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 percent of placebo recipients manifested the nocebo effect: unexpected deteriorations of health.’ 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.” Social isolation, work stress and hostility comprised additional risk factors.
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 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.
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
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). 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.
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. The placebo had found its way into surgical rooms.
Somatic pathwaysIn 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.
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. In patients suffering from Parkinson’s disease, a placebo injection promoted dopamine secretion in a similar way to that caused by amphetamine administration. 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. 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.
Article from Nexus Magazine June-July 2007