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The placebo effect refers to the feeling of health improvement in the human body due to positive expectations when receiving ineffective treatment, while the corresponding anti placebo effect is the decrease in efficacy caused by negative expectations when receiving active drugs, or the occurrence of side effects due to negative expectations when receiving placebo, which may lead to the deterioration of the condition. They are commonly present in clinical treatment and research, and can affect patient efficacy and outcomes.

The placebo effect and anti placebo effect are the effects generated by patients’ positive and negative expectations of their own health status, respectively. These effects can occur in various clinical environments, including the use of active drugs or placebo for treatment in clinical practice or trials, obtaining informed consent, providing medical related information, and conducting public health promotion activities. The placebo effect leads to favorable outcomes, while the anti placebo effect leads to harmful and dangerous outcomes.

The differences in treatment response and presentation symptoms among different patients can be partially attributed to placebo and anti placebo effects. In clinical practice, the frequency and intensity of placebo effects are difficult to determine, while under experimental conditions, the frequency and intensity range of placebo effects is wide. For example, in many double-blind clinical trials for the treatment of pain or mental illness, the response to placebo is similar to that to active drugs, and up to 19% of adults and 26% of elderly participants who received placebo reported side effects. In addition, in clinical trials, up to 1/4 of patients who received placebo stopped taking the medication due to side effects, suggesting that the anti placebo effect may lead to active drug discontinuation or poor compliance.

The neurobiological mechanisms of placebo and anti placebo effects
The placebo effect has been shown to be associated with the release of many substances, such as endogenous opioids, cannabinoids, dopamine, oxytocin, and vasopressin. The action of each substance is aimed at the target system (i.e. pain, movement, or immune system) and diseases (such as arthritis or Parkinson’s disease). For example, dopamine release is involved in the placebo effect in the treatment of Parkinson’s disease, but not in the placebo effect in the treatment of chronic or acute pain.

The exacerbation of pain caused by verbal suggestion in the experiment (an anti placebo effect) has been shown to be mediated by the neuropeptide cholecystokinin and can be blocked by proglutamide (which is a type A and type B receptor antagonist of cholecystokinin). In healthy individuals, this language induced hyperalgesia is associated with increased activity of the hypothalamic pituitary adrenal axis. The benzodiazepine drug diazepam can antagonize hyperalgesia and hyperactivity of the hypothalamic pituitary adrenal axis, suggesting that anxiety is involved in these anti placebo effects. However, alanine can block hyperalgesia, but cannot block overactivity of the hypothalamic pituitary adrenal axis, suggesting that the cholecystokinin system is involved in the hyperalgesia part of the anti placebo effect, but not in the anxiety part. The influence of genetics on placebo and anti placebo effects is associated with haplotypes of single nucleotide polymorphisms in dopamine, opioid, and endogenous cannabinoid genes.

A participant level meta-analysis of 20 functional neuroimaging studies involving 603 healthy participants showed that the placebo effect associated with pain only had a small impact on pain related functional imaging manifestations (referred to as neurogenic pain signatures). The placebo effect may play a role at several levels of brain networks, which promote emotions and their impact on multifactorial subjective pain experiences. Brain and spinal cord imaging shows that the anti placebo effect leads to an increase in pain signal transmission from the spinal cord to the brain. In the experiment to test the response of participants to placebo creams, these creams were described as causing pain and labeled as high or low in price. The results showed that pain transmission regions in the brain and spinal cord were activated when people expected to experience more severe pain after receiving treatment with high priced creams. Similarly, some experiments have tested pain induced by heat that can be relieved by the potent opioid drug remifentanil; Among participants who believed that remifentanil had been discontinued, the hippocampus was activated, and the anti placebo effect blocked the drug’s efficacy, suggesting that stress and memory were involved in this effect.

