Truman Green's science rumours

March 28, 2010

The Placebo Effect by Truman Green

Filed under: Uncategorized — trugreen1 @ 11:33 pm

 

As I was determined to continue participating in strenuous sports such as tennis, running and basketball well into my forties, I often attended my doctor’s office complaining of pain from various over-stressed ligaments, tendons and muscles. The treatment was always the same: advice to “take it easy” and a prescription for a non-steroidal antiinflammatory drug such as Naproxen or Voltaren or, in cases of suitable wincing, the occasional prescription for acetaminophen with codeine.

Often, wary of the upset stomach that would accompany the use of these NSAIDS,  I noticed that I could achieve a more rapid healing without actually taking the medications, but merely by attending my doctor’s office for further sessions of fast advice and new prescriptions.

Eventually it became clear that it wasn’t always necessary to keep the appointment. Merely making the phone call often provided a reduction of pain during the few days before the actual visit. I remember once remarking about this to my doctor, but he merely smiled without acknowledging the comment,  perhaps in order not to encourage appointments that would be cancelled at the last minute, or perhaps not to extinguish whatever therapeutic benefit I was receiving from my confidence in his healing abilities. I also recall sometimes being suspicious that the healing was merely coincidental with the passage of time.

In order to decide if time was the true healing mechanism, I would sometimes endure the discomfort as long as possible before making an appointment. My finding was that the sudden healing that would occur before the visit–or soon after– must be attributable to whatever mysterious mind-body pathways account for the therapeutic benefit known as the placebo effect. Definitions for this response are extremely varied in the literature but the online website, MedicineNet.com provides an unusually straight-forward explanation:

“A fake treatment, an inactive substance like sugar, distilled water, or saline solution can sometimes improve a patient’s condition simply because the person has the expectation that it will be helpful. The more a person believes they will benefit from a treatment the more likely it is that they will experience a benefit.”

                                                  The nocebo effect.

The opposite response–known as the nocebo effect–can be induced by the introduction of negatively-perceived cues  such as the stress that may induce hypertension during a patient’s visit to a medical clinic or hospital, known as the “white coat syndrome.” Knowledge of the nocebo effect is particularly important to those who may have been diagnosed and treated for hypertension if it appears only during certain high-stress situations such as the visit to the doctor’s office, or an emotional or physical confrontation which induces the “fight or flight” response.

The psychological stress that is commonly regarded as a trigger for a renewal of symptoms of herpes virus infection also fits into the catetory of nocebo effects. After the initial infection, both viruses–known as herpes virus types I and II–are never removed from the body, but remain latent in the nerve ganglia waiting for a stress-related reduction of immune surveillance in order to renew their replication inside of cells on the faces or genitals of sufferers.
                                                     
                                                  Pavlov’s dog

In his famous conditioning work, Ivan Pavlov, the Russian scientist, discovererd that he could induce salivation in dogs if he could condition them to associate secondary stimulation with prior presentation of food. It is very likely that mere visits or phone calls to a doctor’s office which induce healing are operating as conditioned responses, especially if prior expectation of healing has been followed by subjective perceptions of improvement.

In a recent experiment on placebo conditioning, presented in The Scientific American Mind, Feb, 2009, it was found that rats whose immune systems have been shut down by Cyclosporine A–a drug used to prevent rejection of transplant organs–will have similarly-depressed immune systems when the Cyclosporine A is exchanged for sweetened water. It was also found that placebo-conditioned rats with transplanted hearts survived longer than non-placebo–conditioned control animals. An experiment with Cyclosporine A, using men as the test subjects, yielded similar results. As recounted in The Scientific American Mind article, men who have strong faith in the safety of their prostate medications are 50% less likely to develop impotence than those who have been made aware of the possibility of impotence as a side effect.(1)

                                Is the placebo benefit imagined or real?

Several researchers have found that the therapeutic value attributed to the placebo effect was due to poorly-designed trials. In l997 G.S.Kienle and H.Kiene re-visited the classic work of Henry Beecher, whose writing had set a benchmark in placebo research, and found that most of the improvements listed by Beecher could be explained by:  

     Spontaneous improvement fluctuation of symptoms, regression to  the mean, additional treatment,
     conditioned switching of placebo treatment, scaling bias, irrelevant response variables, answers of
     politeness, experimental subordination, conditioned answers, neurotic or psychotic misjudgement
     psychosomatic phenomena or misquotation.(2)

A 2001 article in the New England Journal of Medicine by Danish researchers, Asbjorn Hrobjarstsson and Peter Gotzsche present the results of a metaanalysis of 114 studies in which they found that therapeutic benefit attributed to the placebo effect were more likely due to sample sizes that were too small.(3)

Studies such as those which question the therapeutic benefit of placebos have been contradicted by studies which confirm the benefit. Margaret Talbot, writing in the New York Times, January 9, 2000, recounts a study in which doctors successfully treated warts by suggesting to patients that the warts would disappear concurrently with the wearing off of coloured dye with which they had been painted. Similar findings were obtained when dentistry patients, whose wisdom teeth had been extracted, obtained the same analgesic benefit from either a real or sham application of ultrasound if both patient and dentist believed that the machine was functional. Also, according to Talbot: “Fifty-two percent of colitis patients treated with placebo in 11 different trials reported feeling better–and 50 percent of the inflamed intestines acutally looked better when assessed with a sigmoidoscope.”(4)

