LOS ANGELES—Psychosocial stimuli such as therapeutic medical rituals, verbal suggestions, and the characteristics of the therapeutic setting activate the same biochemical pathways as drugs that are given in routine clinical practice. This neurobiologic effect, known as the placebo response, suggests that psychologic factors may interfere with pharmacologic agents, said Fabrizio Benedetti, MD, at the 54th Annual Scientific Meeting of the American Headache Society.
Therapeutic rituals can include taking a pill, receiving an injection, and undergoing surgery, as well as practices associated with complementary and alternative medicine. Numerous biologic mechanisms are connected to these rituals, noted Dr. Benedetti, Professor of Neurophysiology and Human Physiology at the University of Turin Medical School in Italy. “There is not a single placebo response,” he said. “Actually, there are many placebo responses across many therapeutic interventions across different medical conditions.”
Placebo Mechanisms in Pain
Researchers frequently study pain when investigating the placebo response. Dr. Benedetti cited the example of a woman who experienced limited range of movement due to pain following thoracotomy surgery. When she was given a sugar pill along with a verbal suggestion of a decrease in pain, the limitation to the range of movement disappeared, demonstrating placebo analgesia.
“When we study the placebo response, we study what happens in a patient’s brain after the presentation of all these rituals in clinical and medical practice,” Dr. Benedetti told Neurology Reviews.
There are two phases to the placebo response—anticipatory and pain inhibition, Dr. Benedetti explained. In the anticipatory phase, the ritual of the therapeutic act leads to positive expectations, which, in turn, activate the descending pain-modulating system in the brain. The descending pain-modulating system has an inhibitory, analgesic effect on the transmission of pain.
Positive expectations can achieve an analgesic effect through two neurochemical systems, and the pathways used depend on whether patients were exposed to opioid or nonopioid drugs prior to receiving the placebo, said Dr. Benedetti. Those exposed to an opioid drug, such as morphine, show activation in the mu-opioid receptors, while those exposed to ketorolac, a nonopioid drug, activate a memory for the CB1 cannabinoid receptors.
Dr. Benedetti also noted the existence of the nocebo response, in which “you can modulate pain in the opposite direction.” If a patient with limited range of motion following thoracotomy receives a placebo that is described as a hyperalgesic drug, that person will experience an increase in pain. This increase in pain is reflected by activation of cholecystokinin and deactivation of mu-opioid receptors and D2 and D3 dopamine receptors.
In addition to pain, Parkinson’s disease has emerged as a model for understanding the neurobiology of the placebo response. According to Dr. Benedetti, there is a “substantial” release of endogenous dopamine in the striatum when patients with Parkinson’s disease are given a placebo along with positive verbal suggestions. Thus, telling patients that their motor performance is going to improve is approximately as effective as a full dose of amphetamines, he said.
To study the placebo response at the level of a single neuron, Dr. Benedetti and his colleagues conducted deep brain stimulation in a group of patients with Parkinson’s disease. Following placebo administration, patients who are good placebo responders had a significant decrease in muscle rigidity, and, at the single neuron level, they showed a “dramatic reduction” in the firing rate of subthalamic neurons, noted Dr. Benedetti.
“Unfortunately, not all patients respond in this way,” he said. “There are good placebo responders, and there are those Parkinson’s patients who do not respond to placebo at all.”
Good placebo responders often differ from nonresponders due to a learned response, as treatment-naïve patients do not always respond to placebo. “But if you give a placebo after repeated administration of an effective treatment, you can bet that virtually all patients will respond to placebo,” said Dr. Benedetti.
In one study, patients were given two days of treatment with sumatriptan, which has an effect on growth hormone, followed by a placebo treatment on day three. The patients showed a typical endocrine response to sumatriptan on day one and day two, as well as a small but significant placebo response on day three. This favorable response occurred regardless of whether the patients received positive or negative verbal suggestions.
Dr. Benedetti characterized this example of the placebo response as an unconscious mechanism that does not depend on conscious expectation, similar to classical conditioning. “The placebo response is a learning phenomenon,” he said.
Genetic variants offer a second explanation for the difference between placebo responders and nonresponders, he added. More research is needed to examine possible variants in Parkinson’s disease and pain, but studies of anxiety and depression have shown that certain genotypes respond well to placebo treatment.
In clinical practice, therapeutic rituals may lead to a placebo response even when an actual drug is given. Dr. Benedetti and his colleagues examined this occurrence further by comparing the open administration of painkillers in a routine clinical scenario with administration of painkillers via a hidden injection performed by a computer. Patients received the hidden injection in a hospital setting, but they were not aware of when the injection was given. Thus, expected therapeutic rituals were eliminated, and researchers could separate the psychologic effect of drug administration from the psychodynamic effect.
Dr. Benedetti cited a study of four painkillers—buprenorphine, tramadol, ketorolac, and metamizol—in which a hidden injection was less effective than an open injection in all cases and was nearly ineffective for ketorolac and metamizol.
Yet when the experiment was performed with morphine, there was no difference between the hidden and open injection conditions. “Morphine is really effective,” commented Dr. Benedetti.
These results, as well as other research examining therapeutic rituals and biochemical pathways, have implications for both clinical trials and clinical practice. Hidden injection experiments may allow researchers to better establish which drugs are effective, while clinical protocols designed to capitalize on the placebo response could reduce patient intake of potentially toxic drugs. There are ethical considerations with using the placebo response in clinical practice, noted Dr. Benedetti, but clinicians might be able to develop protocols in which, for example, morphine is given several days in a row to treat postoperative pain, followed by a placebo. “In the long run, you can decrease the use of morphine,” he said.
However, placebo responses will affect medical practice regardless of whether a protocol is used. “Different psychologic factors, like emotion, and different cognitive factors may influence the action of the drugs we give in routine clinical practice,” Dr. Benedetti concluded.
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