Expectations, Language Hints, and Framework Effects
The molecular events and neural network changes underlying placebo and anti placebo effects are mediated by their expected or foreseeable future outcomes. If the expectation can be realized, it is called expectation; Expectations can be measured and influenced by changes in perception and cognition. Expectations can be generated in various ways, including previous experiences of drug effects and side effects (such as analgesic effects after medication), verbal instructions (such as being informed that a certain medication can alleviate pain), or social observations (such as directly observing symptom relief in others after taking the same medication). However, some expectations and placebo and anti placebo effects cannot be realized. For example, we may conditionally induce immunosuppressive responses in patients undergoing kidney transplantation. The proof method is to apply neutral stimuli previously paired with immunosuppressants to patients. The use of neutral stimulation alone also reduces T cell proliferation.

In clinical settings, expectations are influenced by the way drugs are described or the “framework” used. After surgery, compared to masked administration where the patient is unaware of the administration time, if the treatment you will receive while administering morphine indicates that it can effectively alleviate pain, it will bring significant benefits. Direct prompts for side effects can also be self fulfilling. A study included patients treated with beta blocker atenolol for heart disease and hypertension, and the results showed that the incidence of sexual side effects and erectile dysfunction was 31% in patients who were intentionally informed of potential side effects, while the incidence was only 16% in patients who were not informed of side effects. Similarly, among patients who took finasteride due to benign prostate enlargement, 43% of patients who were explicitly informed of sexual side effects experienced side effects, while among patients who were not informed of sexual side effects, this proportion was 15%. A study included asthma patients who inhaled nebulized saline and were informed that they were inhaling allergens. The results showed that about half of the patients experienced breathing difficulties, increased airway resistance, and decreased lung capacity. Among asthma patients who inhaled bronchoconstrictors, those who were informed of bronchoconstrictors experienced more severe respiratory distress and airway resistance than those who were informed of bronchodilators.

In addition, language induced expectations can cause specific symptoms such as pain, itching, and nausea. After language suggestion, stimuli related to low-intensity pain can be perceived as high-intensity pain, while tactile stimuli can be perceived as pain. In addition to inducing or exacerbating symptoms, negative expectations can also reduce the efficacy of active drugs. If the false information that medication will exacerbate rather than alleviate pain is conveyed to patients, the effect of local analgesics can be blocked. If the 5-hydroxytryptamine receptor agonist rizitriptan is mistakenly labeled as a placebo, it can reduce its efficacy in treating migraine attacks; Similarly, negative expectations can also reduce the analgesic effect of opioid drugs on experimentally induced pain.

Learning mechanisms in placebo and anti placebo effects
Both learning and classical conditioning are involved in placebo and anti placebo effects. In many clinical situations, neutral stimuli previously associated with the beneficial or harmful effects of drugs through classical conditioning can produce benefits or side effects without the use of active drugs in the future.

For example, if environmental or taste cues are repeatedly paired with morphine, the same cues used with placebo instead of morphine can still produce analgesic effects. In psoriasis patients who received interval use of reduced dose glucocorticoids and placebo (so-called dose extending placebo), the recurrence rate of psoriasis was similar to that of patients receiving full dose glucocorticoid treatment. In the control group of patients who received the same corticosteroid reduction regimen but did not receive placebo at intervals, the recurrence rate was as high as three times that of the dose continuation placebo treatment group. Similar conditioning effects have been reported in the treatment of chronic insomnia and in the use of amphetamines for children with attention deficit hyperactivity disorder.

Previous treatment experiences and learning mechanisms also drive the anti placebo effect. Among women receiving chemotherapy due to breast cancer, 30% of them will have expected nausea after exposure to environmental cues (such as coming to the hospital, meeting medical staff, or entering a room similar to the infusion room) that were neutral before exposure but had been associated with infusion. Newborns who have undergone repeated venipuncture immediately exhibit crying and pain during alcohol cleansing of their skin before venipuncture. Showing allergens in sealed containers to asthma patients can trigger asthma attacks. If a liquid with a specific odor but without beneficial biological effects has been paired with an active drug with significant side effects (such as tricyclic antidepressants) before, the use of that liquid with a placebo can also induce side effects. If visual cues (such as light and images) were previously paired with experimentally induced pain, then using these visual cues alone can also induce pain in the future.

