Prescribing a placebo
Placebos are one of the "holy cows" of pharmaceutical investigation. Drug trials have to be "double-blind placebo controlled" to be of any scientific value. The placebo, formerly called a "sugar pill" is the standard (the null point) against which to measure the effect of a drug. That makes perfect sense, wouldn't you agree? Hundreds of millions of dollars are spent on trials that test the efficacy of new drugs and the relative prevalence of their side effects against a "placebo".
"What - placebos are not standardized and placebo ingredients are never disclosed?" Those were the thoughts racing through my head when I read a recent article from the Health Sciences Institute in Baltimore. Prof Beatrice Golomb explains how reticent pharmaceutical companies are about the ingredients of their "sugar pills". It seems that pharmaceutical companies routinely make their own placebo pills for each trial and even formulate them to mimic expected drug reactions.
Incredible as it may seem, this of course tends to destroy any pretense of "scientific drug testing". Could that be the reason for some of those hundreds of thousands of deaths reportedly caused by pharmaceutical drugs every year and why the medical system has become a leading cause of death in the Western world?
Aiming to Please
July 21, 2003
As a clinical research tool, a placebo is often referred to as nothing but a sugar pill - neutral and benign. In
fact, "placebo" comes from the Latin word meaning "I shall please." Everything about the word would seem to be guileless. Or that's what the general thinking is anyway.In last week's e-Alert "Seeing Red" (7/16/03) I told you about two different studies in which red clover extract was tested in the treatment of menopausal hot flashes. In both studies, the group of women who received red clover showed about the same rates of success in controlling hot flashes. But the subjects in the placebo group in one study reported almost no effect at all, while in the other study the placebo subjects had almost the same results as the red clover group.
How could the results of these two placebo groups be so different? One strong possibility: The placebos may have been very different. Because contrary to common thinking, clinical research trials - especially pharmaceutical trials - bring a whole new meaning to the old Latin idea of "I shall please."
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The importance of being inert
--------------------------------------------------------------There was a time when doctors would prescribe phony medication - sugar pills - to their patients who they regarded as hypochondriacs. They called the pills "placebo" and when the patients reported positive results the idea of the placebo effect was born.
These days, placebo pills are used in clinical trials to measure the true effect of a drug or supplement. They are thought to be made of inert substances designed to have no effect. But consider this: there's no such thing really as an inert substance. For instance, placebo pills are still called sugar pills. Is sugar inert? Far from it, of course. If you take a sugar pill, your body will have a reaction, especially if you happen to have an insulin disorder. But if you're given that same pill as part of a drug research trial, your reaction becomes a factor in the research.
That may seem like nothing (what real difference could a little boost of sugar make?) but sugar and other supposedly inactive ingredients are not the issue. Not in the least.
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A little secret
--------------------------------------------------------------When a pharmaceutical company tests its products, where do you suppose they get placebo pills? Do they place an order with a placebo pill manufacturer? Or does Nestle's candy company run a little side business to supply researchers with sugar pills?
The fact is, drug companies make their own placebo pills for research purposes, and for each individual study they create a unique placebo formula - sometimes purposely including ingredients that match ingredients in the drugs being tested. But at no time do the contents of the placebos have to be revealed.
Does that sound "inert" or "inactive" to you? Suddenly the idea of a "sugar pill" doesn't seem so innocent anymore.
Before conducting human trials for drugs, pharmaceutical companies are often fully aware of many of the side effects of the products they're testing. So, for instance, if a drug is known to cause dizziness and nausea, the drug company running the test wants the placebo to have the same side effects. And they have an explanation for this. They say the placebo should mimic the drug being tested so that the control group of the experiment will have side effects similar to the placebo group. Without that, they claim, the results of a blind study would be compromised.
There are plenty of gray areas to debate in that logic, but for the moment let's focus on the idea of what they call an "active placebo," designed to mimic the side effects of a tested drug. And with that in mind let's look at an advertising campaign for the allergy medication called Claritin. In the Claritin TV spots, when it comes to the moment to list the side effects, the voice-over says, "The most common side effects with Claritin, including headache, drowsiness, fatigue and dry mouth, occurred about as often as they did with a sugar pill."
