I've been disabled for ten. I have no office
or funding for my research, so I work at home. My telephone number is
unlisted. Alex, a young man from the other end of the country, had obviously
gone to considerable trouble to find me.
"I'm taking Prozac for
panic attacks and depression," Alex told me. "I was nearly housebound
by agoraphobia once. I was okay for three years, but things got stressful
at work and the problems returned."
"Prozac is a reasonable
choice for your disorder," I said. "What's the problem?"
"I've gotten much worse
since starting the drug. I get terribly agitated now, and my heart pounds
and I can't sleep. I get so shaky sometimes, I'm afraid to go out. I'm
withdrawing And depressed again. I think the Prozac is making me worse."
"What do your doctors
say?"
"They say that the side
effects from the Prozac -- the insomnia and palpitations -- show that
it is working, and that I should wait it out."
I sighed quietly. This was
awful advice, but not unusual. Although I already knew the answer, I asked,
"What dose of Prozac are you taking?"
"Twenty milligrams a day."
Twenty mg -- that's what Lilly
and Company, Prozac's manufacturer, recommends initially for otherwise
healthy people ages eighteen to sixty-five, and that's what physicians
prescribe. Unfortunately, neither Alex nor his physicians knew that early
research had already shown that doses one half or even one quarter Lilly's
recommended amount are all that some patients need (1, 2).
Anything greater commonly causes
side effects including agitation, insomnia, rapid heart rate, and consequent
depression and social withdrawal. These are signs that Alex was being
over-dosed.
Alex isn't alone. In 1998 an
extensive study published in the Journal of the American Medical Association
(JAMA) showed that 106,000 people die annually in American hospitals from
medication side effects (3).
Medication reactions are the
fourth leading cause of death in the United States, dwarfing the number
of deaths caused by automobile accidents, AIDS, alcohol and illicit drug
abuse, infectious diseases, diabetes, and murder. In addition to the medication-related
deaths, the JAMA study also tallied 2,216,000 severe medication reactions
in U.S. hospitals annually.
Because of the especially rigorous
methods the researchers applied, even these numbers may not present the
full picture. The authors defined serious side effects narrowly, including
only clearcut reactions causing permanent disability, hospitalization,
or death. Thus, they excluded side effects that disable people for weeks
or months, side effects such as dizziness or sedation that cause automobile
accidents or falls and broken limbs, side effects that require emergency
interventions, and side effects that prolong hospitalizations or force
people to miss work.
And the authors didn't even
try to count the largest category of all -- side effects occurring in
outpatients. Overall, the authors excluded side effects that occur far
more often than the ones they included.
Despite omitting so many side
effects, the JAMA study still recorded numbers reaching epidemic proportions.
And, as the authors noted, this side-effect epidemic wasn't new: "The
incidence has remained stable over the last 30 years (4)."
Because it is sometimes difficult
to place such statistics in everyday terms, consider this: 106,000 deaths
a year averages out to nearly 300
deaths a day, every day. In comparison,
about 85 people died from accidents linked to faulty Firestone tires.
The Firestone deaths occurred over a period of several years -- medication
reactions kill 300 people every day. Yet, it was the Firestone deaths
that dominated the news for several weeks and drew Congressional hearings.
Deaths from all major airline
crashes in the United States average less than 300 annually, but one airplane
crash gets more media attention and governmental scrutiny than the 300
medication-related deaths that occurred not only the same day as the airline
crash, but also every day before and after for decades.
Why has this epidemic of side
effects gone unrecognized? Deaths from medication reactions rarely look
any different than natural deaths. There's no visible wreckage to videotape,
no crash sites to horrify and fascinate viewers. As media people say,
"No film, no story."
Medication deaths often occur
quietly in hospitals, emergency rooms, and homes. When medication-related
deaths occur, it is often unclear at first whether the cause was the medication,
the illness, or other factors. In other words, to much of the media, there's
nothing sexy about side effects.
Moreover, the public likes
to believe that our hospitals and medications are safe and that our doctors
are taking every reasonable precaution.
Facing the failure of a major
industry is never comfortable. How many decades did it take recognize
the drunk driving problem? To bring the dangers of cigarettes to public
awareness? To mandate seatbelts in cars? Maybe with medication side effects
it's the same: We'd rather not know.
It might be different if the
public received an accurate account of the scope of the side-effect epidemic.
Alex' experience, for example, may have been severe enough to drive him
to contact an unfamiliar doctor 2,500 miles away, but his case will never
be counted in the side-effect statistics.