Knowing the experiences of others can also lead to placebo and anti placebo effects. Seeing pain relief from others can also cause a placebo analgesic effect, which is similar in magnitude to the analgesic effect received by oneself before treatment. There is experimental evidence to suggest that social environment and demonstration can induce side effects. For example, if participants witness others reporting the side effects of a placebo, report pain after using an inactive ointment, or inhale indoor air described as “potentially toxic,” it can also lead to side effects in participants exposed to the same placebo, inactive ointment, or indoor air.

Mass media and non professional media reports, information obtained from the Internet, and direct contact with other symptomatic people can all promote the anti placebo reaction. For example, the reporting rate of adverse reactions to statins is correlated with the intensity of negative reporting on statins. There is a particularly vivid example where the number of reported adverse events increased by 2000 times after negative media and television reports pointed out harmful changes in the formula of a thyroid drug, and only involved specific symptoms mentioned in the negative reports. Similarly, after public promotion leads community residents to mistakenly believe that they are exposed to toxic substances or hazardous waste, the incidence of symptoms attributed to the imagined exposure increases.

The impact of placebo and anti placebo effects on research and clinical practice
It may be helpful to determine who is prone to placebo and anti placebo effects at the beginning of treatment. Some features related to these responses are currently known, but future research can provide better empirical evidence for these features. Optimism and susceptibility to suggestion do not seem to be closely related to the response to placebo. There is evidence to suggest that the anti placebo effect is more likely to occur in patients who are more anxious, have previously experienced symptoms of unknown medical reasons, or have significant psychological distress among those taking active drugs. There is currently no clear evidence regarding the role of gender in placebo or anti placebo effects. Imaging, multi gene risk, genome-wide association studies, and twin studies may help elucidate how brain mechanisms and genetics lead to biological changes that serve as the basis for placebo and anti placebo effects.

The interaction between patients and clinical physicians can affect the likelihood of placebo effects and the reported side effects after receiving placebo and active drugs. The trust of patients in clinical physicians and their good relationship, as well as honest communication between patients and physicians, have been proven to alleviate symptoms. Therefore, patients who believe that physicians are empathetic and report symptoms of the common cold are milder and shorter in duration than those who believe that physicians are not empathetic; Patients who believe that physicians are empathetic also experience a decrease in objective indicators of inflammation, such as interleukin-8 and neutrophil count. The positive expectations of clinical physicians also play a role in the placebo effect. A small study comparing anesthetic analgesics and placebo treatment after tooth extraction showed that physicians were aware that patients receiving analgesics were associated with greater pain relief.

If we want to use the placebo effect to improve treatment outcomes without adopting a paternalistic approach, one way is to describe the treatment in a realistic but positive way. Raising expectations of therapeutic benefits has been shown to improve patient response to morphine, diazepam, deep brain stimulation, intravenous administration of remifentanil, local administration of lidocaine, complementary and integrated therapies (such as acupuncture), and even surgery.

Investigating patient expectations is the first step in incorporating these expectations into clinical practice. When evaluating the expected clinical outcomes, patients can be asked to use a scale of 0 (no benefit) to 100 (maximum imaginable benefit) to assess their expected therapeutic benefits. Helping patients understand their expectations for elective cardiac surgery reduces disability outcomes at 6 months post surgery; Providing guidance on coping strategies to patients before intra-abdominal surgery significantly reduced postoperative pain and anesthesia medication dosage (by 50%). The ways to utilize these framework effects include not only explaining the suitability of treatment to patients, but also explaining the proportion of patients who benefit from it. For example, emphasizing the efficacy of medication to patients can reduce the need for postoperative analgesics that patients can control themselves.

In clinical practice, there may be other ethical ways to utilize the placebo effect. Some studies support the efficacy of the “open label placebo” method, which involves administering a placebo along with the active drug and honestly informing patients that adding a placebo has been proven to enhance the beneficial effects of the active drug, thereby enhancing its efficacy. In addition, it is possible to maintain the effectiveness of the active drug through conditioning while gradually reducing the dosage. The specific operation method is to pair the drug with sensory cues, which is particularly useful for toxic or addictive drugs.

