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FDA Consumer magazine
January-February 2000
The Healing Power of Placebos
by Tamar Nordenberg

One patient stands out in the memory of Stephen Straus, M.D., for her remarkable recovery, more than 10 years ago, from chronic fatigue syndrome. The woman, then in her 30s, was "very significantly impaired," says Straus, chief of the Laboratory of Clinical Investigation at the National Institute of Allergy and Infectious Diseases. "She had no energy, couldn't work, and spent most of her time at home." But her strength was restored during a study to test the effectiveness of an experimental chronic fatigue drug.

"She and her parents were so thrilled with her recovery that they were blessing me and my colleagues," recalls Straus, the principal investigator on that study.

Like many drug studies, the chronic fatigue medication trial was a "placebo-controlled" study, meaning that a portion of the patients took the experimental drug, while others took look-alike pills with no active ingredient, with neither researchers nor patients knowing which patients were getting which.

It's human nature, Straus explains, for patients and investigators alike to try and guess in each case: Is it the real drug or a dummy pill? But people shouldn't kid themselves, he says, that they can consistently tell the actual drug from the sham by seeking out tell-tale signs of improvement.

Turns out, the woman's quick turnaround from chronic fatigue occurred after taking placebo pills, not the experimental drug. Straus says, "She was amazed by the revelation that she'd gotten better on placebo."

Research has confirmed that a fake treatment, made from an inactive substance like sugar, distilled water, or saline solution, can have a "placebo effect"--that is, the sham medication can sometimes improve a patient's condition simply because the person has the expectation that it will be helpful. For a given medical condition, it's not unusual for one-third of patients to feel better in response to treatment with placebo.

"Expectation is a powerful thing," says Robert DeLap, M.D., head of one of the Food and Drug Administration's Offices of Drug Evaluation. "The more you believe you're going to benefit from a treatment, the more likely it is that you will experience a benefit."

To separate out this power of positive thinking and some other variables from a drug's true medical benefits, companies seeking FDA approval of a new treatment often use placebo-controlled drug studies. If patients on the new drug fare significantly better than those taking placebo, the study helps support the conclusion that the medicine is effective.

Benefiting from Belief

Researchers have been studying the placebo effect for decades. In 1955, researcher H.K. Beecher published his groundbreaking paper "The Powerful Placebo," in which he concluded that, across the 26 studies he analyzed, an average of 32 percent of patients responded to placebo. In the 1960s, breakthrough studies showed the potential physiological effects of dummy pills--they tended to speed up pulse rate, increase blood pressure, and improve reaction speeds, for example, when participants were told they had taken a stimulant, and had the opposite physiological effects when participants were told they had taken a sleep-producing drug.

Yet, even after 40 years, big questions remain about the interplay of psychological and physiological mechanisms that contribute to the placebo effect. Today's brain imagery techniques do lend support, though, to the theory that thoughts and beliefs not only affect one's psychological state, but also cause the body to undergo actual biological changes.
The phenomenon needn't baffle us, says Michael Jospe, a professor at the California School of Professional Psychology who has studied the placebo effect for more than 20 years. He points out that all people experience physiological reactions to anticipation and stress--something like the fight-or-flight response--that help them to survive and cope. When you step out of your office and a spider jumps out at you, Jospe analogizes, "you'll get a fright and have a physiological reaction. And the next time you go out that way, the thought that it could happen again can produce a physiological reaction before you even open the door." So, he says, the relationship between a thought and a negative psychophysiological reaction like fear is something we experience daily.

That goes for positive associations, too, Jospe continues. "The placebo effect is part of the human potential to react positively to a healer. You can reduce a patient's distress by doing something which might not be medically effective." It's like kids and Band-Aids, Jospe says. "When you put a Band-Aid on a child and it has stars or comics on it, it can actually make the kid feel better by its soothing effect, though there's no medical reason it should make the child feel better."

There is no medical reason, either, that look-alike placebo tablets used in a 1997 study of benign enlargement of the prostate gland should have made the study participants feel better. But in this Canadian study, more than half of the men who got the placebo pills reported significant relief from their symptoms, including faster urine flow. Researcher J. Curtis Nickel theorized that the patients' positive expectations of the experimental drug's benefits may have caused therapeutic smooth muscle relaxation by decreasing nerve activity affecting the bladder, prostate and urethra. Study participants on placebo complained of side effects, too (sometimes called the "nocebo" effect), ranging from impotence and reduced sex drive to nausea, diarrhea and constipation.

It's this powerful placebo effect, coupled with the fact that many medical conditions involve a natural course of better and worse periods (arthritis and multiple sclerosis are examples of diseases with flair-ups and lulls), that can make it difficult to know if a health upswing should be credited to a drug effect. One way to account for such variables in a drug study: give one group of patients placebo and another the experimental drug, and see if the drug group's health improvements sufficiently surpass those from placebo. In Straus' study, the chronic fatigue syndrome drug failed to adequately demonstrate its superiority over dummy pills.