His doctors didn't recognize
Alex' side effects, and even if they had, they probably wouldn't have
reported them to the FDA. "Most physicians feel that detecting adverse
reactions is a professional obligation, but relatively few actually report
such reactions [to the FDA]," states Goodman and Gilman's The Pharmacological
Basis of Therapeutics, one of medicine's most respected drug references
(5).
Dr. Brian Strom, former chairman
of the department of biostatistics and epidemiology at the University
of Pennsylvania, told the New York Times in 1997: "Most doctors don't
know the system [for reporting medication reactions to the FDA] exists
(6)." When speaking to medical groups, Dr. Strom showed a slide of
an FDA Medwatch form and asked: "How many of you have ever seen that?"
Usually, less than a third raise their hands.
Yet, it is from voluntary reports
from physicians that side-effect statistics are derived. Physicians, however,
often feel that so-called minor side effects -- the ones that make millions
of people like Alex feel merely miserable or unable to function normally
-- aren't worth reporting.
Reporting more serious reactions
may raise questions about treatment or lead to lawsuits. Another highly
regarded drug reference, Melmon and Morrelli's Clinical Pharmacology:
Basic Principles in Therapeutics, commented: "Drug-induced complications
can mimic and therefore be attributed to disease-induced problems.
When therapy fails, we [physicians)
frequently can attribute the failure to the disease and escape blame.
Probably nowhere else in professional life are mistakes so easily hidden,
even from ourselves (7)." The result is that only one in twenty side
effects is reported to authorities (8, 9).
Drug companies and medical
institutions have their own reasons for underestimating the full scope
of the side-effect epidemic. Dr. David Bates, an associate professor of
medicine at the Harvard Medical School, wrote in JAMA:
Hospitals have had strong incentives
not to identify too many of these adverse drug events. Reporting large
numbers of adverse events and any serious preventable event brings intense
scrutiny from regulators and the public. Thus, most hospitals have relied
on spontaneous reporting,
which only identifies about 1 in 20 adverse reactions and leads
to the perception that injuries from ADRs are less common than they really
are (10).
Even the Food and Drug Administration
acknowledges that adverse drug reactions are grossly underreported. In
March, 2000, Dickinson's FDA Review reported on its interview with Jerry
Phillips, associate director of the Office Of Post-Marketing Drug Risk
Assessment at the FDA:
"These reports, however,
are generally believed by experts to grossly understate the actual situation,
Phillips said. In the broader area of adverse drug reaction data, the
250,000
reports received annually probably represent only 5% of the actual reactions
that occur (11)."
A simple extrapolation from
these numbers reveals a total of
five million medication reactions each year -- and this is
still probably an underestimate.
However, one by one, the public
is learning about the perniciousness of the side-effect epidemic. Knowledgeable
people have told me that their elderly parents died not from their illnesses,
but from being prescribed too many too powerful medications. Dozens of
websites now exist where patients can discuss medication reactions that
have caused major reactions or disabilities that their physicians have
ignored.
Many physicians dismiss anecdotal
reports or cases posted on the Internet, but scientific discovery often
begins with individual reports of an unrecognized or poorly understood
problem. These reports, especially when hundreds of in-depth, medically
credible descriptions are listed, should be taken seriously, because they
represent another unrecognized aspect of the side-effect epidemic.
It might be different if the
side-effect epidemic was caused by a few bad drugs. Every industry produces
some lemons. Thus, the FDA has had to remove ten prescription drugs (plus
a vaccine and an anesthetic) within the last four years. But, as this
book will document, the problem extends well beyond these few. Instead,
it involves hundreds of drugs including top-sellers like Viagra, Premarin,
Prozac, Lipitor, Celebrex, and Motrin.
Because the problem is so large
and so many drugs are involved, blame is difficult to assess. In addition,
these same drugs help millions of people, which further obscures the many
problems they cause, why they cause them, and how easily many of these
side effects, like Alex', could be avoided.
Consider, for example, one
class of medications: women's hormones. When I was a medical intern in
1971, I treated a young woman with a blood clot in her lower leg (thrombophlebitis).
She required hospitalization and bed rest for nearly two weeks. She was
lucky: Hundreds of women like her died each year when such clots broke
free and coursed to their lungs.
These clots were caused by
birth control pills -- pills that in the 1960s and 1970s contained three
to eight times more estrogen and progesterone than actually needed (12,
12A). That's 300 to 800 percent more of these powerful hormones than today's
pills -- doses that exposed millions of women to greatly increased risks
of blood clots, strokes, and death.
