Placebo: I will please
The placebo effect is a fascinating biological phenomenon that is really very mysterious - it has powerful medicative properties but nobody is quite sure how it works. It represents a transition zone between mind and body, and the 'power of positive thinking', but can we truly will ourselves better?
Placebos or 'dummy pills' are routinely used during clinical trials to assess the true efficacy or usefulness of the drug or treatment under investigation: they are known as the 'negative control' of the trial, as they are supposedly inert, with no pharmacological effects or biological properties. However, there are several disorders that display a pronounced placebo effect, whereby the status of the patient shows improvement despite only being subjected to a superficial intervention.
I first became interested in the power of placebo when I was giving a series of lectures on clinical trials to science postgrads that were based on antidepressant drugs, and their efficacy in treating depression. I must have read hundreds of papers detailing clinical reports for X antidepressant or Y compound, and I got suspicious... from what I could see, the long-term efficacy (i.e., after a year of treatment) of antidepressants was only marginally higher than that of the placebo, which stood at approximately 40% (this means that 40% of initially depressed subjects taking an antidepressant or placebo were considered depression-free after a year. Of course, this means that 60% were still considered depressed, which is really not good enough - however, this is another issue!).
Here, I am going to look a bit more closely at the placebo effect by examining its underlying biological mechanisms, and I will also briefly discuss the implications for healthcare, and how it can be harnessed for our benefit.
Placebos or 'dummy pills' are routinely used during clinical trials to assess the true efficacy or usefulness of the drug or treatment under investigation: they are known as the 'negative control' of the trial, as they are supposedly inert, with no pharmacological effects or biological properties. However, there are several disorders that display a pronounced placebo effect, whereby the status of the patient shows improvement despite only being subjected to a superficial intervention.
I first became interested in the power of placebo when I was giving a series of lectures on clinical trials to science postgrads that were based on antidepressant drugs, and their efficacy in treating depression. I must have read hundreds of papers detailing clinical reports for X antidepressant or Y compound, and I got suspicious... from what I could see, the long-term efficacy (i.e., after a year of treatment) of antidepressants was only marginally higher than that of the placebo, which stood at approximately 40% (this means that 40% of initially depressed subjects taking an antidepressant or placebo were considered depression-free after a year. Of course, this means that 60% were still considered depressed, which is really not good enough - however, this is another issue!).
Here, I am going to look a bit more closely at the placebo effect by examining its underlying biological mechanisms, and I will also briefly discuss the implications for healthcare, and how it can be harnessed for our benefit.
An example...
A clinical trial was conducted many years ago to explicitly investigate the placebo phenomenon. Subjects experiencing cancer pain were either informed or not informed about the details of a clinical trial they participated in, and their subjective feelings of pain were subsequently recorded. Interestingly, it was found that placebo intervention in the informed group was significantly more effective than naproxen (a non-steroidal anti-inflammatory drug, similar to aspirin) in the unaware group. Also, concealment decreased the placebo response...
This is quite intriguing! However, awareness of the influence of placebo had been around at least since the 1950s, when Henry Beecher published an article entitled 'The Powerful Placebo' detailing the effect. In this article, he stated that placebos could induce 'objective changes at the end organ which may exceed those attributable to potent pharmacological action'. In the interests of scientific objectivity, it should be noted that the studies included in Beecher's assessment had failed to include a no-treatment group, and it was possible that patients experienced spontaneous remission, which would appear like a positive placebo response. In addition, a later meta-analysis [a meta-analysis is a super-review of the scientific literature and all the studies conducted in a defined research field, that attempts to address specific questions related to that field] conducted by Hrobjartsson and Gotzsche in 2001 concluded that there was little evidence that placebos had any clinical effects, apart from the alleviation of headaches and post-operative pain.
