There is no morphine on the battlefield, so saline is used to relieve pain. Do you believe it? | Uncovering the secret of the placebo effect (Part 1)

Why can saline sometimes relieve pain, even as effectively as morphine? Why can patients get better faster if they trust their doctors? These phenomena are all related to the placebo effect. The "Placebo Effect" series takes you through several milestones in the scientific research of the placebo effect over the past seventy years, and finally focuses on the important impact of the doctor-patient relationship on clinical medical outcomes.

Written by He Xiaosong (Retired Professor of University of California, Davis School of Medicine)

“It is the natural forces within us that truly heal.”

—Hippocrates (460-370 BC)

Introduction: The Miracle of the Field Hospital In the last year of World War II, the battlefields of Europe were in flames and the casualties among the soldiers were heavy. In a front-line field hospital of the US Army, the supply of morphine injections for pain relief was very tight. One day, a seriously injured soldier was sent from the front line and needed surgery immediately. However, the morphine in the hospital had run out. Military doctor Henry Beecher was worried that if the pain was not relieved in time, not only would the operation be extremely painful, but it might also induce fatal cardiovascular shock. In a hurry, a nurse said "Morphine is here" and grabbed a bottle of saline and injected it into the wounded. A miracle happened - the wounded quickly calmed down, and the operation was successfully completed without shock.

In the following months, the same thing happened several times, and saline seemed to have the same analgesic effect as the strongest analgesic morphine. This incident completely overturned Dr. Beecher's concept of drug effects. After the war, he returned to Harvard Medical School in the United States and opened up a new field in modern clinical medicine with a group of like-minded colleagues - the scientific study of the placebo effect.

Placebo: comfort or deception? The English term "placebo" originated from Psalm 116 in the medieval Latin version of the Bible, and its original meaning is "I will please (God)". As early as the 18th century, William Cullen, the dean of the Royal College of Physicians of Edinburgh, Scotland, and a famous doctor, gave patients with reduced doses of therapeutic drugs to please and comfort them when they encountered incurable patients. Cullen called it placebo. He did not think that this practice could cure the disease, but believed that letting patients take placebos would help relieve symptoms. Influenced by Cullen, the "Hooper's Medical Dictionary" compiled by the famous British doctor Robert Hooper in the early 19th century defined placebo as "a drug whose main purpose is to please patients rather than to treat them". As for whether placebo can really improve patients' symptoms and its value in clinical practice, it was not explained. The efficacy of placebo has also become a focus of controversy for a long time.

Before the term placebo was officially introduced into the medical field, it had already been used for different purposes.

In the middle of the 18th century, a German doctor named Franz Mesmer proposed a set of theories about human health and disease. He believed that there were some invisible channels in the human body, which were filled with liquids that could be magnetized, called "animal magnetism"; and he had the ability to control the flow of these magnetic liquids in the patient's body through various means, including through thoughts, to achieve the purpose of curing diseases. For example, he could use his power to magnetize a bottle of water, and the patient would react as long as he touched the bottle of water, or touched another object that had touched the bottle of water, or even just got close to the bottle of water.

Mesmer first began to implement this treatment in Vienna, and later moved to Paris. In Paris, his clinic became so famous that patients had to wait for several weeks to make an appointment. So Mesmer simply changed the one-on-one treatment to a group treatment. In his consulting room, the lights were dim, and there was a basin of water in the middle of the room. The patients who were being treated sat around the basin holding hands. One of them held an iron rod in one hand and dipped it into the water. With the other hand, he held the finger of another patient, and the magnetism flowed through each patient's body in turn. Mesmer wore a leather coat full of magnets and issued various instructions in a complex program. The patients then went into a state of involuntary convulsions, sometimes lasting for hours. An eyewitness wrote: "Seeing such a reaction, you have to admit that there is a powerful force controlling the movements of these patients, and this power can only come from the magnetic therapist!" Subsequently, the patients' various symptoms, including mental illness, pain, and even blindness, were suddenly cured!

The upper class of Paris had a group of Mesmer's fanatical fans, including the French Queen Marie-Antoine. King Louis XVI himself did not care at first and allowed Mesmer to open his clinic. But later, seeing that Mesmer's business was booming, the king gradually became suspicious, so in 1784 he commissioned a group of top French scientists and doctors to investigate Mesmer's magnet therapy. The investigation team included Antoine Lavoisier, known as the "father of modern chemistry", and Benjamin Franklin, the first ambassador of the newly established United States of America to France, a famous scientist, writer and social activist.

The investigation team began to work meticulously. The first step was to check whether the "animal magnetism" claimed by Mesmer actually existed. After research, it was found that the so-called "animal magnetism" could not be detected by sight, hearing, smell, or taste, and it could not be detected by magnets. In this case, why did some patients who received treatment have such violent reactions, from coughing, pain, sweating, to mania and convulsions?