Proof in the Placebo

FDA doesn't require that a drug study include a placebo control group, DeLap says, only that its design be capable of establishing a drug's safety and effectiveness. Non-placebo types of drug studies include "head-to-head" studies, which compare the experimental drug to an existing treatment, and historically controlled studies, which compare the new drug's effects with information gathered in the past about the expected progression of a medical condition.

Often, however, a placebo control can provide the clearest insight into what a treatment can accomplish, according to DeLap, especially with some psychiatric and other drugs in which the placebo effect is known to play a particularly weighty role. In fact, DeLap says, in some cases the placebo effect "makes it almost hopeless, statistically" to use studies that test a new treatment side-by-side against an existing one and determine whether the new treatment works.
The placebo controls that have traditionally been used to test medications have recently been used, too, to test the effectiveness of surgical procedures. In one well-publicized study sponsored by the National Institutes of Health, half of the Parkinson's disease patients enrolled in the trial underwent a sham surgery in which doctors drilled holes into their skulls but didn't implant the potentially beneficial human fetal tissue in their brains.

While FDA doesn't evaluate the safety or effectiveness of most surgical techniques, the agency does regulate surgical implantation of animal cells or re-engineered human tissues. The agency has approved at least one sham surgery-controlled trial, which will study the effectiveness of implanted pig fetal cells for Parkinson's.

Even with the powerful scientific advantages of including a placebo control, researchers and FDA must look at each treatment individually to decide if the use of placebos is appropriate and ethical. In fact, much medical research does not involve a placebo control because "it's just not an option, ethically," DeLap says.

To determine whether a placebo-controlled trial is acceptable, drug company and FDA experts ask: For what condition is this drug being tested? What is the natural progression of the disease? How serious is the risk if a patient gets a placebo rather than an active treatment?

In DeLap's specialty, oncology, placebo-controlled studies are often unacceptable because of the great risk to cancer patients of any treatment delays. For a headache, on the other hand, patients in a study may be uncomfortable for a time, but are not at risk of a lasting health impact. So, for those conditions in which the downside of being on placebo is modest and short-lived, DeLap says, it's an individual's prerogative to say, "I know what I'm getting into, and I want to further this scientific research."

To help ensure that patients know the pros and cons of enrolling in a study, each participant must sign an "informed consent" form, which clearly explains:
the purpose of the study 
what enrollees will be asked to do (take a pill twice a day for three months, for example, and
visit the doctor once a week for blood and other laboratory tests) 
the possible benefits and known adverse reactions associated with the experimental treatment 
other therapies that are available for their condition. 

Even willing participants can't sign away their right to a well-designed study, though, DeLap points out. "We can't fall into the trap of thinking that, once someone says 'I'm willing to participate,' their consent covers us for deficiencies. Our responsibilities go way beyond getting informed consent." One such responsibility: As a study progresses, researchers monitor results so if major positive or negative drug effects are seen, the study can be stopped. The first major clinical study of the AIDS drug AZT (zidovudine), for example, was halted early when researchers saw that AZT patients were living significantly longer than others in the study.

Still, some critics say today's safeguards are not sufficient and oppose the use of placebo-controlled studies in almost all drug research. Patients desperately seeking to end their suffering, some say, may not be capable of giving true informed consent.

DeLap and other FDA experts view any far-reaching ban on placebos in research as paternalistic. "We at FDA don't have an ethical blind spot, as some would suggest," DeLap says. "A patient's right to the best treatment is always paramount. But the social hope is that careful scientific research can help us learn beyond a shadow of a doubt what works and what doesn't, so that these patients' kids will have better treatments available to them."

Tamar Nordenberg is a staff writer for FDA Consumer

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Notes and Insights:

Happy Birthday!
Happy Birthday Betsey!! Check out all the birthdays at community/birthday/ and make sure to send them an arthritis-friendly e-card: cgi-bin/postcards/postcard.pl 

Wanna help?
Having surgery? Starting a new drug or treatment? Filing for disability? Keep an Arthritis Insight journal so all of our members can share and learn from your experience. If you want to keep a journal just let us know. 
Write an article! We always need articles on all subjects relating to arthritis. 
C'mon folks, we can't do this without you.

Gimpfest 2001-Chicago here we come! 
Gimps from all over will invade Chicago in May! There will be fun, food and a whole lot of laughing going on! It's a chance to meet your online support pals in person, a chance to get some real hugs from your chat room pals. A good time will be had by all! For all the details see http://fadedjeans.com/chicago

Special Offers for Arthritis Insight Members
Whenever possible we will try get to our sponsors to agree to discounts and the like for our members. Here are our current special offers:

Sore No More gel (http://www.sorenomore.com ) will send a free sample of the pain relieving gel to any Arthritis Insight Community Member who emails them at dma@glogerm.com.  