Only apparent in certain disorders
It is now more or less accepted that placebos affect only some medical disorders, which possibly share an underlying pathological mechanism. For example, the psychiatric conditions of obsessive-compulsive disorder and schizophrenia are relatively resistant to placebo, while, according to a paper published by Evans in the journal Medical Hypotheses in 2005, those disorders with a strong inflammatory component such as depression, stomach ulcers, and pain, ARE more receptive to placebo intervention. This has led to the development of an inflammation theory to explain the placebo effect.
In inflammation, the four physiological manifestations of swelling, redness, heat, and pain, co-exist with a host of systemic effects of a psychological nature, known collectively as 'sickness behaviour'. These include depression-like symptoms such as apathy and anhedonia, or the inability to feel pleasure. Evans proposes that the underlying biological mechanism responsible for these psychological and physiological symptoms is suppressed by administration of placebo. But how???
In inflammation, the four physiological manifestations of swelling, redness, heat, and pain, co-exist with a host of systemic effects of a psychological nature, known collectively as 'sickness behaviour'. These include depression-like symptoms such as apathy and anhedonia, or the inability to feel pleasure. Evans proposes that the underlying biological mechanism responsible for these psychological and physiological symptoms is suppressed by administration of placebo. But how???
The brain & the placebo effect
An interesting study carried out by Levine and others in 1978 shed some light on the role of endogenous opioids and endorphins in mediating the placebo effect. Endorphins are the body's own natural painkillers, and are released in response to physical stress or insult, including intensive exercise. These researchers reported that placebo relief of post-operative pain was blocked by naloxone, which prevents the action of such opioids. These findings raised even more questions: for example, how can administration of an inert substance cause the release of endorphins? And why are they not released in response to pain alone? Why is intervention necessary? Despite these reservations (and see * below!), this study provides evidence of a biochemical pathway that links belief in the efficacy of a treatment with distinct biological processes at the tissue level: this is pretty amazing!
More recent studies have used brain imaging technology to investigate this issue more carefully. The role of placebo in pain has been most widely studied, as placebo-induced analgesia (or pain relief) is a highly robust finding, and the implications for pain management are profound. A part of the brain called the rostral anterior cingulate cortex (rACC) has been implicated in analgesia mediated by opioids, and consequently, has been the focus of many neuroimaging studies investigating the placebo effect. Using PET scanning technology (a form of imaging that uses blood flow in specific parts of the brain as a measure of how stimulated that region is, and therefore, how active it is) Petrovic and colleagues found in 2002 that there was a similar activation of the rACC and adjacent areas of the brain during either opioid or placebo treatment for pain, but not when the pain was untreated. From this and other studies, it seems to be the case that the rACC plays a central role in mediating the perception of pain by the individual.
Other brain regions implicated in the placebo effect are those that are involved with learning and conditioning, and expectancy of reward. In this regard, the neurotransmitter dopamine is crucially important. The work of de la Fuente-Fernandez and co-workers has shown that placebo increases dopamine release in specific parts of the brain that are involved in reward. This has implications for the treatment of disorders that have a strong dopaminergic component, such as Parkinson's disease (which is also highly receptive to placebo intervention). In addition, some researchers believe that the dopaminergic system interacts with the opioid system, resulting in placebo-induced analgesia (*this could answer the questions raised by Levine's opioid study; perhaps the dopamine release associated with placebo is necessary to kickstart the opioid system). The emergence of dopamine as being one of the key facilitators of the placebo effect makes sense. As mentioned above, dopamine is central to reward expectancy, which is hugely driven by conditioning cues that predict the probability of reward occurrence. Therefore, interaction with a trained medical professional and placebo intervention could be considered cues that signal 'reward' or alleviation of distress. The neurochemical changes associated with this expectancy can then trigger alterations in downstream effectors, such as pain perception mechanisms or the inflammation response.
