A PWP friend of several years has been visiting for a few days. She was here to help me with my first post-op visit which had to be completed off meds. As she drove away last night she had tears in her eyes and thanked me for what I have done for her and all PWPs by participating in the CERE-120 trial, in the attempt to find a cure for this disgusting disease we all must endure daily for the rest of our lives.

Science has never come easy. It is filled with risks, whether it is testing a new vaccine for the first time or traversing the galaxies as astronauts in search of whatever they search for out there in the dark void of space. It isn’t easy and never will be. As I sit here this morning typing away on this reply, and having just returned from Philly yesterday evening, I find it hard to believe that I may have been shammed. My scores were significant yesterday. My tremor is still present, but is it far less than it has been in many years. If this is a placebo effect, I will keep it!! But if it is from the “real thing” then yippee…are we another step closer to a “cure” for this crappy disease…maybe so. Did I take a sham risk for the sake of everyone in this thread and in the PD community as a whole. Yes.

As Howard stated above, “we are the pioneers” of our PD generations. The author of this thread took a very pioneering leap of faith a few years ago by being one of the original six Spheramine recipients in a Phase I trial…talk about unknown…yes, I know it did not include a sham component, but Phase II has included sham. Some of us are willing to take the risks that come with pioneering, some are not. In either case, it is a personal decision. Sham surgery is deemed by many physicians as necessary to “view” the placebo effect, which can be. It is entirely possible that after a time sham may be abandoned as unnecessary.

Did I take the sham component of CERE-120 lightly…NO!! But, the day came when I had to make a decision to take the risk involved or not. I had to ask myself, do I continue with this decision and why. The why was a selfish choice. I knew that my only option at this point was DBS…hardware, battery change surgeries, programming, risk of infection and hardware removal, the possibility of having to endure the surgery a second time to replace what was removed, etc. Now some might say, but DBS is a known and that taking that risk is a no-brainer…no sham involved. Okay, so that makes it okay? It is still an invasion to the brain, with the risk of infection greater than CERE-120. The risk of infection with DBS isn’t just the brain, but the other parts of the body. My personal reaction could have also happened with DBS…seizure from brain swelling. Would I do the CERE-120…absolutely!

Do those of you here in this thread think that sham has never been used in other surgical settings.

The Connection.org, Show Originally Aired: 7/16/2002
http://www.theconnection.org/shows/2...716_b_main.asp

“Sham ops on arthritic knees are as successful as the real thing, which is to say, neither works at all. Faked surgery has some ethicists worried. It's one thing to hand out candy, quite another to slice into flesh on a hunch that it's worthless, exposing patients to the dangers of anesthetics and infections. But finding out what really works and what's wishful thinking could save money, time, and misery for the many creaky-jointed amongst us.”

Will we ever get passed either of the two views below…both valid. Hopefully Not! This topic…sham surgery…needs to stay of the table of discussion.

University of South Florida, Sham surgery may put patients at risk
http://student.bmj.com/back_issues/0300/news/52a.html

“Researchers carrying out sham surgery have pointed out that all clinical trials have been approved by review boards at bodies such as the US National Institutes of Health and the Food and Drug Administration. They also argue that subjects in the trials have decided to participate and that preventing patients from deciding what risks they are willing to take is a direct violation of the principle of autonomy.

“But many researchers are unhappy with the use of sham surgery in finding a treatment for Parkinson's disease. Dr Ruth Maklin of the Albert Einstein College of Medicine in New York has voiced her opposition to the surgery in the New England Journal of Medicine. "Performing a surgical procedure that has no expected benefit other than the placebo effect violates the ethical and regulatory principal that the risk of harm to subjects must be minimised in the conduct of research," said Dr Maklin.”

Sham Surgery Returns as a Research Tool
By SHERYL GAY STOLBERG, April 1999
http://www.nytimes.com/library/revie...cs-review.html

“In 1939, long before high-tech drugs came along to treat the chest pain known as angina, an Italian surgeon named Fieschi devised a simple technique. Reasoning that increased blood flow to the heart would ease his patients' pain, he made tiny incisions in their chests and tied knots in two arteries. The results were spectacular. Three quarters of all patients improved." One third were cured.

“Two decades later, the National Institutes of Health paid a young cardiologist in Seattle, Dr. Leonard A. Cobb, to conduct a novel test of the Fieschi technique. Cobb operated on 17 patients. Eight had their arteries tied; the other nine got incisions, nothing more. In 1959, the New England Journal of Medicine published his findings: The phony operations worked just as well as the real thing.

“That was beginning of the end of the procedure, known as internal mammary artery ligation; within two years, it became a footnote in the medical history texts. It was also the beginning and the end, apparently, for sham surgery in this country. By the early 1970s, an ethics revolution had transformed human experiments, and the idea of surgery as placebo was unthinkable.

“Unthinkable until now. Sham surgery is on the rise, to the horror of some doctors who say it is immoral and to the delight of others who say it is time to apply the same rigorous scientific standards to surgery as to the rest of the medical profession. And with it comes a host of thorny questions.