A sugar pill? Really? Just what kind of "sugar pill" were the researchers using that caused headache, drowsiness, fatigue and dry mouth? Sounds to me like a sugar pill with a little something added. But they want us to believe that this medication will produce side effects no more serious than what you'd get with a TicTac.
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The whistle blower
--------------------------------------------------------------Dr. Beatrice Golomb, MD, PhD, is an assistant professor of medicine at the University of California, San Diego, and has been actively fighting the research establishment's claim that placebos are inactive substances. Dr. Golomb wants scientists to provide a list of placebo ingredients so trial results can be properly evaluated.
To level the playing field, Dr. Golomb suggests that drug companies start divulging all placebo ingredients. She also recommends that a standardized set of placebos be developed that would have known and predictable side effects. This would go a long way toward eliminating the pharmaceutical industry's cynical manipulation of test data.
As you might suspect, the drug companies are not very receptive to Dr. Golomb's idea of letting go of this aspect of product testing that they have full control over.
Meanwhile, what about physicians and researchers who work independently from the pharmaceutical giants - do they know the truth about placebos supplied by drug companies? Right now it's hard to tell just how widespread this knowledge is. According to the National Center for Complementary and Alternative Medicine at the National Institutes of Health (NIH), the placebo effect is defined as "desirable physiological or psychological effects attributable to the use of inert medications." From that statement it would appear that NIH officials either believe that placebos are genuinely inactive, or they're not admitting that they know
better.Or maybe they're just feeling drowsy, dizzy, irritable and nauseous from a sugar pill someone gave them.
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Related articlesPlacebo's power goes beyond the mind
Nature - letters to the editor
Why do pharmaceutical drugs injure
Dummy drug provides pain relief
The Scotsman: Delving into mind over matter
"On average, placebo effects cure anything between 30 to 90 per cent. That has been written up in many scientific journals. I thought, Why not see if you could extend it..."Jane Russell on the Placebo Effect
Placebos are not always inert, they can have actual ingredients ... drug companies have begun to produce "active placebos." These pills, unlike the sugar or starch pills of old, contain ingredients that mimic the common side effects of the drug under study. An active placebo might, for example, cause dry mouth if the drug to be tested was Elavil, but it probably wouldn't cause drowsiness because Elavil is used to treat sleep disorders. It would be important to know whether people slept better with a placebo that wouldn't have that effect. Sometimes a prescription medication is used as an active placebo. In a study published in the New England Journal of Medicine (Mar. 2005), the combination of morphine and gabapentin for relief of neuropathic pain was compared to each drug alone and to an active placebo. The placebo used was lorazepam, a benzodiazepine medication with anxiety and sedative properties, with a common effect of dizziness. Two of the most common side effects of both morphine and gabapentin are dizziness and sleepiness.Study Verifies Power of Positive Thinking
Your medicine really could work better if your doctor talks it up before handing over the prescription. Research is showing the power of expectations, that they have physical -- not just psychological -- effects on your health. Scientists can measure the resulting changes in the brain, from the release of natural painkilling chemicals to alterations in how neurons fire. It's a new spin on the so-called placebo effect -- and it begs the question of how to harness this power and thus enhance treatment benefits for patients.The fool's gold that heals
Drug companies are the most profitable businesses in the world - ever seeking new diseases for which they can provide new 'miracle' medicines. But the fact is, Jacky Law reports, a simple sugar pill can often be just as effectiveThe healing power of placebos
Marco Visscher - Ode issue: 33
A sugar pill, a salt solution, a doctor in a white jacket - these all have the power to cure as long as the patient believes in their healing qualities. That seems impossible. So what does science say about the elusive placebo effect? Very little research has been done in this area of medicine. The pharmaceutical industry can't profit; after all, they can't make money from sugar pills. It is often forgotten that the effect could help people and shave billions off spiralling health-care costs. If researchers could gain more insight into how the effect works, it would stand as one of the biggest medical breakthroughs in history. Some people are convinced that the effect proves that strength of mind is sufficient to heal the body. Placebos have ... proven successful in treating depression, anxiety, stress, warts and ulcers - sometimes in as many as 60 to 70 percent of the cases. There are ... objective effects everyone can measure. Placebo treatments have been shown to lower blood pressure and cholesterol levels as well as improve reaction speeds, pulse rates and immune-system activity. Ultimately, the placebo phenomenon points to a strange paradox in modern medical science. As soon as an alternative-health treatment proves successful, it is dismissed as the placebo effect. It works only because people believe in it. Yet this explanation appears to contradict one of the foundations of medical science, which stresses that the mind and body are separate, therefore ruling out the possibility of healing through belief.
