Motivation and emotion/Book/2024/Pain and placebo

Pain and placebo:
What is the placebo effect in pain management and how does it work?

Multimedia presentation (3 min)

Overview

Figure 1. Williams Intense stomach pain. Scenario William, a 33 year old man, has been having very dull but constant stomach for the past month or so, it hasn't been debilitating to hes chosen to ignore it until now, in favor of getting more shifts at work. Unfortunately William recently experienced a sudden sharp pain in his stomach, and went to the hospital in unbearable pain. initially William was struggling with his pain even with the painkillers his doctor had put him on, because of this William chose to go back to his doctor to see if he could get anything stronger prescribed. To Williams surprise, his doctor didn't change anything about his medication, instead offering William a small container full of sugar pills. William was confused, he knew the pills had no kind of drug in them, so how were they meant to help? Despite this Williams doctor absolutely insisted that they would help him manage the pain, so much so that William figured he may as well go with it, he wasn't the doctor after all. To Williams surprise the sugar pills helped immensely, despite him initially thinking them to be useless, his trust in his doctor made the pills actually work.

A placebo is a treatment method that uses a treatment without any medicinal value on its own, rather relying on the the expectation or conditining of the patient to create medicinal value, the theory behind why placebos work focus on two major aspects, the expectation of the patient and any treatment that has been conditioned into the patient. These situations of conditioning and expectations can both create real change in the patient by modulating the release and blockage of various neurotransmitters and receptors, in order to activate a wide variety of brain regions, these placebos can be implemented by health professionals by promoting positive expectation in the client either through instructions from their doctor or through observing others have successful treatment, or through classical conditioning. Unfortunately due to the nature of the treatment, it is somewhat rooted in deception, which raises many concerns surrounding informed consent of the patient, however there are ways to implement the treatment without deception, and even in situations where it may be deemed necessary, there are still ways to allow the autonomy of the patient informing them of some level of deception. Placebos unfortunately will not work consistently from person to person, as there are considerable impacts that a person's personality can have on the efficacy of the treatment.

Focus questions: What is a placebo? What theories explain placebos? How do placebos affect the body? How are placebo treatments implemented? What are the ethical implications of placebos? How do individual differences effect placebos?

What is a placebo?

A placebo refers to a treatment in which a person's expectations about their treatment contribute to the person's outcomes. For example, a man given a placebo, while being told it is cold medicine, might still see reductions in symptoms, due to him believing the medicine he is taking is real (Colloca, 2019).

The placebo response is the situation in which a placebo treatment provides positive outcomes to the patient (Belcher et al., 2018)

The nocebo response, however, is when a placebo treatment causes negative outcomes for the patient, via making current symptoms worse or creating symptoms on its own (Belcher et al., 2018).

Placebo analgesia is the treatment of pain via the use of a placebo (Muller et al., 2016).

Theories of placebo

Expectancy theory

Expectancy theory states that the placebo response is dictated by the patients' expectations of the treatment, with patients that believe that their placebo will work and be effective being more likely to experience a placebo response (Koshi & Short. 2007). It is important to note that this theory goes both ways, in the same way that positive expectations of a medication working could provide a powerful placebo response, at the same time negative expectations of a medication and its effects could cause a powerful nocebo response, worsening symptoms. Based on expectancy theory it is also possible for non-placebo medications to have an increased risk of side effects based off of the expectancy of the patient to experience those side effects (Stewert-Williams & Podd. 2004)

Conditioning theory

Conditioning theory focuses on placebos as instances of classical conditioning, it states that a person can be conditioned to receive health benefits from a medication or other physiological altering substance/event by associating its effects with other factors (Koshi & Short. 2007). The primary difference between these two theories, and the reason why this form of classical conditioning is not simply seen as setting expectations of Expectancy theory is that conditioning theory shows that the expectancy of a placebo effect does not necessarily have to be conscious in order for the effect to take place. Not only that but it also provides a method to be able to analyze placebo effects in animals that we can't communicate with (Stewert-Williams & Podd. 2004).

