General Medicine
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History
One of the first documented uses of placebos as controls was by a French royal commission created by Louis XVI in 1784 and led by Benjamin Franklin. Franz Mesmer claimed to have uncovered “animal magnetism” that he believed contained healing properties. Franklin’s commission tested Mesmer’s theory by exposing patients to “mesmerised” objects or to placebos, without telling the subjects which ones they were being exposed to. They found that patients’ responses were unrelated to whether or not the object had been mesmerised and concluded that “animal magnetism” had no scientific basis.[1]
As double-blind placebo-controlled trials came into more frequent use, the placebo effect was considered a nuisance variable that needed to be controlled for. However, in 1955 Beecher reviewed just the placebo group results of 15 studies and found a 35% improvement in symptoms from placebo treatment.[1,2]
Experiments on the Placebo Effect
In the 1980s, a trial of pain relief after dental surgery compared open administration of either placebos or analgesics, given by a nurse in the room in view of the subject compared to hidden administration (the patients were unaware when the dose was given) via an automated intravenous (IV) pump. It was found that the open administration of a placebo had equivalent pain relief to hidden IV administration of 8mg of morphine. They also found that naloxone blunted some of the open administration placebo’s pain reduction indicating a naloxone-antagonizable component of placebo-induced analgesia. The authors felt that a substantial component of treatment response to open treatments could be attributed to the placebo effect.[1,3]
One trial compared open to hidden administration of pain and anti-anxiety medication. In one arm, post-operative patients were told they were getting IV pain medication with the doctor present in the room. The other group received the pain meds without being told when they were being administered. In other experimental arms, diazepam was administered IV in either an open or hidden manner. There was significantly more relief of pain and reduction of anxiety in the open treatment groups than in the hidden groups and in fact diazepam was found to have no effect in the hidden administration group. This provided some evidence that the placebo effect did not only occur with placebo use, but that active treatments may also involve a placebo component that contributes to the treatment response.[1,4]
In another trial, open ketorolac dosing was found to be more effective than hidden administration. However, when naloxone was added to ketorolac in the open treatment group, pain relief dropped to similar levels as the hidden group. As this effect was not from blocking the effects of the ketorolac, it was suggested that part of the placebo effect in the open administration group may be from endogenous activation of opioid pain receptors which were blocked with the naloxone.[4,5]
In a different trial, subjects were given repeated doses of IV ketorolac for pain relief as conditioning, with one group receiving only ketorolac with no statement that it would relieve their pain. The other group receiving ketorolac plus a verbal suggestion that the injection would relieve their pain. After the conditioning phase, when given a placebo injection that included naloxone, the ketorolac only conditioned group still had similar levels of pain relief, while in the placebo plus verbal expectation group there was partial blocking of pain responses by naloxone. One of the main findings emerging from this study is that cognitive factors such as the expectation of pain relief activated endogenous opioid systems which was blocked by the naloxone.[1,6]
Placebo analgesic effects are not only modulated by the opioid system but other systems such as the dopamine, cannabinoid, and cholecystokinin systems appear to be involved. When placebo analgesia was given after previous ketorolac conditioning for pain in a 2011 trial, administering rimonabant (a CB1 cannabinoid receptor antagonist that was later removed from the market due to adverse effects) blocked the conditioned analgesic effects of the placebo. This was felt to indicate involvement of the endogenous cannabinoid system in some placebo effects.[1,7]
One trial compared standard care for irritable bowel syndrome (IBS) with another group of patients getting standard care plus placebo treatment. The authors found that despite the fact that the patients in one group had been told that their additional treatment was a placebo, the placebo significantly improved IBS symptoms. The authors concluded that the benefit was attributable to the placebo effect and challenged the concept that deception is necessary to elicit a placebo effect.[1,8]
A systematic review and metanalysis also found a significant effect from open label placebos, where the patients were aware the treatment was a placebo.[9]
A number of studies have found a nocebo effect where placebos cause adverse effects. In Beecher’s 1955 study, placebo patients complained of headaches (25%), fatigue (18%), and nausea (10%) from the placebos.[1,2]
What Causes the Placebo effect?[1]
One theory is that the placebo effect is a learned response, where verbal, conditioned, and social cues form expectations that trigger the central nervous system and can generate placebo effects. Cues that initiate placebo effects do not need to be identical to those that have previously been experienced, but only share some features. A placebo response does not necessarily rely on conscious awareness, and in fact may be largely subconscious.
