A placebo has been defined as “a substance or procedure… that is objectively without specific activity for the condition being treated”. Under this definition, a wide variety of things can be placebos and exhibit a placebo effect. Pharmacological substances administered through any means can act as placebos, including pills, creams, inhalants, and injections. Medical devices such as ultrasound can act as placebos. Sham surgery, sham electrodes implanted in the brain, and sham acupuncture, either with sham needles or on fake acupuncture points, have all exhibited placebo effects. Bedding not treated to reduce allergies has been used as a placebo to control for treated bedding. The physician has even been called a placebo; 33–34 a study found that patient recovery can be increased by words that suggest the patient “would be better in a few days”, and if the patient is given treatment, that “the treatment would certainly make him better” rather than negative words such as “I am not sure that the treatment I am going to give you will have an effect”. The placebo effect may be a component of pharmacological therapies: Pain killing and anxiety reducing drugs that are infused secretly without an individual’s knowledge are less effective than when a patient knows they are receiving them. Likewise, the effects of stimulation from implanted electrodes in the brains of those with advanced Parkinson’s disease are greater when they are aware they are receiving this stimulation. Sometimes administering or prescribing a placebo merges into fake medicine.
The placebo effect has sometimes been defined as a physiological effect caused by the placebo, but Moerman and Jonas have pointed out that this seems illogical, as a placebo is an inert substance which does not directly cause anything. Instead they introduced the word “meaning response” for the meaning the brain associates with the placebo, which causes a physiological placebo effect. They propose that the placebo, which may be unethical, could be avoided entirely if doctors comfort and encourage their patients’ health. Ernst and Resch also attempted to distinguish between the “true” and “perceived” placebo effect, as they argued that some of the effects attributed to the placebo effect could be due to other factors.
The placebo effect has been controversial throughout history. Notable medical organizations have endorsed it, but in 1903 Richard Cabot concluded that it should be avoided because it is deceptive. Newman points out the “placebo paradox”, – it may be unethical to use a placebo, but also unethical “not to use something that heals”. He suggests to solve this dilemma by appropriating the meaning response in medicine, that is make use of the placebo effect, as long as the “one administering… is honest, open, and believes in its potential healing power”. Another possible resolution of the ethical dilemma might come from the “honest placebo” effect found in a 2010 study. at Harvard Medical School, where patients with irritable bowel syndrome experienced a significant beneficial effect even though they were told the pills they were taking were placebos, as compared to a control group who received no pills.
History
The word ‘placebo’, Latin for “I will please”, dates back to a Latin translation of the Bible by Jerome. It was first used in a medicinal context in the 18th century. In 1785 it was defined as a “commonplace method or medicine” and in 1811 it was defined as “any medicine adapted more to please than to benefit the patient”, sometimes with a derogatory implication but not with the implication of no effect. Placebos were widespread in medicine until the 20th century, and they were sometimes endorsed as necessary deceptions. In 1903 Richard Cabot said that he was brought up to use placebos, but he ultimately concluded by saying that “I have not yet found any case in which a lie does not do more harm than good”. In 1961 Henry K. Beecher found that surgeons he categorized as enthusiasts relieved their patients’ chest pain and heart problems more than skeptic surgeons. In 1961 Walter Kennedy introduced the word nocebo.
Mechanism of the effect
The phenomenon of an inert substance resulting in a patient’s medical improvement is called the placebo effect. The phenomenon is related to the perception and expectation which the patient has; if the substance is viewed as helpful, it can heal, but if it is viewed as harmful, it can cause negative effects, which is known as the nocebo effect. The basic mechanisms of placebo effects have been investigated since 1978, when it was found that the opioid antagonist naloxone could block placebo painkillers, suggesting that endogenous opioids are involved.