Combination of theories

Rather than being opposing theorys its actually necessary to understand both theories in order to understand a fuller picture of placebo effects, while both theories can explain a variety of placebo effects, neither can explain all, meaning both are valid theories that explain necessary components of the placebo effect process (Stewert-Williams & Podd. 2004).

Quiz

A doctor encouraging a patient to believe a placebo will relieve their pain is related to which theory?

	Expectancy theory
	Conditioning theory

How does a placebo manage pain

Despite the lack of actual medication in a placebo, the expectations and conditioning of the patient has an effect on the various parts of the brain and various neurotransmitters, leading to the treatment of pain (Amanzio et al. 2013).

There are a great number of factors that influence the neuropharmacology of placebo analgesia, during the response are large amount of both endogenous opioids and dopamine is released, at the same time cholecystokinin is inhibited (Abhishek & Doherty, 2013). This is because a large amount of the brain structures that seem to be involved in the placebo analgesia response are connected via pathways controlled by opioids. It's for this same reason that cholecystokinin is inhibited during the process, as it has the opposite effect on placebo analgesia, effectively preventing the endogenous opioids from causing the reaction.

This is further supported by an early study that was able to prevent a placebo response from occurring via naloxone, which also blocks endogenous opioids (Perfitt et al. 2020)

In addition, a part of placebo analgesia is controlled by dopamine output, with the activity within the nucleus accumbens being controlled by dopamine and having a positive impact on the placebo response (Abhishek & Doherty, 2013).

Since the placebo analgesia effect does seem to primarily be controlled by endogenous opioids, there are a large amount of brain regions that all show activity during the placebo analgesia response, including these regions listed by Zubieta and Stohler (2009) The Rostral anterior cingulate, dorsolateral pre-frontal cortex, orbitofrontal cortex, insula, nucleus accumbens, amygdala, medial thalamus, periaqueductal gray.

Further, the pregenual rostral anterior cingulate cortex, dorsolateral pre-frontal cortex and orbitofrontal cortex seem to primarily be active before and in the later stages of placebo analgesia, seemingly causing parts of the brain to respond to specific methods of placebos (Abhishek & Doherty, 2013) (Amanzio et al. 2013). additionally, the activation of the dorsolateral pre-frontal cortex and orbitofrontal cortex has been linked to a decrease in activity via pain responsive areas (Holmes et al. 2016).

Quiz

Which of these is inhibited during the placebo analgesia response?

	Dopamine
	Endogenous opioids
	Cholecystokinin

How are placebo treatments implemented?

Verbal method

Closely related to expectancy theory, giving verbal cues is how a medical professional can influence a patient's expectations regarding treatment and the success thereof. Theoretically a professional could provide a placebo tablet to a patient and inform them that it is a powerful painkiller, Assuming the patient trusts the professional, this would cause the patient to believe that what they are being treated with is a powerful painkiller, and they would expect a reduction of pain. Hopefully then the patients' expectations would influence their body and cause a successful treatment (Belcher et al., 2018). It should also be noted that verbal cues do not rely solely on deception of the patient, this method of placebo treatment can also be used while openly informing the patient of the placebo. (Evers, et al. 2018)

Conditioning

The basis of conditioning theory, the method of using conditioning in order to induce placebo effects starts with the use of a conventional treatment, for example pain killers for pain, and then associates an unconditioned stimulus to the effect of the pain killers, which could be a separate treatment, for example another separate pill, or even the physical feeling of ingesting the pain killers. After the patient has been conditioned to associate the unconditioned stimulus with pain relief, the original painkiller can be replaced with a placebo that matches the unconditioned stimulus and can still maintain the treatment ability (Belcher et al., 2018).

Social learning

Social observational learning in placebo is a method in which the patient observes someone else undergoing the treatment that they will soon be put on, and observing the effects on the other person, meaning if a patient sees another patient take a placebo, and the other patient expresses pain relieving effects, the first patient is likely to experience the same effects given the placebo (Belcher et al., 2018).

Test your knowledge!