“The results of the first sham brain surgery study were reported last week in Toronto by a team of neurologists. Forty people with Parkinson's disease participated. Each had neurosurgery: four tiny holes, drilled through the forehead into the skull. But only half got the injections of fetal cells that might have repaired their damaged brains; the other half got nothing. One year later, three members of the placebo group said their symptoms had improved.”

Sham surgery can be ethical and safe
http://jnnp.bmj.com/cgi/content/full/74/2/202
"Sham surgery is justified in clinical trials in Parkinson’s disease provided strict criteria are followed to ensure that it is used safely and effectively, according to an article which defends the practice in judging outcome of fetal tissue implantation treatment.

"Sham surgery is controversial and used rarely. Its recent use in two trials assessing treatment for Parkinson’s disease has, naturally enough, provoked much ethical debate. According to bioethicist Ruth Macklin, the concept of sham surgery controls produces, "tension between the highest standards of research and the highest standards of ethics." Other critics see the bigger picture, recognising that clinical trials need to benefit patients, society, and research, though still opposing sham surgery as unnecessary.

"The article’s author, a neurologist, emphasises the paramount need to exclude false positive results in these trials in the interests of patient and public safety. In Parkinson’s disease this need can be fulfilled only by sham surgery controls, he argues, because of the significant and sustained placebo effect reported in medical clinical trials and its confounding of subjective outcomes so often relied on for assessing treatment. A recently published trial using sham surgery controls in the United States showed that despite promising initial results the long term results differed little between treatment and control arms because of the significant surgical placebo effect. "The recent experience with intracerebral fetal tissue grafting for Parkinson’s disease suggests that sham surgery controls can be done in a safe and ethical manner."

Full Article: http://jme.bmj.com/cgi/content/full/...665fdbf66171c3

Listen - New York Public Radio
http://www.wnyc.org/shows/radiolab/episodes/2007/05/18

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Benefiting from Belief
http://www.fda.gov/fdac/features/2000/100_heal.html

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."

Placebos in the Doctor's Office: Opposing Views

Today, when 26-year-old Jennifer Kennedy (not her real name) from Rockville, Md., has a panic attack, she simply distracts herself with a book or crossword puzzle. But at their height, several years ago, the attacks scared her so much that she finally went to the emergency room. "I thought I was going to die from a heart attack," says Kennedy.

She didn't believe her doctor when he told her to "just relax" and she would feel okay, and he ended up prescribing pills. He didn't tell her until two weeks later, after her panic attacks had subsided, that the pills were simply placebos with no active medical ingredient.

Those who oppose the use of placebo pills in medical practice say that such deceit can undermine the essential trust between patient and doctor. Gastroenterologist Michael Kirsch, M.D., has called doctors who prescribe placebos outside medical research "con artists." Kirsch asks in a 1998 editorial in Priorities, the magazine of the nonprofit American Council on Science and Health, "If using placebos therapeutically is ethical and reasonable, shouldn't we encourage judges to render extralegal activist rulings, winegrowers to bottle 'placebo' vintages, curators to display masterpiece look-alikes misleadingly, and journalists and newscasters to sanitize news?" He continues, "In such a world, all of us would be groping for truth in a hall of mirrors."

But placebo researcher Michael Jospe disagrees with what he calls this "strict, grumpy approach that concludes that any doctor who uses placebos is acting unethically." Some circumstances, he says, justify this kind of benevolent deception--like when a patient insists on a medicine that is unnecessary and carries needless risks.

"You've got to be there on the oncology ward," Jospe says, "and see how suffering people get so demanding of drugs that might be extremely harmful to them. If you look at sugar pills in the broader context of a supportive doctor-patient relationship rather than just as ripping off the patient, you may come to a different conclusion" about the ethics of placebos.

It's not uncommon for a patient to feel betrayed initially upon hearing that they were given a placebo, Jospe says, but a sensitive doctor can explain to the patient, "No, that the placebo worked doesn't mean you're crazy. You were just in distress and thus more prone to reacting to anything with the potential to help."

Kennedy admits to feeling deceived when she first found out the pills her doctor prescribed were fake, but says she now appreciates the doctor's decision to prescribe the placebo. "At first, I felt stupid. But that day at the hospital, the doctor must have realized I wasn't going to accept 'you're fine, it's all in your mind.' The placebo helped me realize that I'm not unhealthy and I'm going to be okay. Now, I think it's really neat that something that didn't really affect me had such a big effect on my life."

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The Placebo Effect: The Triumph of Mind over Body
http://www.nexusmagazine.com/article...eboEffect.html
A growing body of research reveals not just psychological and perceptual components to the placebo effect but also a biochemical substrate to the mechanism.

Extracted from Nexus Magazine, Volume 14, Number 4 (June - July 2007)
From our web page at: www.nexusmagazine.com

by Peter Arguriou © 2007

A neglected phenomenon
One of the most commonly used terms in medical language is the word placebo. The placebo effect is used as a scale for evaluating the effectiveness of new drugs. But what exactly is the placebo effect and what are its consequences in the deterministic structure of Western medicine?
The placebo effect has been frequently abused by health professionals to denote and stigmatise a fraud or fallacy. Alternative therapies have often been characterised as merely placebos. But the placebo effect is not a fraudulent, useless or malevolent phenomenon. It occurs independently of the intentions of charlatans or health professionals. It is a spontaneous, authentic and very factual phenomenon that refers to well-observed but uninterpreted and contingent therapies or health improvements that occur in the absence of an active chemical/pharmacological substance. Make-believe drugs-drugs that carry no active chemical substances-often act as the real drugs and provoke therapeutic effects when administered to patients.