Next, the investigation team invited one of Mesmer's disciples to bring several patients who were most responsive to magnetization therapy to Franklin's residence for testing. They first asked the magnetist to magnetize a tree in the orchard, and then took the patient into the orchard and asked him to find the magnetized tree. Sure enough, the patient began to sweat and have a headache after approaching a tree, and then fainted, but it was not the tree magnetized by the magnetist. The magnetist explained that all the trees in the orchard were more or less indirectly magnetized by the tree, and the patient was particularly sensitive to magnetism, so approaching any tree would make him comatose.

The investigation team then conducted several similar experiments. A woman claimed that she had a reaction to magnetized water. So the investigation team first asked the magnetic therapist to magnetize a cup of water, and then used the same cup with unmagnetized water to send it to her. The woman fainted on the spot. After waking up, she was still tired and weak. At this time, she was given a cup of water that had not been treated by the magnetic therapist, but she was told that it was magnetized water. The woman immediately became energetic!

In their final report to King Louis XVI, the investigation team concluded that Mesmer's theory had no scientific basis and that any improvement in the patients' feelings was due to their imagination. Although they did not provide a satisfactory explanation for the patients' behavior during treatment, the report was still a fatal blow to Mesmer. He then disappeared from Parisian high society and spent the rest of his life in obscurity in the countryside.

The experiments conducted by Lavoisier, Franklin and their colleagues were the first clinical trials to use a placebo (unmagnetized wood or water) as a control, although they did not use the word "placebo". The important impact of this work was that it linked the effects of a certain therapy (Mesmer's "magnetization therapy") to "imagination". In other words, the effects of "magnetization therapy" were completely illusory and existed only in the patient's subjective imagination.

Back to the military doctor Beecher mentioned at the beginning of this article, although before he observed the miraculous effect of saline solution replacing morphine in relieving pain on the battlefield, there were already some doctors like Dr. Cullen who, when faced with terminal illnesses that had no medical effects, used inert substances such as sugar pills and starch as medicine to comfort patients facing death. However, most people just thought that doing so was at least harmless and did not believe that there would be any real effect. Many people in the medical community even believed that this practice was somewhat fraudulent.

"Powerful Placebo" After World War II, Beecher and his colleagues began to systematically study placebos. The first goal was to determine whether the efficacy of placebos objectively existed or was just the patient's subjective conjecture, as Lavoisier and Franklin judged on "magnetic therapy". The research method is to compare the conventional drugs used to treat these diseases with placebos according to the different symptoms of the patients. For example, one of the sequelae of surgery is chronic pain that lasts for many years, and morphine is a common drug for relieving such pain. The researchers gave the patients different doses of morphine or placebo (normal saline for injection and lactose for oral administration), and then recorded the degree of pain relief of the patients. Each patient was tested with morphine or placebo in turn. The patients themselves and the researchers who provided the drugs and recorded the symptoms did not know whether morphine or placebo was used in each experiment. This is the so-called double-blind test.

The researchers found that some patients felt that their pain was effectively relieved after using the placebo. The phenomenon observed by Dr. Beecher on the battlefield was confirmed. This effect of the placebo is called the placebo effect. In addition to pain, the researchers also conducted similar controlled trials on other diseases such as anxiety, colds, and coughs, further proving that the placebo effect is universal.

The presence or absence of pain and its severity mainly depend on the patient's subjective description, and different people have very different tolerance for pain. Is there any objective indicator that can be used to determine the existence of the placebo effect and quantitatively measure the strength of the effect?

A trial involving patients with anxiety disorders found that after the patients were injected with a saline placebo, they experienced a series of physiological changes in adrenal cortical activity, which were similar to those caused by the injection of adrenocorticotropic hormone (ACTH), including an increase in neutrophils in the blood, a decrease in lymphocytes and eosinophils, an increase in the uric acid/creatinine ratio, etc. These results clearly show that the placebo effect is not limited to the psychological level, and the patient's physiological response can also be affected by the placebo.

In 1955, Beecher summarized 15 studies on placebos that he and other researchers had conducted over the years and published them in the Journal of the American Medical Association under the title "The Powerful Placebo" [1]. These studies involved a total of 1,082 patients and concluded that, without the patients' knowledge, the average efficacy of placebos in treating a variety of conditions (including pain, nausea, cough, anxiety, colds, etc.) was 35.2%. The fact that placebos are effective for such a wide range of conditions suggests that all these conditions may have some common underlying mechanism, and that placebos may be acting on this common mechanism. The article also emphasized the importance of using the double-blind method, randomly grouping subjects, alternating between placebos and drugs on the same patients, and using mathematical methods to analyze the observed results when conducting such studies.