The death rate from thromboembolism
alone was 600 percent higher
with the original high-dose pills. I don't know where my patient
is today, but she probably is now worrying about the increased risks of
breast cancer that have been reported with these high-dose pills (13-16).
How many women have been harmed by these excessive doses that were prescribed
in the United States for twenty-eight years? Some data exist, but the
full extent of the damage has never been defined.
Perhaps my patient, after entering
menopause, received hormone therapy for hot flashes. If she was prescribed
Premarin for hot flashes at the dosage recommended by its manufacturer,
Wyeth-Ayerst, she might have received double or even quadruple the amount
she actually needed. Wyeth-Ayerst recommended 1.25 mg of Premarin as its
initial dose for hot flashes from 1964 through 1999, long after medical
experts had shown that 0.625 mg and even as little as 0.3 mg were sufficient
for many women (17-19).
Premarin is perhaps the
most prescribed drug ever; in
1999 alone, women purchased more than 47 million prescriptions in the
United States. Yet even in 2000, after Wyeth-Ayerst finally reduced its
recommended starting dose for hot flashes to 0.625 mg, this amount remains
excessive for some women (20-22). Similarly, the recommended doses of
Premarin for preventing osteoporosis have been unnecessarily high for
many women (23, 24).
Meanwhile, estrogens
like Premarin have been linked to increased rates of breast cancer (25,
26) -- and it is likely that the higher the dose of estrogen, the greater
the risk. Has my patient been affected? How many thousands of women have
been harmed over the years? We'll never know, and the side-effect statistics
will never reflect them.
Why weren't lower, safer, effective
doses of these hormones, as used today, developed decades earlier? The
technology existed in the 1960s to determine the lowest, safest doses
of these potent drugs. But the intense, fast-paced competition of the
medication marketplace frequently spurs drug companies to conduct small,
brief, insufficiently extensive studies on the dosages of new drugs (27)
-- dosages that will be taken by millions of people.
The result is that only belatedly,
years or even decades later, do we discover that lower doses are not only
effective, but avoid many side effects. Of course, by this time, tremendous
damage has been done to people and their families.
The story is the same with
many drugs -- not just obscure drugs, but many top-selling drugs. The
problem encompasses the entire field of medication therapy, as recognized
experts have attested:
Carl Peck, M.D., former director
of the FDA's Center for Drug Evaluation and Research: "There are
noteworthy examples in drug development of failing to get the dose right
when a drug is first marketed (28)."
Dr. Raymond Woosley, the chairman
of the department of pharmacology at Georgetown: "The US society
has invested in developing wondrous new pharmacologic therapies but has
failed to invest adequately in their safe use (29)."
Dr. Norman Sussman, editor
of Primary Psychiatry: "There are lots of problems with the current
system of drug testing. Often it fails to detect efficacy and, more often
than would be desired, misses significant side effects (30)."
Dr. Marcia Angell, former editor-in-chief
of the New England Journal of Medicine: "To rely on the drug companies
for unbiased evaluations of their products makes about as much sense as
relying on beer companies to teach us about alcoholism (31)."
The result of these shortcomings?
Dr. Thomas J. Moore of Georgetown University, Dr. Bruce Psaty of the University
of Washington, and Dr. Curt Furberg of Wake Forest University determined
that "51% of approved drugs have serious adverse effects not detected
prior to approval (32)."
Think about this -- more than
half of our drugs, after being deemed "safe" by the FDA and
then prescribed to millions of people, are subsequently detected to have
previously unrecognized, medically serious side effects. No wonder we
have a side-effect epidemic.
When the majority of our drugs
are approved with serious risks, the threat isn't small. Forty-six
percent of Americans take at least one prescription drug dally (33).
That's more than 128 million people. Most of these people are taking medications
long-term, so their exposures aren't brief. Twenty-five percent of Americans
take multiple prescription drugs every day.
In 1999, Americans purchased
2,587,575,000 prescriptions -- that's nine prescription drugs (as well
as several over-the-counter drugs) for every person in America.
Americans paid $125
billion for these prescriptions -- $50 per prescription on average. One
would think that with so much cost and utilization, medications would
be our most carefully manufactured and safest products. Yet, as Dr. Bates
wrote: "Only after drugs leave the trial setting and are used in
sicker patients do their true risks become apparent (34)."