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March 2005:
The placebo effect(from a March 2005 article in New Scientist by Michael Brooks)
DON'T try this at home. Several times a day, for several days, you induce pain in someone. You control the pain with morphine until the final day of the experiment, when you replace the morphine with saline solution. Guess what? The saline takes the pain away.
This is the placebo effect: somehow, sometimes, a whole lot of nothing can be very powerful. Except it's not quite nothing. When Fabrizio Benedetti of the University of Turin in Italy carried out the above experiment, he added a final twist by adding naloxone, a drug that blocks the effects of morphine, to the saline. The shocking result? The pain-relieving power of saline solution disappeared.
So what is going on? Doctors have known about the placebo effect for decades, and the naloxone result seems to show that the placebo effect is somehow biochemical. But apart from that, we simply don't know.
Benedetti has since shown that a saline placebo can also reduce tremors and muscle stiffness in people with Parkinson's disease (Nature Neuroscience, vol 7, p 587). He and his team measured the activity of neurons in the patients' brains as they administered the saline. They found that individual neurons in the subthalamic nucleus (a common target for surgical attempts to relieve Parkinson's symptoms) began to fire less often when the saline was given, and with fewer "bursts" of firing - another feature associated with Parkinson's. The neuron activity decreased at the same time as the symptoms improved: the saline was definitely doing something.
We have a lot to learn about what is happening here, Benedetti says, but one thing is clear: the mind can affect the body's biochemistry. "The relationship between expectation and therapeutic outcome is a wonderful model to understand mind-body interaction," he says. Researchers now need to identify when and where placebo works. There may be diseases in which it has no effect. There may be a common mechanism in different illnesses. As yet, we just don't know.
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October 2005: Discussion over the use of placebo in clinical trials is heating up. Here is a communication from Vera Hassner Sharav of the ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP) www.ahrp.org
A debate in PLoS Medicine addresses the question: Should researchers test an experimental treatment against placebo to prove the superiority of the new treatment ?The ethical standards for research adopted by the World Medical Association as defined in the principles of the Declaration of Helsinki (DOH) state:
"The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods."
A note of clarification (in 2000) states: "in general this methodology [placebo] should only be used in the absence of existing proven therapy"
This affirms the clinical and ethical perspective of responsible practitioners and patients for whom "the crucial question in evaluating a new treatment is how it compares with the standard available treatment, and not whether it is better than placebo."
In a debate published in PLoS, both sides acknowledge that the likelihood that -- "the best current mehtods" -- i.e., those approved by the FDA and recommended in physician practice guidelines -- may not necessarily be safe and effective because the standard of "proof" used by the FDA is often invalid or unreliable.
Andreas Stang, Hans-Werner Hense, Karl-Heinz Jöckel argue: "the important issue is to decide when it is that we can call a therapy "standard"—that is, when can we speak of an indisputable benefit that would make a currently available treatment's use in a trial control group ethically imperative?"
They acknowledge the unreliability of the evidence: "Clinical guidelines or recommendations based on high quality evidence SOMETIMES exist to support use of such a therapy."
Indeed, all too often currently marketed, widely recommended treatments, have not been proven safe and effective -- certainly not in every controlled clinical trial in which they were tested. Under FDA's lax standards drugs are approved even if they failed to demonstrate efficacy in 10, 20, 50 -- unlimited number of trials -- as long as they can show two trials in which a new treatment shows an effect greater than placebo. And the trials are not designed to detect rare, but severe, even deadly safety hazards.
