Editor’s note: The North American Pain School (NAPS) took place 19-24 June 2022 in Montebello, Québec City, Canada. NAPS – an educational initiative of the International Association for the Study of Pain (IASP) and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and presented by the Quebec Pain Research Network (QPRN) – brings together leading experts in pain research and management to provide trainees with scientific education, professional development, and networking experiences. This year’s theme was “Controversies in Pain Research.” Five of the trainees were also selected to serve as PRF-NAPS Correspondents, who provided firsthand reporting from the event, including interviews with NAPS’ Visiting Faculty members and Patient Partners, summaries of scientific sessions, and coverage on social media. Here, PRF-NAPS Correspondent Joseph Lesnak, a PhD candidate at the University of Iowa, US, provides coverage of a talk by NAPS Visiting Faculty member Catherine Bushnell, National Institutes of Health, Maryland, US.
For a long time, I’ve been interested in the placebo effect – when the beneficial effect of a particular treatment arises from the patient’s expectations of the treatment, rather than the treatment itself. The fact that an individual can take an inert substance to produce pain relief is fascinating. Fortunately, the first day of NAPS began with a great presentation on placebos by Visiting Faculty member Catherine Bushnell. Since the 2022 NAPS theme was “Controversies in Pain Research,” Bushnell focused her talk on three controversies involving the mechanisms, research, and ethics of placebos.
Is placebo analgesia one phenomenon or a heterogeneous mix of mechanisms?
Bushnell stated there are two main ways that placebo analgesia is created experimentally – expectation and conditioning. Placebo effects driven by expectation are created through verbal instruction. For example, by instructing people that you are giving them an analgesic drug, it produces the expectation that the drug will produce pain relief. But how does this expectation produce pain relief?
One theory is that expectation may change an individual’s mood or anxiety levels. It has been demonstrated that one’s psychological state or mood has a significant impact on pain via descending pathways in the brain (Bushnell et al., 2013). These brain pathways are responsible for controlling endogenous analgesic mechanisms by facilitating or inhibiting painful input from the periphery. Therefore, by improving one’s psychological state, there is an increase activation of descending pain pathways to decrease pain.
It is also theorized that placebo effects driven by expectation can also produce pain relief through alterations in attention (i.e., distraction analgesia). The idea is that if an individual expects a particular drug to alleviate their pain, they will start to pay less attention to their symptoms. It has been demonstrated that modulating attention can also increase activation of descending pain pathways to produce analgesia (Bushnell et al., 2013).
In fact, pharmaceutical companies use these tactics to their advantage in television advertising (at least in the US). Their commercials show scenes that are designed to improve mood and focus attention away from pain. Companies frequently show scenes of families partaking in enjoyable activities such as walking on a beach, eating dinner outside, or working in a garden. Companies also regularly place dogs in their advertisements – who doesn’t feel a little better when they see a cute pup?
The second theory posits that conditioning results in placebo analgesia. Conditioning is the psychological phenomenon through which we learn to pair a stimulus or behavior with a response. In the case of placebo analgesia, the theory is that years of taking drugs and interacting with healthcare professionals – which produces a physiological change – has created a learned response that when we take a prescribed pill, we will feel better.
But how does expectation and conditioning produce pain relief from a neurobiological standpoint? There are likely multiple neurochemical and anatomical mechanisms involved. It has been demonstrated that placebo analgesia can be blocked by inhibiting our endogenous opioid and endocannabinoid systems (Amanzio and Benedetti, 1999Benedetti et al., 2011). Additionally, blocking activation of the prefrontal cortex reduces placebo analgesia (Holmes et al., 2016Krummenacher et al., 2010).
Is placebo analgesia produced via one mechanism? Is the mechanism the same for all individuals? Bushnell thinks that is unlikely. She argues there are potentially multiple factors involved in the placebo effect that lead to wide individual differences in placebo analgesia and its mechanism.