In many drug trials, the manufacturers of the drug sadly discover that their product is in no way superior to the effect of a placebo. But that does not mean that a placebo equates to a null response of the human organism. On the contrary, a placebo denotes non-chemical stimuli that strongly motivate the organism towards a therapeutic course. That is, the placebo effect is dependent not on the drug's effectiveness but solely on therapeutic intention and expectation.

Effects of positive and negative thinking
The placebo effect has been often misunderstood as a solely psychological and highly subjective phenomenon. The patient, convinced of the therapy's effectiveness, ignores his symptoms or perceives them faintly without any substantial improvement of his health; that is, the patient feels better but is not healthier. But can the subjective psychological aspect of the placebo effect account for all of its therapeutic properties? The answer is definite: the placebo effect refers to an alternative curative mechanism that is inherent in the human entity, is motivated by therapeutic intention or belief in the therapeutic potential of a treatment, and implies biochemical responses and reactions to the stimulus of therapeutic intention or belief.

But placebos are not always beneficial: they can also have adverse effects. For example, administering a pharmacologically inactive substance to some patients can sometimes bring about unexpected health deteriorations. A review of 109 double-blind studies estimated that 19 per cent of placebo recipients manifested the nocebo effect: unexpected deteriorations of health.1 In a related experiment, researchers falsely declared to the volunteers that a weak electrical current would pass through their head; although there was no electrical current, 70 per cent of the volunteers (who were medical students) complained of a headache after the experiment.
In a group of patients suffering from carotid atherosclerosis, prognosis and progression of the disease were burdened when their psychological health was bad (i.e., they were affected by hopelessness or depression). In another group of carotid atherosclerosis patients, prognosis and progression were burdened not only by hopelessness but also by hostility. In patients with coronary heart disease, hopelessness was a determinative risk factor.4 Social isolation, work stress and hostility comprised additional risk factors.5
Positive or negative thinking seems to be a decisive risk factor for every treatment, perhaps even more important than medical intervention.
The nocebo effect appears to have a specific biological substrate. A group of 15 men whose wives suffered from terminal cancer participated in a small perspective study. After their wives' deaths, the men experienced severe grief that caused immunodepression. The spouses' lymphocytes for a period of time after their wives' deaths responded poorly to mitogenes. Grief had assaulted their immune system. The study proposed that grief and grief-induced immunodepression resulted in high- level mortality of the specific group.

A short history of a small miracle
The term placebo (meaning "I shall please") was used in mediaeval prayer in the context of the phrase Placebo Domino ("I shall please the Lord") and originated from a biblical translation of the fifth century AD.7 During the 18th century, the term was adopted by medicine and was used to imply preparations of no therapeutic value that were administered to patients as "decoy drugs". The term began to transform in 1920 (Graves8), and through various intermediate stages (Evans and Hoyle, 19339; Gold, Kwit and Otto, 193710; Jellinek, 194611) was fully transformed in 1955 when it finally claimed an important portion of the therapeutic effect in general. Henry K. Beecher, in his 1955 paper "The Powerful Placebo", attributed a rough percentage of 30 per cent of the overall therapeutic benefit to the placebo effect.
In certain later studies, the placebo effect was estimated at even higher, at 60 per cent of the overall therapeutic outcome. In a recent review of 39 studies regarding the effectiveness of antidepressant drugs, psychologist Guy Sapirstein concluded that 50 per cent of the therapeutic benefits came from the placebo effect, with a poor percentage of 27 per cent attributed to drug intervention (fluoxetine, sertaline and paroxetine). Three years later Sapirstein, along with a fellow psychologist Irving Kirsch, processed the data from 19 double-blind studies regarding depression and reached an even higher percentage of therapeutic results attributed to the placebo effect: 75 per cent of depression therapies or ameliorations were placebo induced!

Hróbjartsson and Gotzsche (200114, 200415) doubted the effectiveness of the placebo phenomenon, attributing it solely to the subjective factors of human psychology. And indeed, there is a major aspect of the placebo effect related to psychology. In two studies where placebos were exclusively administered, the placebo effect seemed to be effected from the subject's perception of the applied therapy, i.e., two placebo pills were better than one, bigger pills were better than smaller, and injections were even better.
The placebo induced a reaction not only to the therapy but also to its form, suggesting that the placebo phenomenon is shaped according to the personal symbolic universe of the patient. Before the placebo response occurs, human perception has already interpreted the applied therapy and has prepared a certain response to it. It would appear that not only chemical but also non-chemical stimuli participate in the motivation of the human organism towards therapy.

But is the placebo reaction solely a psychological phenomenon or does it have additional tangible somatic effects?