It doesn't have to be this
way. As Dr. Bates also wrote, "Although some risks are inevitable,
they can be significantly reduced (35)." I agree -- side effects
can be significantly reduced, but they aren't. The inadequate methods
by which drugs are developed and prescribed are why.
Weary of seeing avoidable side
effects affect patient after patient, I began investigating the origins
of this problem. With a background in general medicine, pain research,
general pharmacology and psychopharmacology, and experience as a staff
member at UCLA, UCSD (the University of California, San Diego), and at
the world's largest naval medical center at Balboa Hospital in San Diego,
I began voicing my concerns publicly in 1988.
First I wrote letters to medical
journals and authored health columns in a local newspaper. Beginning in
1996, I began publishing lengthy articles describing my findings in respected
medical journals such as the Archives of Internal Medicine (36-38), Postgraduate
Medicine (39), Geriatrics (40), The Annals of Pharmacotherapy (41, 42),
and Drug Safety (43).
After more than a decade of
research conducted without any influences, I found that the drug companies
dominate the entire process of medication therapy -- from early research
to ultimate usage -- as few other industries control their products today.
Drug company research and development often serves marketing strategies
more than sound science or patients' safety.
The many ways that drug companies
accomplish this is discussed in depth in Chapter 9, but here is a glimpse
-- derived from numerous medical journal articles including JAMA (44),
the New England Journal of Medicine (45), and Lancet (46) -- of the methods
that drug companies use in accomplishing their goals:
Drug companies can choose research
study designs that are more likely to produce favorable results rather
than designs that might provide more accurate results.
Drug companies can conduct
multiple studies on new drugs, and then select and publish the most favorable
ones while suppressing the rest.
Drug company studies can measure
a drug's effectiveness in multiple ways, then select and publish only
the best results. Sometimes these favorable results have little to do
with whether the drugs will help patients.
Drug companies hire professional
writers to prepare articles according to company guidelines, using favorable
phrases and terms selected by the companies.
Drug companies hire high-profile
experts to place their names on drug company-generated articles, although
the experts have not participated in the studies and their financial connections
with the drug companies are not disclosed.
These excesses might be unimportant
if drug company research represented a small portion of all medication
research. However, the drug companies underwrite 70 percent of all medication
research today (47). This gives the pharmaceutical industry tremendous
power over the entire medication research effort, including the threat
of lawsuits or loss of future funding for physicians wanting to publish
unfavorable findings (48).
More and more, drug companies
are requiring researchers to sign confidential agreements before receiving
any funding, giving the companies the power to suppress findings they
don't like.
The pharmaceutical industry's
ability to amass wealth while hospitals and medical centers struggle financially
has allowed the drug companies to intrude into the arena of independent
academic medicine (49). This intrusion is so great that in 2000, Dr. Angell
issued an astonishing article -- "Is Academic Medicine for Sale?"
-- in the New England Journal of Medicine:
Academic medical institutions
are themselves growing increasingly beholden to industry.... Some academic
institutions have entered into partnerships with drug companies to set
up research centers and teaching programs in which students and faculty
members essentially carry out industry research....
When the boundaries between
industry and academic medicine become as blurred as they now are, the
business goals of industry influence the mission of the medical schools
in multiple ways.... The influences of the marketplace should not become
woven into the fabric of academic medicine. We need to remember that for-profit
businesses are pledged to increase the value of their investors' stock.
That is a very different goal from the mission of medical schools (50).
Despite the concerns of Dr.
Angell and other experts, drastic reductions in insurance and Medicare
payments have placed great pressure on medical institutions and research
physicians to accept the money -- and terms -- of the drug companies.
At the same time, the drug
companies spend billions targeting office physicians, as well as new interns
and residents, with gifts, free meals, travel subsidies, and subsidized
symposia presenting the drug companies' spin on their medications (51,
52).
Beyond these direct influences,
drug companies exert broad influence over the drug information received
by doctors and consumers. The vast majority of everything physicians and
consumers read and know about medications comes from the drug companies.
Medication package inserts, drug advertising toward physicians and consumers,
and the information in the ubiquitous Physicians' Desk Reference (PDR)
(53) come directly from the drug companies.
Where do most doctors turn
for medication and dosage information? To the PDR, to drug company representatives
who make the rounds of doctors' offices, and to advertising in medical
journals. Yet, the medication information offered by these drug company-supported
sources is often biased, incomplete, and sometimes inaccurate.
Please see the continuation
of this article in the next issue of my newsletter.
References
Over
Dose: The Case Against the Drug Companies: Prescription Drugs, Side Effects,
and Your Health
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