Expectancy and conditioning
Placebos exert an “expectancy” effect whereby an inert substance which is believed to be a drug has effects similar to the actual drug. Placebos can act similarly through classical conditioning, where a placebo and an actual stimulus are used simultaneously until the placebo is associated with the effect from the actual stimulus. Both conditioning and expectations play a role in placebo effect, and make different kinds of contribution. Conditioning has a longer lasting effect, and can affect earlier stages of information processing. The expectancy effect can be enhanced through factors such as the enthusiasm of the doctor, differences in size and color of placebo pills, or the use of other interventions such as injections. In one study, the response to a placebo increased from 44% to 62% when the doctor treated them with “warmth, attention, and confidence”. Expectancy effects have been found to occur with a range of substances. Those who think a treatment will work display a stronger placebo effect than those who do not, as evidenced by a study of acupuncture.
Because the placebo effect is based upon expectations and conditioning, the effect disappears if the patient is told that their expectations are unrealistic, or that the placebo intervention is ineffective. A conditioned pain reduction can be totally removed when its existence is explained. It has also been reported of subjects given placebos in a trial of anti-depressants, that “Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated.”
A placebo described as a muscle relaxant will cause muscle relaxation and if described as the opposite, muscle tension. A placebo presented as a stimulant will have this effect on heart rhythm, and blood pressure, but when administered as a depressant, the opposite effect. The perceived consumption of caffeine has been reported to cause similar effects even when decaffeinated coffee is consumed, although a 2003 study found only limited support for this. Alcohol placebos can cause intoxication and sensorimotor impairment. Perceived ergogenic aids can increase endurance, speed and weight-lifting ability, leading to the question of whether placebos should be allowed in sport competition. Placebos can help smokers quit. Perceived allergens which are not truly allergenic can cause allergies. Interventions such as psychotherapy can have placebo effects. The effect has been observed in the transplantation of human embryonic neurons into the brains of those with advanced Parkinson’s disease.
Because placebos are dependent upon perception and expectation, various factors which change the perception can increase the magnitude of the placebo response. For example, studies have found that the color and size of the placebo pill makes a difference, with “hot-colored” pills working better as stimulants while “cool” colored pills work better as depressants. Capsules rather than tablets seem to be more effective, and size can make a difference. One researcher has found that big pills increase the effect while another has argued that the effect is dependent upon cultural background. More pills, branding, past experience, and high price increase the effect of placebo pills. Injection and acupuncture have larger effect than pills. Proper adherence to placebos is associated with decreased mortality.
Motivation may contribute to the placebo effect. The active goals of an individual changes their somatic experience by altering the detection and interpretation of expectation-congruent symptoms, and by changing the behavioral strategies a person pursues. Motivation may link to the meaning through which people experience illness and treatment. Such meaning is derived from the culture in which they live and which informs them about the nature of illness and how it responds to treatment. Research upon the placebo treatment of gastric and duodenal ulcers shows that this varies widely with society: those in Germany having a high rate placebo effect while those in Brazil a low one. Placebo effects in treating gastric ulcers is low in Brazil, higher in northern Europe (Denmark, Netherlands) and extremely high in Germany. But the placebo effect for hypertension is lower in Germany than elsewhere Social observation can induce a placebo effect such when a person sees another having reduced pain following what they believe is a pain reducing procedure.
The placebo effect can work selectively. If an analgesic placebo cream is applied on one hand, it will reduce pain only in that hand and not elsewhere on the body If a person is given a placebo under one name, and they respond, they will respond in the same way on a later occasion to that placebo under that name but not if under another.
Placebo effect and the brain
Functional imaging upon placebo analgesia shows that it links to the activation, and increased functional correlation between this activation, in the anterior cingulate, prefrontal, orbitofrontal and insular cortices, nucleus accumbens, amygdala, the brainstem periaqueductal gray matter, and the spinal cord.
These changes can act upon the brain’s early stages of information processing: research using evoked brain potentials upon painful laser pulses, for example, finds placebo effects upon the N2–P2, a biphasic negative–positive complex response, the N2 peak of which is at about 230 ms, and the P2 one at about 380 ms. They occur not only during placebo analgesia but after receiving the analgesic placebo (the areas are different here, and involve the medial prefrontal cortex, posterior parietal cortex and inferior parietal lobule).