Arthritis Ease-A FREE* 10-Day Supply of Arthritis-Ease® - a $15.00 Value - is Waiting For You
http://tabaks.com/mj.htm?id=megaj3  

Weekly News Summary
Tina Underwood

FDA APPROVES CENTOCOR'S REMICADE AS FIRST-LINE RHEUMATOID ARTHRITIS THERAPY
The US Food And Drug Administration (FDA) has approved Centocor Inc.'s Remicade (infliximab) for combination use with methotrexate as a first-line therapy to inhibit the progression of structural damage in patients with moderate-to-severe rheumatoid arthritis, the company said on Tuesday.
http://rheumatology.medscape.com/32017.rhtml?srcmp=rheu-010501  
(requires free registration)

REMICADE POSSIBLY LINKED TO TUBERCULOSIS
Twenty-eight people throughout North America and Europe have developed tuberculosis -- and one patient died -- soon after they were given the anti-inflammatory monoclonal antibody Remicade (infliximab), the European Agency for the Evaluation of Medicinal Products (EMEA) reported recently.
http://rheumatology.medscape.com/32014.rhtml?srcmp=rheu-010501  
(requires free registration)

RHEUMATOID ARTHRITIS ITSELF A RISK FACTOR FOR OSTEOPOROSIS IN MEN
Reduced bone mineral density (BMD) in men with rheumatoid arthritis (RA) is common, according to a report in the December issue of the Journal of Rheumatology.
http://rheumatology.medscape.com/32007.rhtml?srcmp=rheu-010501 
(requires free registration)

HEPATITIS C INFECTION MORE PREVALENT IN LUPUS PATIENTS THAN HEALTHY CONTROLS
The prevalence of hepatitis C virus (HCV) infection is higher in patients with systemic lupus erythematosus (SLE) than in healthy control subjects, according to a report published in the December issue of Arthritis and Rheumatism.
http://rheumatology.medscape.com/32182.rhtml?srcmp=rheu-011201 
(requires free registration) 

Medicare HMO Rates to Rise 2% to 5% in 2002
Federal payments to HMOs participating in the Medicare program next year are expected to increase about 2% for many of the 174 Medicare+Choice health plans. However, those operating in rural and lower cost areas of the nation could see rates rise by as much as 5%, based on a reading of preliminary 2002 payment rates released by the US Health Care Financing Administration (HCFA) late last week. http://dailynews.yahoo.com/h/nm/20010116/hl/medicare_1.html 

Many People May Be Deficient in Vitamin B-12 
By Suzanne Rostler 
NEW YORK (Reuters Health) - A deficiency of vitamin B-12 is often thought to be a problem that only occurs in the elderly. But the vitamin deficiency--which can cause anemia, dementia and severe nerve damage--may be more common than once believed, researchers suggest.
http://dailynews.yahoo.com/h/nm/20010116/hl/vitamins_1.html 

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A Closing Thought

JRA "Jesus Real Angels"

A meeting was held quite far from Earth
Its time again for another birth,
Said the Angles to the Lord above,
"This special child will need much love.
His progress maybe very slow,
Accomplishments he may not show
And he'll require extra care
From the folks he meets down there.
He may not run as easily as others,
He may not play sports like his brother.
He will have days when he can't laugh or play.
He will have days when he yells, "JUST MAKE THE PAIN GO AWAY!"
In many ways he won't adapt
And some will say he's a handicap
His thoughts at times will seem far away
It could be all the pain he's in that day.
So lets be careful where he's sent.
We want his life to be content.
Please Lord find parents who
Will do a special job for you.
They will not realize right away
They leading role they are asked to play.
They will be upset with you at first,
There faith will come in
And relies it could be worse.
Find teachers and friends who will make there lives bolder.
And that he and his family can lean on their shoulders.
With this child sent from above
Comes a stronger faith and greater love
And soon everyone who has helped him by given
Will realize he's a gift from heaven.
This precious charge so meek and mild
He is heavens SPECIAL CHILD."
By Kyle Hellem & his mom Lori

Kyle Hellem was diagnosed 2 years ago with JRA, polyarticular. For these past 2 years he has made 100's of copies of this poem and mailed them out and made JA pins for JA week in March. Last year he was on the front of the local paper trying to get the word out about JA. He talks to his school and to whoever is willing to listen about this disease. He attends CAMP JAMM in Illinois at Hasting Lake. Last year he took up collects from stores so that all the kids would have great prizes. He is already on the go this year for JA WEEK and CAMP.
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Staff
Page last updated on January 17, 2001