Thus, Erick H. Turner (a former FDA medical officer) and Martin R. Tramèr argue that FDA's approval standards are not proof of efficacy -- they only indicate an assumption of efficacy which all too often is proven wrong.
"If a drug with historical evidence of efficacy could be relied upon to be unfailingly effective—and placebo unfailingly ineffective—in all future clinical trials, we would readily admit that placebo is unnecessary and therefore unethical. The reality is that "proven effective therapy"—better called "assumed effective therapy" (AET)—often fails to show superiority to placebo. This is not because these drugs are in fact ineffective, but because the trials in question lack assay sensitivity . Assay sensitivity is defined as the ability of a trial to distinguish an effective from an ineffective therapy."
Turner and Tramer make a strong case when they cite the unpublished FDA antidepression drug trial data first analyzed by Khan (2000; 2003) then by others.
"Khan et al. gained access to unpublished, as well as published, clinical trials data on antidepressants from the Food and Drug Administration (FDA) via the United States Freedom of Information Act. They obtained the FDA review documents on 51 clinical trials on nine antidepressants approved between 1985 and 2000. Of 92 active treatment arms (all involving doses that were eventually approved), 47 (51%) failed to demonstrate statistical superiority to placebo. Of these, there were seven cases (15%) in which the placebo arm was actually superior to AET. Thus, it can be seen that the phrase "proven effective therapy" should be taken with a grain of salt."
"Now, what if the FDA had not had the benefit of looking at the placebo arms and relied on an equivalence or noninferiority design comparing study drug with AET?
Khan et al. list 12 flexile-dose studies in which (now approved) study drug outperformed AET (previously approved antidepressants). Many opponents of placebo would argue that each of these 12 trials provides ample evidence for efficacy of the study drug. However, because these trials did include placebo arms, we discover that in four of them (33%), neither AET nor study drug beat placebo. (In fact, in two of these four trials, AET was numerically inferior to placebo.) Therefore, in these four antidepressant trials, the two "active" drugs were not equally effective, but rather equally ineffective. This critical distinction would have been lost without placebo, and it would have been impossible to ascertain that these seemingly positive trials were in fact false positive trials."
"The problem of assay sensitivity is not confined to antidepressants or even to psychotropic drugs in general. A meta-analysis by Tram, et al found that, among 52 possible comparisons between the "proven" antiemetic ondansetron and placebo, 19 (37%) failed to show a difference."
Turner and Tramèr further argue that placebo trials are better at uncovering safety issues: "The declaration is silent on the possibility that omitting placebo can lead to problems, too, as we have now witnessed with Vioxx."
The placebo issue clearly needs further debate focusing on the best interest of the patients who are subjects of trials. It would be wrong to defend placebo merely to overcome the confounding unreliable findings from poorly designed trials. Improving the standards and quality -- and thereby the reliability of clinical trial findings -- should be the first order of the day for institutional review boards (IRBs), clinical trial investigators, funding agencies, the FDA, and the journals. The research stakeholders' financial interests have undermined public safety, resulting in preventable human casualties.
See: the placebo debate in two issues of PLoS Medicine: March 2005 | Volume 2 | Issue 3 | and June 2005
journal.pmed.0020072-S.pdf
journal.pmed.0020187-S.pdf
FDA's drug approval process is being roundly criticized: the agency's standards for evaluating safety and efficacy of new treatments have been shown to be demonstrably flawed; faulty judgments most often benefit commercial interests while harming consumers. It is a matter of record that the FDA has allowed blatant conflicts of interest to taint the approval process, and this tainted process led to the marketing of drugs whose safety and efficacy FDA officials knew were largely unproven--since in most of the pre-marketing trials, they failed. Such drugs were nevertheless unleashed on an unsuspecting public and allowed to be aggressively marketed for large populations. FDA's tacit complicity in the concealment of negative data from the public, opens the FDA to charges of negligence;Even as these major shortcomings have been uncovered, the FDA has asserted in briefs submitted to several courts — the latest in Utah -- that its authority pre-empts every other authority -- state and judicial. FDA's counsel argument implies that even if the agency fails to perform its legal obligation to ensure that the public was warned about "reasonable evidence" of hazardous drug effects, manufacturers may not issue warnings on their products' labels without an FDA directive.