Later generations have raised objections to some of Beecher's work, such as the placebo study on patients with colds. Common viral colds, if not complicated by bacterial infections, will mostly heal naturally in three to five days or a week, even without any treatment. In Beecher's study, in addition to the experimental group taking medication and the control group taking placebos, a group of patients who did not receive any treatment was not included. In this way, the improvement of symptoms in the placebo control group was uniformly attributed to the placebo effect, and the actual effect of the placebo may be exaggerated. Despite this, the influence of the article "Powerful Placebo" was so far-reaching that it was still frequently cited more than half a century later. Beecher was therefore called the "Father of Placebo Research."

Randomized double-blind: The gold standard for determining efficacy. The study by Beecher et al. also found that the therapeutic effect of placebo varies from person to person, and not all patients respond to placebo. Patients who respond to placebo (called placebo responders) have a stronger analgesic effect when using morphine than patients who do not respond to placebo (placebo nonresponders). It is speculated that the total analgesic effect of placebo responders when using morphine is composed of two parts, one part comes from the placebo effect, and the other part comes from the pharmacological effect of morphine. According to Beecher's quantitative research results, the placebo effect accounts for about half of the total analgesic effect of these patients when using morphine.

Based on these results, Beecher and others put forward an important point: for any drug, only by using the randomized double-blind method and using a placebo without pharmacological effects as a control for clinical trials can the influence of the placebo effect be eliminated and the true efficacy of the drug itself be determined. This is also the method used by Lavoisier, Franklin and others when investigating Mesmer's "magnetic therapy". In the following years, Beecher and his colleagues spared no effort to call for this. Their efforts finally led to a major change in the US drug regulatory policy.

In 1962, the U.S. Congress passed a drug effectiveness amendment, which stipulated that when drug manufacturers apply to the U.S. Food and Drug Administration (FDA) for a license to market any new drug, in addition to proving its safety, they must also provide sufficient evidence of its effectiveness. Such evidence can only come from randomized double-blind controlled clinical trials, using inert placebos as controls to prove that the new drug is effective; or using existing drugs that are known to have proven efficacy as controls to prove that the new drug is at least as effective as existing drugs. Before this, new drug manufacturers only needed to prove that the drug was safe to be allowed to be put on the market.

While the FDA was implementing new standards for the approval of new drugs, it also reviewed the efficacy of thousands of drugs that had been approved for marketing before 1962. The total number of indications claimed on the labels of these drugs exceeded 16,000, and the workload of the review was extremely huge. As of 1984, among the more than 3,000 drugs that had completed the review, about two-thirds were determined to be effective and could continue to be used; the remaining one-third were determined to be ineffective and their licenses were revoked because their actual efficacy - if they were indeed effective - did not exceed that of placebos, and the amount of money that patients had paid for them over the years was incalculable!

The impact of this major cleanup of the US pharmaceutical market has spread beyond the country's borders. Since the 1990s, evidence-based medicine has gradually developed into the mainstream of contemporary clinical medicine. Its core idea is that doctors must combine their personal clinical experience with the best clinical evidence available in the medical community to determine the treatment plan for each patient. For drugs, the results of randomized double-blind controlled clinical trials are the gold standard for the best clinical evidence.

Expected psychology and placebo effect The work of Beecher and others convincingly shows that the therapeutic effect of placebo does not exist only in the patient's imagination, but is an objective reality. How is this effect caused? Beecher believes that the therapeutic effect of placebo originates from the patient's expected psychology of improvement of symptoms. This positive expected psychology leads to benign physiological changes, which promotes the development of the disease in a good direction. Beecher found that the therapeutic effect of placebo varies from person to person. The strength of the response to placebo has nothing to do with the patient's gender and IQ, but has a significant relationship with the patient's educational background, personality, attitude and habits.

In 1973, two researchers in New York, USA, studied the quantitative relationship between expectation and placebo effect[2]. They used a randomized double-blind method to divide chronic pain patients into several groups and gave them different doses of analgesics. The higher the dose, the stronger the analgesic effect. After the effect of the drug wore off and the pain subsided, the patients were given the drug again, but this time they were actually given a placebo. The patients' pain was indeed relieved by the placebo effect, and the degree of relief was related to the effect of the first use of the analgesic: the larger the dose of the analgesic given first, the better the analgesic effect of the placebo given later, indicating that the higher the expectation value, the stronger the placebo effect.

In this experiment, the expectation of pain relief came directly from the experience of taking painkillers in the same experiment. In daily life, the expectation can also come from some more distant and indirect experience.