Psychiatric illnesses are particularly susceptible to the suggestive mechanism of placebos. Several studies regarding the performance of antidepressants have found that their comparison to placebos yields efficacy results that are very similar to those of placebos. A l996 review of 39 clinical trials performed at the University of Connecticut, under the leadership of psychologist, Guy Sapirstein, Phd, found that 50% of the benefit of medications such as Prozac, Zoloft and Paxil could be attributed to the placebo effect.(5)

                     Placebos and the gold standard of efficacy trials

In the field of medical science the most important involvement of the placebo effect is in the development of synthetic pharmaceutical drugs which are assessed for efficacy by comparing their performance to that of inert placebo pills or substances. Since l955, when Henry Beecher wrote The Powerful Placebo, his recommendations that clinical trials be randomized, double-blinded and placebo-controlled have been accepted as the gold standard of assessing the efficacy and safety of medications. In general, the results are assessed by subtracting the percentage of those who benefit from the placebo from the percentage of those who benefit from the candidate treatment to arrive at a net benefit. The reliability of this net benefit in assessing the usefulness of the candidate drug is then compared to a probability standard known as the P-value, which gauges the liklihood that the results were either significant or a matter of chance.

                                Is the placebo effect getting stronger?

According to a popular article in Wired Magazine by Steve Silberman, the placebo effect has been getting stronger since the l980s. In follow-up studies of long-established drugs such as Valium and Prozac their performance against placebo’s has diminished. Not only has the placebo effect increased in general, but several important anomalies have appeared. Drugs that do well in one geographic location might fail in another, and those with acceptable efficacy compared to placebos among one culture might fail when tested in another. Even the same tests in identical locations might fail when attempts to reproduce results are performed with a different set of scientific personnel, so that conclusions that were at one time judged to be reliable may be viewed as only the opinions of the researchers.(6)

Several large drug manufacturers have focused their resources on trying to deal with this complicating development, and several organizations have been established such as a large-scale data-sharing program under the Foundation for the National Institutes of Health, and Merck’s Placebo Trials Response Drug Trials Survey.(7) Drug makers have historically considered the results of their clinical trials to be proprietary information, and if they have managed to obtain conclusive information about the cause of the increases in the placebo effect, they have not yet divulged it to the media. 

It is very difficult to believe that human nature has changed enough in the last thirty years to account for increases in the placebo effect. Until drug manufacturers divulge the results of their investigations, and large meta-analyses of placebo performance increases are published and reviewed by science writers and independent clinical trial reviewers, claims that the placebo response in humans has increased must remain within the realm of science rumour–not science fact. If, in fact, the claims of increased effectiveness in the placebo response are true, it must also be asked: “Why are drugs becoming less effective?”
                                                        
                                Are trial placebos inert substances?

Beatrice Golomb, an assistant professor of medicine at the University of California, believes that drug companies have been producing placebos which are not entirely inert, but which contain ingredients that mimic the side effects produced by drugs. According to Golomb, such similarities are maintained in order to produce more favourable comparisons between the side effects of the placebos and those of the experimental drugs. She presented her findings of this possibility in the article, “Doctoring The Evidence: The Case Against Lying To The Public About Placebos.”(8)  Golomb and others are calling for new legislation that drug companies be required to divulge all ingredients in placebos so that consumers will be able to assess whether performance comparisons are reliable, or if they have been manipulated in favour of the drug manufacturer.
                                                               
                                        Misleading percentages.

Interpreting the results of placebo-controlled clinical trials requires advanced knowledge in clinial trial design, statistics and probability, but it should be remembered that results which indicate the superior performance of drugs over placebos may be misleading. An enlightened understanding of this aspect was presented in the comments section after the article, “Placebos are Getting More Effective,” by Steve Silberman. Commenter Will Spirit writes:

     Typically, for instance, a drug might show response in 60% of patients, whereas 40% do well with a placebo. In  industry studies, this is considered a solid result. If the numbers of trial subjects is large enough, the statistical significance bar is surmounted. All other things being equal (like no one dies from the drug), the medication gets approved.

    Yippee! The corporation promotes it on TV and in magazines, doctors get free samples, and millions…are spending hundreds of dollars a month to swallow this compound. But if you look more closely a 60% drug response and a 40% placebo response, actually means that only 20% of those taking the pill are benefitting from the chemical. “…80%      of those prescribed the medication will get nothing positive from the active ingredient at all.(9)

                   Placebos in Alternative and Conventional Medicine

The Skeptic’s Dictionary, which is available online, lists 40 healing practices, including acupuncture, prayer, faith healing, homeopathy, naturopathy, reflexology, hypnotherapy and psychic surgery, which (in the opinion of the authors of the website), appear to rely on the placebo effect.