Different areas in the higher brain have different functions. The prefrontal involvement could be related to recalling the placebo and maintaining its cognitive presence in a “self-reinforcing feedback loop” (during pain an individual recalls having taken the placebo and reduced pain reinforces its status as an analgesic). The rostral anterior cingulate cortex (rACC) and its subcortical connectivity could be related to the expectation of potential pain stimuli.
The higher brain works by regulating subcortical processes. High placebo responses link with enhanced dopamine and mu-opioid activity in the circuitry for reward responses and motivated behavior of the nucleus accumbens, and conversely, anti-analgesic nocebos responses were associated with deactivation in this part of the brain of dopamine and opioid release. (It has been known that placebo analgesia depends upon the release in the brain of endogenous opioids since 1978.) Such analgesic placebos activation changes processing lower down in the brain by enhancing the descending inhibition through the periaqueductal gray on spinal nociceptive reflexes, while the expectations of anti-analgesic nocebos acts in the opposite way to block this.
The brain is also involved in less studied ways upon nonanalgesic placebo effects:
Parkinson’s disease: placebo relief is associated with the release of dopamine in the brain.
Depression: Placebos reducing depression affect many of the same areas that are activated by antidepressants with the addition of the prefrontal cortex.
Caffeine: placebo caffeinated coffee causes an increase in bilateral dopamine release in the thalamus.
Glucose: the expectation of an intravenous injection of glucose increases the release of dopamine in the basal ganglia of men (but not women).
Methylphenidate: the expectation of intravenous injection of this drug in inexperienced drug users increased the release of dopamine in the ventral cingulate gyrus and nucleus accumbens, with this effect being largest in those with no prior experience of the drug.
Present functional imaging upon placebo analgesia has been summarized as showing that the placebo response is “mediated by “top-down” processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies”. “Diseases lacking major ‘top-down’ or cortically based regulation may be less prone to placebo-related improvement”.
Brain and body
The brain has control over the body processes affected by placebos. Pain, motor fatigue and fever are directly organized by the brain. Other processes usually regulated by the body such as the immune system are also controlled indirectly through the sympathetic and parasympathetic nervous system.
Research upon conditioning in animals shows the brain can learn control over them. In conditioning, a neutral stimulus saccharin is paired in a drink with an agent that produces an unconditioned response. For example, that agent might be cyclophosphamide that causes immunosuppression. After learning this pairing, the taste of saccharin by itself through neural top down control created immunosuppression, as a new conditioned response. Such conditioning has been found to affect a diverse variety of basic physiological processes not just in the immune system but ones such as serum iron levels, oxidative DNA damage levels, and insulin secretion.
This work was originally done on rats, however, the same conditioning of basic physiological processes can also occur in humans. Recent reviews have argued the placebo effect is due to top down control by the brain for immunity and pain. Pacheco-López and colleagues have raised the possibility of “neocortical-sympathetic-immune axis providing neuroanatomical substrates that might explain the link between placebo/conditioned and placebo/expectation responses.”
A recent fMRI study has shown that a placebo can reduce pain-related neural activity in the spinal cord, indicating that placebo effects can extend beyond the brain.
Evolved health regulation
Evolutionary medicine identifies many symptoms such as fever, pain, and sickness behavior as evolved responses to protect or enhance the recovery from infection and injury. Fever, for example, is an evolved self-treatment that removes bacteria or viruses through raised body temperature. These evolved responses, however, also have a cost that depending upon circumstances can outweigh their benefit (due to this, for example, there is a reduction in fever during malnutrition or late pregnancy). According to the health management system theory proposed by Nicholas Humphrey, the brain has been selected to ensure that evolved responses are deployed only when the cost benefit is biologically advantageous. To do this, the brain factors in a variety of information sources, including the likelihood derived from beliefs that the body will get well without deploying its costly evolved responses. One such source of information is the knowledge the body is receiving care and treatment. The placebo effect in this perspective arises when false information about medications misleads the health management system about the likelihood of getting well so that it selects not to deploy an evolved self-treatment.
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