When a doctor treats a patient, even if he does not promise that the medicine will cure the disease, the act of giving the patient or injecting him with a certain "medicine" - whether it is a real medicine or a placebo - the act itself sends a message to the patient: "My medicine will cure your disease." Out of trust in the doctor, the patient accepts this information and therefore develops the expectation that the disease will improve or even be cured.

Why do patients interpret doctors' medication in this way? Where does this trust in doctors come from?

As early as the 19th century, the great Russian physiologist Ivan Pavlov discovered that when hungry dogs see food, they will secrete a lot of saliva. This is an innate physiological reaction of any dog. If another signal is given at the same time as feeding, such as ringing a bell, after several such trainings, the dog will secrete saliva as long as it hears the bell, even if there is no food in front of it. This is because after training, the dog's brain has learned to associate the two stimuli of the bell and food, so that the bell that was originally unrelated to food can also stimulate the physiological reaction of salivation. This reaction is the so-called "conditioned response". By the way, the Chinese word "conditioned reflex" is really a poor translation. Its original meaning in foreign languages ​​refers to "trained response" or "learned response", to distinguish it from the innate "unconditioned response" that does not require learning, such as the reaction of secreting saliva when seeing food.

We may have had this experience in childhood, even if we have forgotten it: we were sick, and our parents took us to see a doctor. We got a shot in the butt and cried in pain. Our parents hurriedly comforted us: "Don't cry, the shot will heal you." Then the disease was cured. We now know that this may be the effect of the medicine, but it may also be just a natural recovery. Over time, the brain's subconscious mind has established such an information channel: sick to see a doctor → injection or medication → recovery. This channel is opened under the specific environmental stimulation when seeking medical treatment. The smell of disinfectant in the air, the doctor's white coat, the feeling of the stethoscope touching the skin, or the posture of the old Chinese doctor holding his breath and concentrating on taking the pulse can all become trigger signals to open this information channel, so we are like Pavlov's trained dog that can secrete saliva when hearing the bell, and we have expectations of recovery from the disease.

In addition to the subconscious information channel derived from one's own experience, if some external information is added, such as you wait in a long line to get a specialist clinic number that is several times more expensive than that of ordinary doctors, or see the "Hua Tuo Reborn" plaque and "Miraculous Hands Bring Back Spring" banners given by patients on the wall of the clinic, this expectation will be further strengthened and transformed into a stronger placebo effect. We have all had this experience: after seeing a doctor, we walked out of the door with the doctor's prescribed medicine or prescription full of hope, and the symptoms have been reduced by three points compared to when we came. The placebo effect occurs even before the drug enters the body!

The strength of this expectation of recovery is often related to the treatment method chosen by the doctor. Compared with oral medication, the placebo effect induced by injectable drugs (especially intravenous drip) may be stronger, because we have long formed a deep-rooted concept: "Injections are more effective and have a stronger effect!" Compared with drug treatment, the effect of surgical treatment may be more easily affected by the placebo effect [3], because "drug treatment is too conservative, and surgical resection can cure it completely!"

At this point, it should not be difficult for readers to understand what happened in Mesmer's magnetic therapy clinic. Before entering his clinic, patients already had this impression: "He cured Her Majesty the Queen's illness!" Mesmer was a natural actor with first-class eloquence and very convincing words, so patients had strong expectations for the treatment effect. Coupled with the whole set of ritualistic treatment procedures, the patients collectively entered a state of being highly susceptible to suggestion. Once reactions such as vomiting and convulsions began to appear in some individuals, they would occur one after another. This phenomenon has a name in medicine: mass hysteria. After the treatment, the placebo effect occurred-the pain was eliminated!

The scientific research on placebos pioneered by Beecher and others has convincingly proved that the placebo effect objectively exists. However, what is the material basis of the placebo effect? ​​It was not until the 1970s, with the development of brain neuroscience, that the answer to this question began to emerge.

(to be continued)

Main references

· Finniss DG. Placebo Effects: Historical and Modern Evaluation. Int Rev Neurobiol. 2018; 139: 1-27.

· Hashmi JA. Placebo Effect: Theory, Mechanisms and Teleological Roots. Int Rev Neurobiol. 2018; 139: 233-53.

· Evans D. Placebo: mind over matter in modern medicine. London: HarperCollins Publishers, 2004.

· Vance E. Suggestible You: The Curious Science of Your Brain's Ability to Deceive, Transform, and Heal. Washington DC: National Geographic Partners, 2016.

References

[1] Beecher HK. The powerful placebo. J Am Med Assoc. 1955; 159: 1602-6.
[2] Laska E & Sunshine A. Anticipation of analgesia: A placebo effect. Headache. 1973; 1: 1–11.[3] Kaptchuk TJ et al. Do medical devices have enhanced placebo effects? J Clin Epidemiol. 2000; 53: 786-92.