Classical conditioning is frequently used to explain the placebo effect. Pavlov paired the ringing of a bell with the administration of morphine, which causes restlessness in dogs. Eventually the dogs became restless on hearing the bell alone, providing some evidence that drug-like placebo effects can be conditioned. The placebo effect may be created and conditioned with stimuli such as syringes, pills or medical personnel that when paired with an active treatment such as a narcotic, may produce a conditioned placebo effect resulting in better pain relief.
Trials with long and short training intervals prior to placebo use found that a higher number of conditioning sessions caused an increase in placebo or nocebo effects. This was felt to indicate that the level of prior experience may be an important determinant of the strength of both placebo and nocebo effects.[10]
Intermittent reinforcement during training was found to produce weaker placebo analgesia than continuous reinforcement, but the placebo effect of intermittent reinforcement was more resistant to extinction.[1]
Verbal suggestions have been shown to be strong cues that can produce a placebo effect consistent with the direction of the verbal suggestion. It has been found that viewing a video of a research confederate reporting less pain when a placebo is used can induce placebo analgesia in the observer.[11] Nocebo effects can also be conditioned by having subjects observe a sham treatment that appears to increase pain in a research confederate which then causes more pain when the treatment is done to the subject.[12]
For the placebo effect to work, the patient has to believe it will work. In a number of studies, subjects who strongly believed in the treatment felt less pain with placebo than those who were less confident in it.[13] The placebo effect for sham surgical interventions tends to be large, with a systematic review of 21 randomized controlled trials (RCTs) concluding that the placebo effect has a significant influence on positive results of actual minimally-invasive surgery.[14]
It has been reported that the placebo effect may be more pronounced in children and adolescents than adults.[15]
Brain Changes With Placebos[1]
Multiple studies using functional MRI (fMRI) have found that pain processing is associated with several brain regions. A meta-analysis of fMRI studies of placebo analgesia identified certain areas of the brain as consistently having less activity during placebo analgesia. Those areas are the insula, dorsal anterior cingulate cortex, thalamus, amygdala and right lateral prefrontal cortex. One study found increased activity of the dorsolateral prefrontal cortex (DLPFC) in anticipation of pain relief, and that the fMRI signal in the DLPFC during anticipation of analgesia correlates with the strength of the placebo effect.[16] It is felt that the DLPFC is crucial in the processing of placebo and nocebo effects. Activation of regions of the brain associated with emotions and not cognitive thought or pain processing, were most predictive of placebo analgesia. This suggests that differences in emotional neurological pathways may be factors in individual variation to placebo analgesia.
In a trial of patients with chronic back pain, connectivity between left medial prefrontal cortex and bilateral insula accurately differentiated between placebo responders and non-responders in one trial, suggesting that an individual’s neurologic pathways can partially explain individual differences in placebo responses.[17]
Genetic Differences
There also appear to be genetic differences in the extent of the placebo effect in individuals. A number of genetic variants have been found to either increase or decrease the placebo effect. Individuals that have variants that increase dopamine activity will tend to have greater effects from placebos.