One of the more dramatic events regarding placebo therapy was reported in 1957 when a new wonder drug, Krebiozen, held promise as the final solution to the cancer problem. A patient with metastatic tumours and with fluid collection in his lungs, who demanded the daily intake of oxygen and the use of an oxygen mask, heard of Krebiozen. His doctor was participating in Krebiozen research and the patient begged him to be given the revolutionary drug. Bent by the patient's hopelessness, the doctor did so and witnessed a miraculous recovery of the patient. His tumours melted and he returned to an almost normal lifestyle. The recovery didn't last long. The patient read articles about Krebiozen's not delivering what it promised in cancer therapy. The patient then had a relapse; his tumours were back. His doctor, deeply affected by the aggravation, resorted to a desperate trick. He told his patient that he had in his possession a new, improved version of Krebiozen. It was simply distilled water. The patient fully recovered after the placebo treatment and remained functional for two months. The final verdict on Krebiozen, published in the press, proved the drug to be totally ineffective. That was the coup de grace for the patient, who died a few days later.

In spite of the melodrama of the Krebiozen case, there is no single case or personal testimony that can denote or prove a therapy to be effective. Statistical studies, not personal testimonies, can verify a proposed therapy's effectiveness, and well-planned studies are able to concur that the placebo phenomenon has somatic properties.

One such study was implemented in 1997. The two study groups consisted of patients with benign prostatic hypertrophy. One group took actual medication while the control group received placebo treatment. The placebo recipients reported relief from their symptoms and even amelioration of their urinary function.18 A placebo has also been reported to act as a bronchodilator in asthmatic patients, or to have the exact opposite action-respiratory depression-depending on the description of the pharmacological effect the researchers gave to the patients and therefore the effect the patients anticipated.

A placebo proved highly efficient against food allergies and, subsequently, impressively effective in the sinking of biotechnologies on the stockmarket. How could that be? Peptide Therapeutics Group, a biotech company, was preparing to launch on the market a novel vaccine for food allergies. The first reports were encouraging. When the experimental vaccine reached the clinical trials stage, the company's spokesperson boasted that the vaccine proved effective in 75 per cent of the cases-a percentage that usually suffices to prove a drug's effectiveness. But the good news didn't last long. The control group, given a placebo, did almost as well: seven out of 10 patients reported getting rid of their food allergies. The stock value of the company plunged by 33 per cent. The placebo effect on food allergies created a nocebo effect on the stockmarket!20 In another case, a genetically designed heart drug that raised high hopes for Genentech was clobbered by a placebo.

As aptly put by science historian Anne Harrington, placebos are "ghosts that haunt our house of biomedical objectivity and expose the paradoxes and fissures in our own self-created definitions of the real and active factors in treatment".

The placebo's pharmacomimetic behaviour can even imitate a drug's side effects. In a 1997 study of patients with benign prostate hypertrophy, some patients on a placebo complained of various side effects ranging from impotence and reduced sexual activity to nausea, diarrhoea and constipation. Another study reported placebo side effects as including headaches, vomiting, nausea and a variety of other symptoms.

The placebo effect in surgery
But how deep can the placebo effect trespass into the well-defined area of medicine? Surely it can't joust with medicine's strike force; it cannot challenge surgery. Or can it?

In 1939, an Italian surgeon named Davide Fieschi invented a new technique for treating angina pectoris (chest pain due to ischaemia or lack of blood/oxygen getting to the heart muscle, usually due to obstruction of the coronary arteries).24 Reasoning that increased blood flow to the heart would reduce his patients' pain, he performed tiny incisions in their chests and tied knots on the two internal mammary arteries. Three quarters of the patients showed improvement; one quarter of them was cured. The surgical intervention became standard procedure for the treatment of angina for the next 20 years. But in 1959, a young cardiologist, Leonard Cobb, put the Fieschi procedure to the test. He operated on 17 patients: on eight of them he followed the standard procedure; on the other nine he performed only the tiny incisions, letting the patients believe that they'd had the real thing. The result was a real upset: those who'd had the sham surgery did as well as those who'd had the Fieschi technique.25 That was the end of the Fieschi technique and the beginning of the documented surgical placebo effect.
In 1994, surgeon J. Bruce Moseley experimented with the surgical placebo. He split a small group of patients suffering from osteoarthritis of the knee into two equal groups. Both groups were told that they would undergo arthroscopic surgery, but only the first group got the real thing. The other group was left virtually untreated, with the doctor performing only tiny incisions to make the arthroscopic scenario credible. Similar results were reported in both groups.

Moseley, stunned by the outcome, decided to perform the trial with a larger statistical sample in order to reach safer conclusions. The results were replicated: arthroscopic surgery was equal therapeutically to the placebo effect.27 The placebo had found its way into surgical rooms.
Perhaps the most impressive aspect of surgical placebo arose in a groundbreaking 2004 study. In the innovative field of stem-cell research, a new approach was taken with Parkinson's disease. Human embryonic dopamine neurons were implanted through tiny holes in the patients' brains. Once again, the results were encouraging. And once again, the procedure failed to do better than a placebo. In this case, the placebo involved tiny holes incised in the skull without implantation of stem cells. As the researchers confessed, "The placebo effect was very strong in this study".