Do experimental studies of the placebo analgesia mechanisms in healthy people tell us what’s happening with patients?
In pain research, clinical studies commonly use healthy volunteers to study placebo mechanisms. The controversy surrounding the use of healthy individuals is that the findings from these studies may not be generalizable to individuals suffering from chronic pain. Bushnell highlighted some of the main differences between healthy volunteers and individuals with chronic pain in the context of placebo research.
From a neurobiological standpoint, it has been demonstrated that individuals with chronic pain have deficits in descending pain pathways, the same pathways claimed to be responsible for placebo analgesia (Bushnell et al., 2013). Individuals with chronic pain have been shown to possess deficits in their endogenous opioid system, and decreased gray matter and cortical thickness in areas of the brain responsible for placebo analgesia. Also, in individuals with chronic pain, prior exposure to pharmaceuticals can reduce opioid binding and alter placebo mechanisms compared to healthy volunteers. These alterations in a neurobiological system make generalizing research from healthy volunteers to those with chronic pain difficult.
There are also differences between healthy volunteers and individuals with chronic pain from a psychological standpoint that would impact the generalizability of placebo research. Individuals with chronic pain may have a different response to real-life treatment than a healthy volunteer in a lab setting. As stated above (while discussing conditioning), your prior experiences with the healthcare system can impact placebo analgesia. An individual with chronic pain will likely have a much different history with the healthcare system than a healthy volunteer. Factors such as memories of previous therapies, interactions with previous doctors and medical professionals, and the sight of medical offices and instruments can play a huge role in a person’s beliefs and thus impact the effectiveness of placebo analgesia.
Does this mean that research into placebo analgesia using healthy volunteers has no relevance? Should we only be using individuals with chronic pain in placebo research? The answers are most likely no and no. While there are differences between healthy volunteers and individuals with chronic pain, this does not mean that research using healthy volunteers is meaningless. By studying healthy volunteers, we are able to get a sense of how physiology, specifically the mechanisms of placebo analgesia, will function under normal conditions. Individuals with chronic pain who have altered placebo analgesia could use this information to demonstrate that they have altered physiology, which could improve access to healthcare and treatments. Research on placebo mechanisms should likely include both healthy individuals and those with chronic pain to fully understand the differences between each group.
What are the ethics of engaging placebo response during real treatments?
Prior to concluding, Bushnell asked one more question: “Is it ethical to try and produce a placebo response in the clinical setting?” Unfortunately, there is no definitive answer. This author believes that the answer to this question will be impacted by how one perceives placebos and the approach used to treat individuals in a healthcare setting.
Placebos can carry a negative connotation since many believe their effects are “all in your head” or that you are tricking a patient to produce an effect. This might lead to the view that placebos are unethical because you are not giving a therapeutically active drug. If you believe any treatment – regardless of its mechanism – that has a beneficial effect is worth trying, then you might be all right with utilizing the placebo effect clinically.
In a similar fashion, the biomedical approach to healthcare directs treatment solely at the underlying pathophysiology. Practicing medicine this way would not allow for the prescription of placebos since they do not have a specific pharmacological mechanism. If you believe in a more holistic or biopsychosocial approach to healthcare, however, you might view placebos as an appropriate treatment if the patient is benefiting from that intervention.
The placebo effect is a controversial topic. There are likely several mechanisms that lead to placebo analgesia that vary across individuals; however, it must be stated that placebo analgesia is a real phenomenon with identified mechanisms. Placebo research performed on healthy volunteers and individuals with chronic pain has led to interesting findings which show how these groups differ in placebo analgesia effectiveness, and their mechanisms. Lastly, utilizing a placebo in the clinical setting is debated, and its use should probably be approached on a case-by-case basis, while considering the preferences of the healthcare provider and patient.
Joseph Lesnak, DPT, is a PhD candidate at the University of Iowa, US. You can follow him on Twitter – @LesnakJoe.