One variant of the catechol-O-methyltransferase (COMT) gene has been found to have less enzymatic activity to break down dopamine, and has been associated with increased dopamine activity in the prefrontal cortex. A study of subjects with irritable bowel syndrome found that carriers of this variant of the COMT gene, which results in higher levels of dopamine, had stronger responses to placebos.[18]
A study looking at the association of MAO-A genotypes with the placebo effect for clinical depression found that individuals with high-dopamine-activity genotypes had greater placebo-induced reduction in depressive symptoms.[1,19]
Another study examined genetic variants in the gene coding fatty acid amide hydrolase (FAAH Pro129 allele), the major degrading enzyme of endocannabinoids. Using PET scanners, it was discovered that individuals with different variants of the gene responded to placebos differently. It was also found that opioid receptor neurotransmissions were different depending on the variant. The authors suggested that this potentially demonstrates that there are interactions between endocannabinoid and opioid receptor neurotransmission in placebo responses.[1,20]
Issues With Using the Placebo Effect Clinically
A Cochrane database review of the placebo effect found that placebo interventions generally do not have important clinical effects. However, in certain settings, particularly for pain and nausea, placebos can affect patient‐reported outcomes. It was difficult for the reviewers to distinguish patient‐reported effects of placebo from biased reporting. The effect of placebos on pain varied in different trials, from negligible to clinically important. They concluded that “Most clinical placebo prescriptions involve deceit and the effect of placebo has not been tested in trials after full disclosure that the patients receive placebo. Therefore, we suggest that placebo interventions are not used outside clinical trials.”[21]
Conversely it appears placebos may have some effect, especially with pain therapy. Clinical issues with using placebos include ethical considerations, such as whether to inform the patient or not. There is variability of effect, and it would not be not known which specific patients would benefit from placebo therapy. There could be medical legal issues if a serious illness is treated with a placebo rather than a standard treatment. Placebo therapy is currently prescribed by some physicians who recommend vitamins for disorders that are not vitamin deficiencies and antibiotics for non-bacterial diseases.[22,23]
Dilute Homeopathic Medications – An example of Placebos in Actual Use?
Although the effectiveness of homeopathic medications is hotly debated, they are diluted so many times that after 30 to 40 one to one-hundred dilutions, it is possible that there is not even one molecule of the original compound left, and some formulations use up to 200 dilutions.[24] Samuel Hahnemann, the inventor of homeopathy, felt that homeopathic medicines retained their therapeutic power when shaken violently during the process of dilution. According to Hahnemann this process, called “potentization”, left a “dematerialized spiritual force” in the solution. Hahnemann felt the more dilute the solution, the stronger the effect.[25]
Thus, diluted homeopathic medications seem to meet all the criteria for an effective placebo. From a scientific pharmacological point of view, the diluted solution may contain no active chemical compounds. However, there is a theory that can inspire belief by the user that it is effective which may potentially trigger endogenous changes similar to those seen in the placebo effect. The placebo effect may therefore make these products effective for some conditions, and they may also be considered effective by patients when used for self-limited disease processes, which reinforces future use. Homeopathic medications are popular, with annual U.S. expenditures for homeopathic medications estimated to have been $6 billion in 2017 and to reach $16 billion by 2024.[26]
Do Homeopathic Medications Work?
A review of systemic reviews of homeopathic medications found many methodological issues in some of the literature and concluded that there was no homeopathic remedy that was demonstrated to yield clinical effects that are convincingly different from placebo.[25] Another meta-analysis suggested that the clinical effects of homeopathic drugs were from a placebo effect.[27]
Conclusions
The placebo effect has some convincing experimental evidence that it is real, and that placebos can cause changes in brain activity and stimulate endogenous opioid and cannabinoid receptors. However, making use of placebos for clinical disease treatment is fraught with ethical and possible medical legal issues if a patient is not informed it is a placebo or if a serious disease is treated with a placebo rather than a proven medication. There also appear to be genetic and individual differences in the strength of positive placebo effects.
It had been shown that subjects who do not know they are getting pain medication have less pain relief than those who are aware of the treatment. The positive effects of a placebo medication appear to stimulate internal receptors such as the opioid receptors improving pain relief both with placebos and standard medications. Practitioners can try to utilize the placebo effect by emphasizing how the medication they are prescribing typically does work well in most people with that patient’s particular condition.
Dilute homeopathic medications seem to fulfill placebo criteria of lacking pharmacological potency, but still providing a belief system that the medication is effective. Their popularity might be partially due to their placebo-like effects.
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References
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