But how can it be that the therapeutic expectancy alone often produces results equal to those from actual surgery? It appears that the mind is exerting control over somatic processes, including diseases. The biochemical traces of this influence are only beginning to be outlined. Modern research indicates a biological, tangible substrate to the placebo effect.

Somatic pathways
In the mid-1990s, researcher Fabrizio Benedetti conducted a novel experiment whereby he induced ischaemic pain and soothed it by administering morphine. When morphine was replaced by a saline solution, the placebo presented analgesic properties. However, when naloxone (an opiate antagonist) was added to the saline solution, the analgesic properties of the water were blocked. Benedetti reached the conclusion that the placebo's analgesic properties were a result of specific biochemical paths. Naloxone blocked not only morphine but also endogenous opioids-the physical pain-relievers.

The endogenous opioids, endorphins, were discovered in 1974 and act as pain antagonists. Benedetti's suggestion of a placebo-induced release of endorphins was supported by findings produced with MRI and PET scans.30 Placebo-induced endorphin release also affects heart rate and respiratory activity.31 As researcher Jon-Kar Zubieta described, "...this [finding] deals another serious blow to the idea that the placebo effect is a purely psychological, not physical, phenomenon".

Further findings support the notion that the placebo effect presents a biochemical substrate in both depression and Parkinson's disease. Analysing the results of PET scans, researchers estimated the glucose metabolism in the brains of patients with depression. Glucose metabolism under placebo presented differentiations that were similar to those caused by antidepressants such as fluoxetine.33 In patients suffering from Parkinson's disease, a placebo injection promoted dopamine secretion in a similar way to that caused by amphetamine administration.34 Benedetti demonstrated that the placebo effect provoked decreased activity in single neurons of the subthalamic nucleus in patients with Parkinson's disease.

From numerous research findings, it is logical and rather safe to conclude that there is a biochemical substrate to the placebo effect. But what is more intriguing to it is its relation to perception. It would appear that perception and the codes and symbols that the animate computer, the brain, utilises in order to process internal and external information strongly determine the potency and form of placebo response.

In a recent study, patients were purposely misinformed that they had been infected by hazardous bacilli and they subsequently underwent treatment. However, there were no bacilli and the treatment administered was a placebo. Guess what? Some of the study subjects developed infection-like conditions that were not treatable by the placebo medication.36 The mind interpreted the fictional bacilli as hazardous and instructed the body to respond to them as if they were real.

Despite the placebo's potency and its importance for a new perception of health where body and mind heavily interact, large numbers of scientists continue to regard the placebo as an insignificant systematic error, a troublesome nought. According to cancer researcher Gershom Zajicek: "There is nothing in the pharmacokinetic theory which accounts for the placebo effect. In order to keep the theory consistent, the placebo effect is regarded as random error or noise which can be ignored."

One of the most perceptive placebo researchers was Stewart Wolf, "the father of psychosomatic medicine", who as early as 1949 had given it a thorough description. Wolf not only defended the placebo as a non-fictional and very "real" phenomenon but also described the placebo's pharmacomimetic behaviour. He was perhaps the first researcher to correlate the placebo effect not only with psychology and predisposition but also with perception. More than half a century ago, he stated that "the mechanisms of the body are capable of reacting not only to direct physical and chemical stimulation but also to symbolic stimuli, words and events which have somehow acquired special meaning for the individual".

In this context, a pill is not merely an active substance but also a therapeutic symbol and thus the organism is able to respond not only to its chemical content but also to its symbolic content. Likewise a bacillus, beyond its physical properties, acquires symbolic properties that can cause an organism's reaction even in the absence of the bacillus.

The presence and extent of the nocebo effect should also be studied in regard to drug resistance. Perhaps drug resistance is a multifactorial phenomenon involving not only microbial evolutionary aptness but also human psyche mechanics. Placebo and nocebo phenomena might prove fundamental not only on the personal level but also in the public health arena.
They might even provide the foundation stone for a new model of health, a new medicine that was envisioned by Wolf in the 1950s: "...in the future, drugs will be assessed not only with reference to their pharmacologic action but also to the other forces at play and to the circumstances surrounding their administration".

Five centuries ago, Swiss alchemist and physician Paracelsus (1493-1541) wrote: "You must know that the will is a powerful adjuvant of medicine." It seems that our scientific arrogance has blinded us to the teachings of the past.

About the Author:
Peter Arguriou was born in Greece in the summer of 1973. He studied medicine at the University of Athens Medical School, but left disappointed by the mechanistic perceptions governing medicine. Later, he briefly studied classical homoeopathy at the Aegean University under Alternative Nobel Prize winner George Vithoulkas. He writes for the Greek press and is the author of eight books (fiction, science fiction, poetry - most of them still unpublished). He is a member of the Hellenic MENSA and currently is working on a book regarding novel epidemics, bad science, the gene promise, the media travesty in coverage of science news, orchestrated propaganda and the corruption of the scientific establishment by big business and political agendas. He can be contacted by email at petrosarguriou@hotmail.com.