More recent studies have used brain imaging technology to investigate this issue more carefully. The role of placebo in pain has been most widely studied, as placebo-induced analgesia (or pain relief) is a highly robust finding, and the implications for pain management are profound. A part of the brain called the rostral anterior cingulate cortex (rACC) has been implicated in analgesia mediated by opioids, and consequently, has been the focus of many neuroimaging studies investigating the placebo effect. Using PET scanning technology (a form of imaging that uses blood flow in specific parts of the brain as a measure of how stimulated that region is, and therefore, how active it is) Petrovic and colleagues found in 2002 that there was a similar activation of the rACC and adjacent areas of the brain during either opioid or placebo treatment for pain, but not when the pain was untreated. From this and other studies, it seems to be the case that the rACC plays a central role in mediating the perception of pain by the individual.
Other brain regions implicated in the placebo effect are those that are involved with learning and conditioning, and expectancy of reward. In this regard, the neurotransmitter dopamine is crucially important. The work of de la Fuente-Fernandez and co-workers has shown that placebo increases dopamine release in specific parts of the brain that are involved in reward. This has implications for the treatment of disorders that have a strong dopaminergic component, such as Parkinson's disease (which is also highly receptive to placebo intervention). In addition, some researchers believe that the dopaminergic system interacts with the opioid system, resulting in placebo-induced analgesia (*this could answer the questions raised by Levine's opioid study; perhaps the dopamine release associated with placebo is necessary to kickstart the opioid system). The emergence of dopamine as being one of the key facilitators of the placebo effect makes sense. As mentioned above, dopamine is central to reward expectancy, which is hugely driven by conditioning cues that predict the probability of reward occurrence. Therefore, interaction with a trained medical professional and placebo intervention could be considered cues that signal 'reward' or alleviation of distress. The neurochemical changes associated with this expectancy can then trigger alterations in downstream effectors, such as pain perception mechanisms or the inflammation response.
Implications!
Even though I am a former pharmacologist, I am EXTREMELY reluctant to take any kind of drugs...there are very few that don't come armed with some kind of side-effects, which can range from being mildly irritating to seriously debilitating. And they can be prohibitively expensive. Therefore, any mechanism that can reduce the need for pharmacological intervention can only be a good thing, right? [Caveat: of course, it is completely different for a disease that derives from a metabolic or biochemical imbalance, such as diabetes. As a disclaimer, therefore, I concede that in many cases pharmacology can save lives and improve quality of life].
The medical profession has long been aware of the power of placebo. Studies have repeatedly shown the prevalence of placebo administration by doctors, including the prescription of unnecessary antibiotics and vitamins. Recognizing this, the British Medical Journal published an editorial in 2004, that contained this extract:
'The placebo effect, thought of as the result of the inert pill, can be better understood as an effect of the relationship between doctor and patient. Adding the doctor’s caring to medical care affects the patient’s experience of treatment, reduces pain, and may affect outcome… doctors continue to use placebos and most think they help'
The medical profession has long been aware of the power of placebo. Studies have repeatedly shown the prevalence of placebo administration by doctors, including the prescription of unnecessary antibiotics and vitamins. Recognizing this, the British Medical Journal published an editorial in 2004, that contained this extract:
'The placebo effect, thought of as the result of the inert pill, can be better understood as an effect of the relationship between doctor and patient. Adding the doctor’s caring to medical care affects the patient’s experience of treatment, reduces pain, and may affect outcome… doctors continue to use placebos and most think they help'
To finish up...
I hope you've enjoyed this outline of the placebo response and its underlying neurobiology! It is a growing research area, and as more and more information becomes available about how to manipulate and exploit placebo, it is probable that healthcare professionals will be keen to apply this knowledge to the treatment of patients. It is important that this method of treatment is not undermined by the perception that it is a 'sham' or potentially dangerous... the scientific evidence is overwhelmingly supportive of a real effect that has a strong biological foundation. In my opinion, patients can be made to feel better simply by receiving an assurance from their doctor that everything is ok, as worry and stress can be the biggest causative factors for many illnesses. Therefore, a supportive and trusting relationship between doctor and patient can often be the best treatment available, which costs nothing apart from a little bit of time and kindness!