A patient expecting a placebo to work because they saw it worked for another patient is an example of which implementation?

	Verbal cues
	Social observational learning
	Conditioning

Ethical considerations

A 47 year old man name Ted experienced a horrible fall one day, falling of a ladder while he was climbing up to his roof, severely injuring both his left arm and leg when he landed on the concrete below. Luckily his husband John was nearby and able to quickly call him and ambulance, getting him to the hospital quickly. during the ambulance ride to the hospital Ted was given painkiller, however even with the painkillers he could barely think due to the pain, once he arrived at the hospital he demanded for him to get more painkillers, the strongest they could find, the doctor seemed reluctant at first but left and returned with the painkillers, he gave Ted a pill and assured him that this painkiller would take care of the pain, that it was the strongest drug available. after the ambulance ride Ted found that difficult to believe. even after an hour Ted had still not experienced any pain relief, he called in a doctor and requested more pain killers. when this new doctor walked in and checked what type of pain killers Ted had been given he was appalled. It turns out Teds first doctor had decided to give him a placebo tablet instead, deciding that his reassurance that the pain would go away would be enough to stop the pain. The new doctor hastily explained the situation, apologized and went and got Ted on some stronger pain killers. After the pain subsided Ted was furious, His doctor had decided to, without informing him at all, provide a sham treatment, that kept him in agony for an hour.

The use of placebos in medical care does have one major ethical concern, that being the possible impacts it can have on informed consent, under most circumstances patients are expected to be able to consent to their own medical care, and have the right to refuse medical treatment, but how does this work when the medical treatment itself uses deception to its benefit?

How is deception used?

As it turns out when it comes to using a placebo, deception is in no way necessary for the treatment. (Alfano. 2015) there are a variety of different ways in which to both properly inform patients of the treatment while still allowing the placebo to function.

One method that a professional may use is authorized concealment in order to avoid a nocebo outcome, they may ask permission from the patient for them to conceal the possible side effects of a drug. This allows the patient the autonomy to agree to being deceived in order to reduce the chances of side effects. This does of course run the risk of a patient developing nocebo effects that are not related to the drug at all, since they are made aware of the existence of side effects while not being told what they are (Alfano. 2015).

Beyond this is the concept of authorized deception, in which the professional would ask the patients permission to lie to them in the future regarding some aspects of their treatment for similar reasons to that of authorized concealment (Alfano. 2015).

These methods of deception are not ideal; however, it is agreed at least among the experts in the field that they may be some situations in which the risk of developing something via a nocebo response in dangerous or likely enough to justify looking in to using these different methods (Evers et al. 2018). Evers and colleagues also agree however that in ideal situations the patient shouldn't have to be deceived at all, and that the risk of nocebo effects can be weakened with appropriate training and wording on the professional's behalf.

In terms of administering a placebo itself there is evidence to suggest that using a double-blind system in which the patient may receive either real medicine or a placebo without either the professional or patient knowing which while still being informed of the process. This does however relate more the research regarding placebos and testing in what situations they may be applicable, rather than actual medical practice. (Miller & Colloca. 2009)

Open-label placebos

Figure 2: A bottle of labeled placebo tablets.

Open-label placebos (see Figure 2) are placebos that are provided to a patient with the patient's full knowledge that it is a placebo, and has no inherent medical effects, however still being encouraged that the treatment will assist them (Colloca. 2019).

Open-label placebos have been found to be able to enhance treatment for patients with chronic pain despite no deception being at play, a study by Carvalho and colleagues (2016) found that the use of an open labeled placebo when paired with the conventional treatment in patients with chronic lower back pain to be extremely effective. Additionally, patients who were originally only receiving the conventional treatment also had a decrease in pain when they started taking the open-labeled placebos. Meaning that even when patients are properly informed, open-label placebos are at the very least effective when paired with other forms of care (Carvalho et al. 2016).

With that being said, while the initial research is promising much of the research into open-label placebos and their efficacy is in its infancy, with some concerns being raised regarding the current literature and its issues with control groups, less than ideal time frames and possible biases. (Blease et al. 2020)

Quiz

True or false? open-label placebos cannot effect the treatment process.

