Placebo and nocebo in the treatment of back pain

Placebo

I Patrick D. Wall, describing the placebo response in a manual on pain, writes that the word "placebo" is mentioned in Psalm 117:9: "Placebo Domo in regione vivorum" in the first line of the evening prayer. Priests and monks harassed people by forcing them to pay for evening prayers. Placebo was an expression of disdain for unpopular and expensive prayers, as Francis Bacon wrote in 1625, "Sing him a song of placebo instead of absolution." Three years later, Burton wrote in The Anatomy of Melancholy, "often a wise physician, or a foolish surgeon, has achieved stranger cases of recovery than a wise physician, because the patient has more confidence in him." Now, more than four hundred years later, the placebo response is still used in medicine and the mechanism behind this phenomenon is becoming better understood.

Placebo is a physiologically inert substance used as a medicine, the positive therapeutic effect of which is associated with the unconscious psychological expectation of the patient. In addition, the term "placebo effect" refers to the phenomenon of non-drug effects, not only of a drug, but, for example, of radiation (sometimes various "flashing" devices, "laser therapy" are used), etc. Lactose is often used as a placebo substance. The degree of manifestation of the placebo effect depends on the suggestibility of a person and the external circumstances of the "treatment", for example, on the size and brightness of the color of the tablet, the degree of trust in the doctor, the authority of the clinic.

The first chief of anesthesiology at the Massachusetts General Hospital, Henry Beecher, published his classic textbook, The Power of Placebo, in 1955. In it, he proposed that the patient's expectation of benefit was sufficient to achieve a therapeutic effect. He also proposed that the overall analgesic effect of morphine was the sum of its medicinal action and the placebo effect. About fifty years later, with the help of modern technology, scientific research was able to provide confirmation of Beecher's hypothesis and prove the neurobiological mechanism of this phenomenon. Modern research has also shown that the placebo effect is far from miraculous. Depending on the conditions, the placebo effect can be narrowly targeted and have a somatotopic organization.

The mechanism of placebo analgesia is considered from several positions. The cognitive theory states that patient expectations play an important role in the placebo response. Patient expectations are the best predictor of outcome in pain management. It is assumed that placebo analgesia may be partially mediated by endogenous opioids, since the effect can be inhibited by the opioid antagonist naloxone. It is suggested that the expectation of pain relief can trigger the release of endogenous opioids in the central nervous system. The conditioned theory states that learning associative connections is important in the placebo response. This theory suggests that the placebo response is a conditioned response to a stimulus that causes relief of symptoms and leads to an improvement in physical condition. Similarities with the classical conditioned reflex described by I. Pavlov in dogs are assumed. He reported dogs that were given morphine in a specific chamber and showed a morphine-like effect when placed back in the same chamber, despite not having been given morphine. Repeated associations between effective analgesics, pain relief, and the therapeutic environment can produce a conditioned analgesic placebo response. As argued above, endogenous opioids may be at least partly responsible for placebo analgesia, since the opioid antagonist naloxone can reverse placebo analgesia. Amanzio and Benedetti, using an experimental model of human ischemic pain, induced a placebo analgesic response with a dummy, drugs (morphine or ketorol), and a combination of the two. The dummy induced a placebo effect that was completely blocked by the opioid antagonist naloxone. The combined use of a placebo and morphine also caused a placebo effect that was completely neutralized by naloxone. The use of morphine without a placebo caused a naloxone-reversible placebo effect. However, the placebo effect caused by taking ketorol and a placebo was neutralized by naloxone only partially. The use of ketorol without a placebo caused a placebo response that was not sensitive to naloxone. The authors concluded that expectation triggers the release of endogenous opioids, while measures to improve physical condition activate specific subsystems.

Positron emission tomography studies have shown that the opioid analgesic and placebo activate the same neural structures, including the rostral anterior cingulate cortex, prefrontal cortex, and brainstem, regions involved in pain modulation. The study also suggests that variation in placebo response between individuals may be related to individual ability to activate this system. Interestingly, those who had a good placebo response showed greater activation of this system during remifentanil analgesia.

Dopamine has been suggested to mediate the expectancy-related placebo effect. A PET study of patients with Parkinson's disease with SP-labeled raclopride showed that placebo-induced endogenous dopamine release was associated with symptom reduction. The magnitude of the dopamine response in the placebo effect was comparable to the therapeutic dose of levodopa.

In 1999, Benedetti et al. further investigated the role of the opioid system in goal-directed anticipation of analgesia. They stimulated the feet and hands with subcutaneous capsaicin. Specific anticipation of analgesia was induced by applying a placebo cream to one of these body parts, with the subject being told that it was a strong local anesthetic. The results showed that a highly somatotopically organized endogenous opioid system integrated anticipation, attention, and body schema.

The placebo response can be enhanced by good doctor-patient interaction. The therapist's expectations and the patient's sense of hope also contribute to the placebo effect.

Nocebo

Often, patients in the placebo arm report side effects similar to those in the actual treatment arm. Such adverse placebo effects have been termed nocebo effects. The cognitive and conditioned mechanisms that trigger the nocebo response are the same as those involved in the placebo response. It is important to take this into account when designing a clinical trial. Informing patients and asking leading questions about adverse effects may influence the results. It is also important that patients often experience symptoms such as fatigue, increased sweating, and constipation at baseline, before the trial begins. To increase the patient's real ignorance, active placebos are sometimes used. An active placebo mimics the drug being studied, causing adverse effects without specifically affecting the underlying disease manifestations.

Placebo effect in the clinic

Research shows that placebo analgesia has a neurophysiological basis and that different individuals show a wide range of placebo responses. It is therefore clear that placebos cannot be used to determine whether a patient is truly in pain or not. Placebo drugs cannot be used as an alternative to analgesics. However, the mechanisms of placebo analgesia that have been uncovered, especially in the doctor-patient interaction, can be used to improve the effectiveness of treatment. The importance of the doctor-patient interaction has been recognized throughout history, but its neurobiological basis is only now becoming clearer. If caregivers used effective techniques in which they believed, and if they communicated this belief to the patient, their treatment would be more effective than the same treatment given by skeptics.