On the contrary, worrisome information, erroneous beliefs, pessimistic expectations, past negative experiences, social information, and treatment environment can lead to side effects and reduce the benefits of symptomatic and palliative treatment. Non specific side effects of active drugs (intermittent, heterogeneous, dose independent, and unreliable reproducibility) are common. These side effects can lead to poor adherence of patients to the treatment plan (or discontinuation plan) prescribed by the physician, requiring them to switch to another medication or add other medications to treat these side effects. Although we need more research to determine a clear association between the two, these non-specific side effects may be caused by the anti placebo effect.

It may be helpful to explain the side effects to the patient while also highlighting the benefits. It may also be helpful to describe the side effects in a supportive manner rather than in a deceptive manner. For example, explaining to patients the proportion of patients without side effects, rather than the proportion of patients with side effects, can reduce the incidence of these side effects.

Physicians have an obligation to obtain valid informed consent from patients before implementing treatment. As part of the informed consent process, physicians need to provide complete information to assist patients in making informed decisions. Physicians must clearly and accurately explain all potential dangerous and clinically significant side effects, and inform patients that all side effects should be reported. However, listing benign and non-specific side effects that do not require medical attention one by one increases the likelihood of their occurrence, posing a dilemma for doctors. One possible solution is to introduce the anti placebo effect to patients and then ask if they are willing to learn about the benign, non-specific side effects of the treatment after becoming aware of this situation. This method is called “contextualized informed consent” and “authorized consideration”.

Exploring these issues with patients may be helpful as erroneous beliefs, worrisome expectations, and negative experiences with previous medication can lead to an anti placebo effect. What annoying or dangerous side effects have they had before? What side effects are they concerned about? If they are currently suffering from benign side effects, how much impact do they think these side effects have? Do they expect the side effects to worsen over time? The answers given by patients may help physicians alleviate their concerns about side effects, making treatment more tolerable. Physicians can reassure patients that although side effects can be troublesome, they are actually harmless and not medically dangerous, which may alleviate the anxiety that triggers side effects. On the contrary, if the interaction between patients and clinical physicians cannot alleviate their anxiety, or even exacerbate it, it will amplify the side effects. A qualitative review of experimental and clinical studies suggests that negative nonverbal behavior and indifferent communication methods (such as empathetic speech, lack of eye contact with patients, monotonous speech, and no smile on the face) can promote the anti placebo effect, reduce patient tolerance to pain, and reduce the placebo effect. The presumed side effects are often symptoms that were previously overlooked or overlooked, but are now attributed to medication. Correcting this erroneous attribution can make the drug more tolerable.

The side effects reported by patients may be expressed in a nonverbal and covert manner, expressing doubts, reservations, or anxiety about the medication, treatment plan, or physician’s professional skills. Compared to expressing doubts directly to clinical physicians, side effects are a less embarrassing and easily acceptable reason for discontinuing medication. In these situations, clarifying and candidly discussing the patient’s concerns may help avoid situations of discontinuation or poor compliance.

The research on placebo and anti placebo effects is meaningful in the design and implementation of clinical trials, as well as the interpretation of results. Firstly, where feasible, clinical trials should include intervention free intervention groups to explain confounding factors associated with placebo and anti placebo effects, such as symptom regression mean. Secondly, the longitudinal design of the trial will affect the incidence of response to placebo, especially in the crossover design, as for participants who received the active drug first, previous positive experiences would bring expectations, while participants who received the placebo first did not. Since informing patients of the specific benefits and side effects of treatment may increase the incidence of these benefits and side effects, it is best to maintain consistency in the benefits and side effect information provided during the informed consent process across trials studying a specific drug. In a meta-analysis where information fails to reach consistency, the results should be interpreted with caution. It is best for researchers who collect data on side effects to be unaware of both the treatment group and the situation of side effects. When collecting side effect data, a structured symptom list is better than an open survey.