A more progressive approach in which placebos are recognized and embraced as a mechanism for healing may be  emerging. The Journal of Alternative and Complementary medicine, edited by Stefan Schmidt of the University of Freebierg, Germany, has published several articles in which this new approach is presented. In the article, “Placebo Research: The Evidence Base for Harnessing Self-Healing Capacities,” authors, H. Walach and WB Jonas lay out their ideas on how to develop a new “science of healing.”(10) In the study, Reconsidering The Placebo Response From A Broad Anthropological Perspective, authors, C Ritenbaugh, C. Thompson, and M. Nichter present their theory that: “Given body/mind/emotional resonance, we suggest that the placebo response is an evolutionarily adaptive trait and part of healing mechanisms operating across many levels–from genetic and cellular to social and cultural.”(11)

Despite pledges of new perspectives, practitioners of conventional medicine, may have been quietly taking advantage of the power of the placebo for many years. In the study entitled, “Academic Physicians Use Placebos In Clinical Practice and Believe in the Mind-Body Connection,” University of Chicago researchers found:  “Although physicians did not widely agree on the definition of a placebo and had a variety of explanations for its mechanism of action, ninety-six percent of the respondents believed that placebos can have therapeutic effects, and up to forty percent of physicians reported that placebos could benefit patients physiologically for certain health conditions.” The study reports that: “Nearly half of the respondents use placebos in clinical practice and most believe in the mind-body connection.”(12)

                                                       Conclusions

The pervasive reality of the placebo effect is that its etiological pathways are still mysterious–whether it is employed as a control in clinical studies to gauge the efficacy and safety of medications, or in the private practice of conventional or alternative medicine. Consumers of synthetic drugs–even those which have achieved certification by out-performing placebos–should keep in mind that large corporations are in business to sell products, and have the financial and intellectual resources to manipulate clinical trials so that findings will support marketing claims and applications to government agencies for product approval.

According to a 1998 report in the Journal of the American Medical Association, 106,000 hospitalized patients die each year in the United States from complications due to the side effects of medications. The vast majority of such drugs
were approved because they out-performed placebos in clinical trials.(13) The lesson to be learned is that all drugs are
potentially dangerous and should be used as a last resort, whether they have been approved or not.

While controversy continues about the ethical implications of placebo usage in medical practice, the use of placebo controls in clinical efficacy trials, and the exact mechanism of healing, knowledge of this response provides an undeniable lesson about illness, wellness and healing: There is an essential relationship between the ability to maintain
a psychological perception of well-being–manifested as confidence, serenity, happiness and optimism–and the body’s ability to maintain good health or to heal itself when illness occurs.

Footnotes

1. The Scientific American Mind, Feb. 25, 2009

2. GS. Kienle, H. Kiene, “The Powerful Placebo Effect: Fact
    or Fiction,” Journal of Clinical Epidemiology Dec. l997

3. Asborn Hrobjartsson, Peter Gotzsche New England Journal
    of Medicine Vol. 344 1594-1602 May 24, 2001, Number 21

4. Margaret Talbot, New York Times Magazine Jan. 9, 2000

5. Guy Sapirstein American Psychological Association 1996 Press Release
    “Placebo Effect Accounts for Fifty Percent of Improvement in
    Depressed Patients taking Antidepressants.”

6. Steve Silberman, “Placebos Are Getting More Effective-Drugmakers are
    Desperate to Know Why.” Wired Magazine 08/24/09

7. Ibid

8. Beatrice Golomb American Journal of Bioethics

9. Steve Silberman, “Placebos Are Getting More Effective-Drugmakers are
    Desperate to Know Why,” Wired Magazine 08/24/09

10. H. Walack WB Jonas, The Journal of Alternative and Complementary
      Medicine “The Evidence Base for Harnessing Self-Healing Capacities.”
     
11. C. Ritenbaugh, C. Thompson M. Nichter, “Reconsidering The Placebo
      Response From a Broad Anthropological Perspective.”

12. Rachel Sherman, John Hickner, “Academic Physicians Use Placebos in
      Clinical Practice and Believe in the Mind Body Connection.”
      Journal of General Internal Medicine Vol 23, Number 1, Jan. 2008

13. Journal of the American Medical Association, “Adverse Drug Reactions
      in Hospitalized Patients,” Vol. 280, Nov. 25, l998

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2 Comments »

  1. Excellent, thank you.

    Comment by Steve Silberman — March 29, 2010 @ 4:04 am

  2. No drug trial controls for Subliminal Distraction exposure. This problem was discovered and solved forty years ago by designers and engineers. They had been hired to modernize the business office. When they introduced their first prototypes in 1964 some of the knowledge workers using those first designs began to have mental breaks. It was the vision startle reflex and the office cubicle was created to deal with it by 1968.

    One of the markers for this exposure is hyper-suggestibility. Drug manufacturers are not aware the discovery was ever made. In Design the phenomenon is believed to cause only a harmless temporary episode of confusion.

    My site is a seven year investigation of Subliminal Distraction. Can you eliminate SD as the cause of your experience?

    Comment by L K Tucker — June 9, 2010 @ 1:43 pm


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