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Source: Mayo Clinic
Dateecember 31, 2003

Placebo Effect: Harnessing Your Mind's Power To Heal
http://www.sciencedaily.com/releases...1231084101.htm

Science Daily — It's true that some people who participate in research studies and take inactive medications called placebos do see health improvements. People taking placebos have experienced reduced pain, healed ulcers, eased nausea and even warts disappeared.

The January issue of Mayo Clinic Women's HealthSource details several theories on how the placebo effect might work:

Benefit from attention: In a placebo-controlled research study, patients often have frequent and intensive medical attention. Some people respond favorably.

Stimulus response: People may have a trained positive response to taking a pill or receiving treatment, whether it's real or not.

Beliefs or expectations, including the meaning you attach to a treatment: A person with positive expectations of the treatment may experience the placebo effect more than someone with lower expectations.

Relationship with your doctor: A person whose doctor is supportive and positive may experience more benefit from a placebo -- or the standard treatment -- than someone who doesn't have that relationship.

Pleasing your doctor: You feel better because -- consciously or unconsciously -- you want to show your doctor that you're a good patient and you appreciate the care.

Probably a combination of many psychological and physiological mechanisms are at work. Research studies and theories hold important clues to solve the mystery behind the placebo effect, but more research is needed to examine how these factors interplay to produce this healing force.

Note: This story has been adapted from a news release issued by Mayo Clinic.

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Tuesday, December 30, 2003
Placebo Effect: Harnessing Your Mind’s Power to Heal

It’s true that some people who participate in research studies and take inactive medications called placebos do see health improvements. People taking placebos have experienced reduced pain, healed ulcers, eased nausea and even warts disappeared.

The January issue of Mayo Clinic Women’s HealthSource details several theories on how the placebo effect might work:

Benefit from attention: In a placebo-controlled research study, patients often have frequent and intensive medical attention. Some people respond favorably.

Stimulus response: People may have a trained positive response to taking a pill or receiving treatment, whether it’s real or not.

Beliefs or expectations, including the meaning you attach to a treatment: A person with positive expectations of the treatment may experience the placebo effect more than someone with lower expectations.

Relationship with your doctor: A person whose doctor is supportive and positive may experience more benefit from a placebo -- or the standard treatment -- than someone who doesn’t have that relationship.

Pleasing your doctor: You feel better because -- consciously or unconsciously -- you want to show your doctor that you’re a good patient and you appreciate the care.

Probably a combination of many psychological and physiological mechanisms are at work. Research studies and theories hold important clues to solve the mystery behind the placebo effect, but more research is needed to examine how these factors interplay to produce this healing force.

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Great Expectations: Why Do Placebos Affect People Differently?

19 Jul 2007
http://www.medicalnewstoday.com/articles/77244.php

Why do some people experience a "placebo effect" that makes them feel better when they receive a sham treatment they believe to be real while other people don't respond at all to the same thing, or even feel worse?

A new study from the University of Michigan Health System may help explain why.

Using two different types of brain scans, U-M researchers have found that the extent to which a person responds to a placebo treatment is closely linked to how active a certain area of their brain becomes when they're anticipating something beneficial.

Specifically, the research finds strong links between an individual's response to a placebo "painkiller", and the activity of the neurotransmitter known as dopamine in the area of the brain known as the nucleus accumbens. That's a small region at the center of the brain that's involved in our ability to experience pleasure and reward, and even to become addicted to the "high" caused by illicit drugs.

The new research, published in the July 19 issue of the journal Neuron, builds on research previously published by the same U-M team in 2005. That study was the first to show that just thinking a placebo "medicine" will relieve pain is enough to prompt the brain to release its own natural painkillers, called endorphins, and that this corresponds with a reduction in how much pain a person feels.

"Receptors for both endorphins and dopamine are clustered heavily in the nucleus accumbens. So, taken together, our studies delve directly into the mechanisms that underlie the placebo effect," says senior author and U-M neuroscientist, psychiatrist and brain-imaging specialist Jon-Kar Zubieta, M.D., Ph.D. "This is a phenomenon that has great importance for how new therapies are studied, because many patients respond just as well to placebo as they do to an active treatment. Our results also suggest that placebo response may be part of a larger brain-resiliency mechanism."

For the current study, Zubieta and his colleagues led by neuroscience graduate student David J. Scott combined information from two types of brain scan to come to their conclusions. They performed PET (positron emission tomography) scans on the brains of 14 healthy volunteers, and fMRI (functional magnetic resonance imaging) scans on those 14, and on 16 other healthy volunteers.

The PET scans focused on brain dopamine, looking at its activity as volunteers were told to expect, and then received, a painful injection of saline solution in their jaw muscle. They were then told to expect, and then received, an injection that they were told could either be a painkiller or a placebo. (Both were in fact placebos.) The fMRI scans looked at volunteers' brains while they played a game. Before each round, they learned that a correct answer would win or lose an amount of money, up to $5.

The PET scans were made using 11C-raclopride, which combines a drug that binds preferentially to dopamine receptors with a short-lived radioactive form of carbon that can be "seen" on PET scans. Throughout the PET scanning session, volunteers were asked to rate their level of pain on a numerical scale, and to describe any emotions they were experiencing.