	True
	False

Individual differences

Optimism

Optimism has been shown to be able to impact the effectiveness of a placebo, including when it comes to pain treatment, out of a group of patients who were undergoing a placebo treatment for pain management those who were considered optimistic were reporting less pain than others in the same condition (Kern et al. 2020). Additionally, in a study designed to cause a nocebo response, participants were led to believe that they were taking a pill that would increase or induce a plethora of negative symptoms. In this case when participants were fully deceived participants considered optimists reported fewer negative symptoms, suggesting optimism plays a role in both inducing placebo responses and inhibiting nocebo responses (Geers et al. 2005).

Pessimism

Pessimism has also been shown to be able to impact the effectiveness of a placebo, however in contrast to optimism it only seems to serve the impacts of the nocebo response, with pessimists more likely to focus on negative aspects of the treatment, they were more likely to experience side effects (Kern et al. 2020) (Perfitt, Plunkett & Jones, 2020). Additionally in the same study by Geers and colleagues (2005) pessimists reported higher amounts of symptoms from the deception-based placebo pill.

Anxiety

While the current research leaves the impact of anxiety on the placebo effect inconclusive, it has been found that anxiety can have an effect on the nocebo response, with higher levels of anxiety predicting a larger nocebo response (Kern et al. 2020) (Perfitt, Plunkett & Jones, 2020).

Empathy

When it comes to the social observational aspect of placebo effects, higher ratings of empathy have been linked to higher rates of observational learning and strength of placebo and nocebo effects (Belcher et al., 2018).

The big five

The big five personality types have been a focus on recent research into how personality traits impact the placebo/nocebo response, however the findings thus far have been mostly inconclusive, with many studies having varying results regarding the existence/impact of the personality traits (Kern et al. 2020).

The Big Five Personality Types

Personality	Placebo Response	Nocebo Response
Openness to experience	Inconsistent evidence supporting an increase	No connection
Conscientiousness	Inconsistent evidence supporting an decrease	Inconsistent evidence supporting an decrease
Extraversion	Inconsistent evidence supporting an increase	No connection
Agreeableness	Inconsistent evidence supporting an increase	No connection
Neuroticism	Inconsistent evidence supporting an increase	Inconsistent evidence supporting an increase

Quiz

True or false? Optimism increases nocebo responses.

	True
	False

Conclusion

A placebo is a treatment that works based off of the expectations of the patient and how they have been conditioned, the uses for the placebo response in pain management, also known as placebo analgesia have been proven as effective, by modifying the patients expectations or through conditioning the treatment is able to get the patient to produce a large amount of endogenous opioids and dopamine to activate a large amount of brain regions and structures in order to dull pain. Treatments can be implemented by expectations being altered through direct contact with a doctor or observational learning, or via classical conditioning. The main concern regarding the treatment is its ethical disadvantages, at least when implemented in a deceptive manor, however the treatment has still proven to be effective while using complete honesty with the patient while being paired with other more conventional treatments, and further research into the more ethical side of treatment is promising. The placebo treatment to also either be hindered or empowered by various personality traits, the main two being optimism in empowering and pessimism in hindering, although there are other personality traits that are being researched for their possible effects.

The most important thing to understand from this chapter is the fact that while placebo effects are effective under deceptive circumstances, they are better put to use with complete honesty whenever possible, allowing the patient their rightful autonomy.