For FDA to claim that its dangerously flawed process for evaluating and monitoring the safety of drugs -- leading to preventable deaths -- nevertheless pre-empts all other authorities, is preposterous. The FDA is neither infallible nor given authority to exempt itself from the checks and balances of our democratic process.
See: http://www.ahrp.org/SuitsDecisions/AmicusKallasFDA.pdf
Contact: Vera Hassner Sharav
212-595-8974
veracare@ahrp.org
See also:Is Your Doctor Prescribing Placebos?
One of the most intriguing processes in medicine is the placebo effect: the healing power of a sham therapy, when it's offered to patients with the suggestion that it will help. Neuroscientists have even observed where and how the placebo effect may work in the brain. In one recent study by University of Michigan researchers, participants who were told they would receive painkillers showed increased production of endorphins — the brain's natural pain reliever — even though they got no analgesic at all.
Kiss And Make It Better? A Placebo Pill For Kids
Buettner, 40, who lives in Severna Park, Maryland, with her husband and two children, envisioned a tablet that would empower parents to do something tangible for minor ills and reduce the unnecessary use of antibiotics and other meds. So she founded Efficacy Brands, which next week will sell chewable, cherry-flavored dextrose tablets, Obecalp, for placebo spelled backward.
The Power of the Placebo — Is Healing All in Our Mind?
Integrative medicine has been dismissed time and again as "the placebo response." Chelation? Oh, it's just a placebo. Homeopathy? Again, it's just a placebo. Yet patients now flock to the doors of integrative physicians who brave the ire of their state medical boards to offer health programs based upon natural approaches and physical, emotional, and spiritual balance. They know that the mind-body connection is vital to a patient's health.
Placebo: Thinking so, makes it so
Talk about "placebo-controlled trials" is too easily taken to imply that "placebo" means "doing nothing". That is far from true. In reality, placebo describes the phenomenon that unconscious and not-understood emotional or mental processes can produce powerful physical effects. A person given a dummy pill and told that it is a drug will often experience the feelings that the drug would induce. Someone given a drug that lowers blood pressure, say, who is told that it raises blood pressure, may actually experience a rise in blood pressure: "placebo" can actually be more powerful than physical medication.Mainstream disciplines are beginning to recognize the power of the placebo response. The National Institues of Health held a workshop in 2000, "The Science of the Placebo: Toward an Interdisciplinary Research Agenda".
Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why.
Behind the scenes, however, MK-869 was starting to unravel. True, many test subjects treated with the medication felt their hopelessness and anxiety lift. But so did nearly the same number who took a placebo, a look-alike pill made of milk sugar or another inert substance given to groups of volunteers in clinical trials to gauge how much more effective the real drug is by comparison. The fact that taking a faux drug can powerfully improve some people's health—the so-called placebo effect—has long been considered an embarrassment to the serious practice of pharmacology.
Placebo treatments stronger than doctors thought
"It's not that placebos or inert substances help," said Linda Blair, a Bath-based psychologist and spokeswoman for the British Psychological Society. Blair was not linked to the research. "It's that people's belief in inert substances help."While doctors have long recognized that placebos can help patients feel better, they weren't sure if the treatments sparked any physical changes.
In the Lancet review, researchers cite studies where patients with Parkinson's disease were given dummy pills. That led their brains to release dopamine, a feel-good chemical, and also resulted in other changes in brain activity.
"Placebo Washout" - Another Outrageous Medical LieBefore a drug company starts to test the effectiveness of a medicine they want to market, they bring together all the volunteers—and they give them a sugar pill.
They tell them, "We're going to give you a sugar pill."
After a ten-day period on these placebos, the researchers weed out the people who improved, got better, feel better. They dump them from the ensuing clinical trial. Bye bye.
posted by Sepp Hasslberger on Friday July 25 2003
updated on Tuesday May 17 2011URL of this article:
http://www.newmediaexplorer.org/sepp/2003/07/25/prescribing_a_placebo.htm
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