Before the painful injection began, but after the volunteers had been told it was coming, they were also asked to guess how much pain relief they'd get from the "painkiller" if they received it. Half the volunteers were women, all in the same stage of their monthly cycle to avoid differences in hormonal state that might affect tolerance of pain - another topic that Zubieta's team has studied.

The PET scans and pain ratings revealed that as a group, the volunteers experienced significant pain relief from the placebo. But when researchers looked at each individual's results, they found that only half of the volunteers reported less pain when they received the "painkiller" placebo.

These placebo responders, as they were dubbed, had significantly more dopamine activity in their left nucleus accumbens than the other volunteers, beginning when they were told the painkiller medicine was about to begin flowing into their jaws. It also turned out that these individuals had also all anticipated the "painkiller" would give good pain relief before they even received it.

Meanwhile, of the seven individuals who didn't experience the placebo effect, four actually reported feeling more pain when the "painkiller" was delivered a phenomenon that has been dubbed the "nocebo" effect and has been observed in other situations.

Just to make sure that the volunteers' pain ratings weren't affected by the fact that they always received painful injections followed by placebo "painkiller", the researchers put a separate group of 18 male volunteers through the same experience twice, but no placebo was actually given, and actual PET scans were not done. Their pain and emotion ratings were significantly different from those of volunteers who received placebo.

"The results of these functional molecular imaging studies indicate that dopamine activity is activated in response to a placebo in a manner that's proportional to the amount of benefit that the individual anticipates," says Zubieta, who is the Phil F. Jenkins Professor of Depression in the U-M Medical School's Department of Psychiatry and a member of U-M's Molecular and Behavioral Neuroscience Institute, Depression Center and Department of Radiology.

The fMRI scans, which were performed on different days from the PET scans, revealed additional information about how individual expectations correlated with their placebo response. Each volunteer had an fMRI scan that looked at blood oxygenation throughout their brain, which allows researchers to spot areas where neurons (brain cells) are especially active as the individual performs a task or plays a game. In this case, the task was a very simple gambling game, in which subjects were scanned while expecting varying levels of a monetary reward or no reward.

As in the PET scans, the nucleus accumbens was a hotbed of activity as the volunteers were told how much money they could win or lose in the next round; as they waited for the round; and as they pressed the button and learned if they had succeeded in winning or avoiding losing money.

Then, the researchers compared the PET and fMRI scans for the volunteers who had had both types of scan. They also compared the ratings of anticipated placebo effect, the analgesia induced by the placebo during the pain studies, and the emotional changes associated with it. They found that those who expected a placebo to help them and got greater benefit from it (more analgesia, better emotional state) were also those who had the most activity in their nucleus accumbens during the anticipation of receiving a reward in the fMRI money game.

In addition to Zubieta and Scott, the study's authors are Christian Stohler, DMD, formerly of the U-M School of Dentistry and now dean of the University of Maryland School of Dentistry; Christine Egnatuk and Heng Wang of the U-M MBNI; and Robert Koeppe, Ph.D., director of the PET Physics Section in the Nuclear Medicine division of the U-M Department of Radiology. The study was funded by the National Institutes of Health.

University of Michigan Health System
2901 Hubbard St., Ste. 2400
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The Placebo Effect Explained Through Identification Of Relevent Brain Region
22 Jul 2007
http://www.medicalnewstoday.com/articles/77299.php

Researchers have pinpointed a brain region central to the machinery of the placebo effect -- the often controversial phenomenon in which a person's belief in the efficacy of a treatment such as a painkilling drug influences its effect.

The researchers said their findings with human subjects offer the potential of measuring the placebo effect and even modulating it for therapeutic purposes. They also said their findings could enable measurements of brain function that "would help determine dysfunctions in cerebral mechanisms that may impair recovery across a number of conditions."

Jon-Kar Zubieta and colleagues published their findings in the journal Neuron, published by Cell Press.

Their studies concentrated on a brain area known as the nucleus accumbens (NAC), a region deep in the brain, known to play a role in expectation of reward. Earlier studies had hinted at involvement of the NAC in the placebo effect, but the nature of that role was unknown, said the researchers.

In their experiments, the researchers told volunteers that they were testing the effects of a new pain-killing drug and that the subjects might receive the drug or a placebo. However, in the experiments, the researchers gave only a placebo injection of a salt solution. The experiments involved asking the subjects to rate their expectation of the pain-killing effects of the "drug" and also the level of pain relief with or without the "drug" that they felt from a moderately painful injection of salt solution into their jaw muscle.

In one set of experiments, the researchers used a molecular tracer scanning technique known as Positron Emission Spectroscopy to measure release from the NAC of the neurotransmitter dopamine - a chemical trigger of the brain's reward response. They found that the greater subjects' anticipation of the pain-killing benefit of the placebo, the greater the dopamine release from the NAC. Also, subjects who reported greater relief from the placebo when they did experience pain showed greater NAC activity when they received the placebo before the pain.

In separate experiments, the researchers studied whether activation of subjects' NAC during reward processing correlated with the magnitude of their placebo effect. They told subjects to expect monetary rewards of different amounts, as their brains were scanned using functional magnetic resonance imaging. The researchers found that the people who showed greater activation of the NAC during this reward-expectation task also showed a greater anticipation of effectiveness of a placebo.