See also

• Placebo (Wikipedia)
• Placebo effect and motivation (Book chapter 2023)
• Placebo effect and emotion (Book chapter 2023)
• Pain and emotion (Book chapter 2013)
• Pain and motivation (Book chapter 2024)

References

Colloca, L. (2019). The Placebo Effect in Pain Therapies. Annual Review of Pharmacology and toxicology, 59, 191-211. https://doi.org/10.1146/annurev-pharmtox-010818-021542

Muller, M., Kamping, S., Benrath, J., Skowronek, H., Shmitz, J., Klinger, R., & Flor, H. (2016). Treatment history and placebo responses to experimental and clinical pain in chronic pain patients. European journal of pain, 20(9), 1530-1541. https://doi-org.ezproxy.canberra.edu.au/10.1002/ejp.877

Abhishek, A., & Doherty, M. (2013). Mechanisms of the placebo response in pain in osteoarthritis. Osteoarthritis and Cartilage, (21(9), 1229-1235. https://doi.org/10.1016/j.joca.2013.04.018

Belcher, M. A,. Ferre, S., Martinez, E. P., & Colloca, L. (2018). Role of placebo effects in pain and neuropsychiatric disorders, Progress in Neuro-Psychopharnacology and Biological Psychiatry, (87), 298-306. https://doi.org/10.1016/j.pnpbp.2017.06.003

Holmes, R. D., Tiwari, A. K., & Kennedy, J. L. (2016) Mechanisms of the placebo effect in pain and psychiatric disorders, The Pharmacogenomics Journal, (16(6), 491-500. https://doi.org/10.1038/tpj.2016.15

Perfitt, J. S,. Plunkett, N., & Jones, S. (2020). Placebo effect in the management of chronic pain, BJA Education, (20(11), 382-387. https://doi.org/10.1016/j.bjae.2020.07.002

Kern, A., Kramm, C., Witt, C. M., & Barth, J. (2020). The influence of personality traits on the placebo/nocebo response: a systematic review. Journal of Psychosomatic Research, 128, 109866. https://doi.org/10.1016/j.jpsychores.2019.109866

Geers, A. L., Helfer, S. G., Kosbab, K., Weiland, P. E., & Landry, S. J. (2005). Reconsidering the role of personality in placebo effects: dispositional optimism, situational expectations, and the placebo response. Journal of Psychosomatic Research, 58(2), 121-127. https://doi.org/10.1016/j.jpsychores.2004.08.011

Koshi, E. B., & Short, C. A. (2007). Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Practice, 7(1), 4-20. https://doi.org/10.1111/j.1533-2500.2007.00104.x

Stewart-Williams, S., & Podd, J. (2004). The placebo effect: dissolving the expectancy versus conditioning debate. Psychological bulletin, 130(2), 324. https://doi.org/10.1037/0033-2909.130.2.324

Zubieta, J. K., & Stohler, C. S. (2009). Neurobiological mechanisms of placebo responses. Annals of the New York Academy of Sciences, 1156(1), 198-210. https://doi.org/10.1111/j.1749-6632.2009.04424.x

Amanzio, M., Benedetti, F., Porro, C. A., Palermo, S., & Cauda, F. (2013). Activation likelihood estimation meta‐analysis of brain correlates of placebo analgesia in human experimental pain. Human brain mapping, 34(3), 738-752. https://doi.org/10.1002/hbm.21471

Alfano, M. (2015). Placebo effects and informed consent. The American Journal of Bioethics, 15(10), 3-12. https://doi.org/10.1080/15265161.2015.1074302

Miller, F. G., & Colloca, L. (2009). The legitimacy of placebo treatments in clinical practice: evidence and ethics. The American Journal of Bioethics, 9(12), 39-47. https://doi.org/10.1080/15265160903316263

Carvalho, C., Caetano, J. M., Cunha, L., Rebouta, P., Kaptchuk, T. J., & Kirsch, I. (2016). Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain, 157(12), 2766-2772. http://dx.doi.org/10.1097/j.pain.0000000000000700

Blease, C. R., Bernstein, M. H., & Locher, C. (2020). Open-label placebo clinical trials: is it the rationale, the interaction or the pill?. BMJ evidence-based medicine, 25(5), 159-165. https://doi.org/10.1136/bmjebm-2019-111209

Evers, A. W., Colloca, L., Blease, C., Annoni, M., Atlas, L. Y., Benedetti, F., ... & Kelley, J. M. (2018). Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychotherapy and psychosomatics, 87(4), 204-210. https://doi.org/10.1159/000490354