The researchers concluded that "These findings are consistent with the hypothesis that this system is involved in the encoding of the 'incentive value' of the placebo, possibly acting as a gate or permissive system for the formation of placebo effects."

They wrote that "The placebo effect then emerges as a resiliency mechanism with broad implications that, given its activation of specific circuits and mechanisms, can be both examined and modulated for therapeutic purposes."

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Article adapted by Medical News Today from original press release.
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The researchers include David J. Scott, Christine M. Egnatuk, Heng Wang, Robert A., Koeppe, and Jon-Kar Zubieta of The University of Michigan, Ann Arbor; Christian S. Stohler of University of Maryland, Baltimore. This work was supported by grants R01 AT 001415 and R01 DA 016423 to J.K.Z. and R01 DE 15396 to C.S.S.

Scott et al.: "Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects." Publishing in Neuron 55, 325-336, July 19, 2007. DOI 10.1016/j.neuron.2007.06.028. http://www.neuron.org/.

Marketing and the Placebo Effect

from Neuromarketing by Roger Dooley
Monday, Jul 23rd, 2007 at 7:33 am
http://www.neurosciencemarketing.com...ebo-effect.htm

placebo-marketingWe all know what the placebo effect is - give a group of patients a sugar pill instead of a medication with active ingredients, and some of them will show an improvement in their symptoms. Drug researchers treat the placebo effect as an annoying artifact that must be eliminated by using double-blind studies. Other health care advocates see it as remarkable evidence of human capacity for self-healing, and a topic that deserves extensive study. But what relevance does it have for marketers? New research shows that the placebo effect is related to the brain’s reward system, and it’s not a big leap to say that much of marketing is trying to achieve a non-medical placebo effect in the minds of customers.

First, the new research: a ScientificAmerican.com article by Nikhil Swaminathan, Expect the Best? Placebos Are for You! New study links expectations of rewards to placebo effect, describes a study performed by neuroscientist and radiologist Jon-Kar Zubieta and colleagues at the University of Michigan, Ann Arbor. Subjects were first tested for their response to a placebo “painkiller” administered prior to a needle stick; as is typical, subjects exhibited different levels of pain relief from the bogus injection. On another day, they participated in a seemingly unrelated game of chance in which they were told they could win money.

Participants were told they could win or lose a certain amount of money each round; they would then push a button to determine the real take. Several of the participants showed a flurry of activity involving dopamine release in the nucleus accumbens while awaiting the outcome, indicating that they were expecting a reward. The people whose nucleus accumbens lit up during the game also reported greater relief from the sham painkillers. “What surprised me the most was the strong link between this element of reward processing and the fact that you can predict the placebo response,” Zubieta says. “The placebo effect is a resiliency mechanism in the brain. … You don’t [really] need the medication, you simply need to be convinced that something is going to work.”

This is significant news for medical researchers, who see new avenues of treatment being opened up. Long before neuromarketing became a buzzword, though, marketers have known about managing expectations. Simply put, marketers know that if they can create an expectation in the mind of their customer, and then not do anything to contradict that expectation, they have a good chance that the customer will find that expectation to be fully met. The “not contradicting” element is the key part of the process. Marketers try to create expectations with just about every customer contact. Often, though, those expectations are crushed, or at least strained, during the actual experience. It’s easy for a marketer to create an expectation of “fast, friendly service” - but if the customer has to wait in line to be served by a surly clerk, the expectation will fail to turn into the customer’s actual perception. Indeed, the dissonance between the promise and the reality may actually increase the customer’s perception of bad service.

But lots of expectations are a bit more nebulous - if a customer is expecting to be served coffee that is “aromatic, rich, and bursting with complex flavor… made using the finest coffee beans from the farthest corners of the globe, picked at the perfect moment, and roasted using a special process to lock in flavor and enhance the taste” and gets a cup that’s not half bad, he may attribute some of those superior characteristics to it. Like the placebo recipients, though, some customers are more likely to be influenced by the message than others. The same kinds of positive individuals who expect to win in a game of chance will probably experience the product as described by the message if there are no major disconnects between them.

Although the reports on the placebo study didn’t describe the personalities of the groups for which the placebo worked vs. those for which it didn’t, I’d assume that the latter group contained individuals more cynical in nature with generally pessimistic expectations. This would be the same type of person who, given a chance to wager a sum of money, would say, “I know I’m just going to lose…” These individuals are likely to cast a jaundiced eye at any marketing effort, assuming that the marketer is exaggerating if not being actually deceptive. (Maybe we’ll do a piece on “marketing to cynics” in the future.)

This concept differs from priming. Priming is more subtle than a placebo because it works entirely below the conscious level. By presenting the subject with non-obvious cues, the subsequent behavior of the subject is altered. In administering a placebo, an overt act is accompanied by a description of the expectated experience, e.g., pain relief, relaxation, etc.

To sum up, the key elements of placebo marketing are,

• Describe the positive experience the customer will have when she uses the product, visits the establishment, etc.
• Ensure that the actual experience doesn’t actually contradict the expectation you have established.
• Understand that some, but not all, customers will end up having the experience you described for them.