Introduction

Imagine waking up to a terrible headache. You quickly rummage in your bag for your usual painkiller. You finally feel the package in your hand, grab it, and without looking, take a pill. Not long after, your headache starts to ease, and the pressure slowly disappears. You are finally more aware of your surroundings and check the package of the pill that you took. To your surprise, you notice that you have taken your vitamin, not your painkiller.

In another case, you have an infection, and the doctor has prescribed an antibiotic. You ask around your friends what their experience with the drug is, and many of them complain about stomachaches. With some doubts, you take the pill and immediately feel a sharp pain in your tummy, without the tablet being dissolved.

These phenomena are known as the placebo and nocebo effects, which describe the mind’s influence on the body in pain perception.

What are the placebo and nocebo effects?

The placebo effect refers to the healing power of an inactive substance (a placebo), which can influence the body and lead to positive changes through the power of the mind. This phenomenon can be generated by multiple factors:^1,2

• Colour of the drug
• Patient’s expectations
• Healthcare professional’s verbal suggestion
• Medical and pharmaceutical treatments, including painkillers and fake surgeries

The nocebo effect refers to the side effects of an inactive substance due to the mind's negative influence on the body. This phenomenon can occur, for example, due to characteristic changes in a familiar medication or warnings about a drug.^3,4 One of the most typical side effects generated by a placebo is pain.⁵

But, how can an inactive drug affect pain perception?

A brief overview of pain perception

Pain is not merely a simple response to an injury, but a complex communication system between the brain and the body, ultimately resulting in our perception of pain. 

The first part of this system is called the ascending pathways. It starts with specialised nerve endings, called nociceptors, that can detect a potentially harmful stimulus. After the stimulus, like a cut or a burn, the nociceptors send a signal via the spinal cord to different parts of the brain, namely, to the thalamus and then the somatosensory cortex, in the parietal lobe. When the signal reaches these areas, we become aware of the pain. However, this pain perception is not fixed, and the brain can modify the intensity of our experience.⁶

The second part of the system is the descending pathways, which act as a biological ‘volume control’ and can adjust our pain perception up and down. This decision is made by several regions in the medulla, in the brain, which sends signals back through the spinal cord to either suppress or amplify pain perception. Neurotransmitters, the messenger molecules between nerve cells, also influence this response and can alter sensation.⁶

The flexibility in the system means that pain is never just a plain experience; various factors, such as emotions and expectations, can shape it. This openness also makes placebo pain relief (or placebo analgesia) and enhanced nocebo pain experience (or nocebo hyperalgesia) possible, making pain a suitable candidate for better understanding these phenomena.

The placebo effect: biology of relief

What happens in someone’s brain when they take vitamins instead of a painkiller?

When someone is taking painkillers, their brain releases a neurotransmitter called endorphin. Endorphin is the body’s natural pain reliever and can reduce stress and improve mood. These molecule acts similarly to the well-known drugs of morphine and codeine, and are capable of reducing pain experience.⁷

At the same time, a small region in the brain called the nucleus accumbens also becomes active, releasing another neurotransmitter, dopamine. This molecule plays a crucial role in regulating reward and other functions, including memory, motivation, and mood. When a person expects pain relief, the increased amount of dopamine in this brain region reinforces the expectation, and the pain is eased.⁸

Another group of neurotransmitters, the endocannabinoids, can also lead to placebo analgesia.⁹ 

A brain-imaging study provides information about what is happening in the brain during placebo-induced pain relief. On the one hand, the results indicate that the regions typically involved in pain processing, such as the previously mentioned thalamus, become less active. On the other hand, brain areas associated with expectations, such as the prefrontal cortex, are becoming more active.¹⁰

These findings suggest that neurotransmitter release and brain activation can physically block the experience of pain, acting as a natural biological pain reliever. 

The nocebo effect: biology of harm

What happens in someone’s brain when they are afraid of a potential side effect, like a stomachache?

This negative expectation causes stress and activates the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a communication system between three organs and is essential for the body’s stress management:

• Hypothalamus: a brain region responsible for maintaining balance in functions such as temperature, hunger, and mood 
• Pituitary gland: a pea-sized structure located below the hypothalamus. It produces hormones and regulates other glands 
•  Adrenal glands, small: triangle-shaped organs located on top of the kidneys, which produce certain hormones to regulate bodily functions 

The activation of the HPA axis results in the release of the hormone cortisol. This hormone plays a crucial role in the fight-or-flight response, placing the body in a state of high alert. Research suggests that this heightened state can cause nocebo hyperalgesia.¹¹ 

Cholecystokinin (CCK) is another key chemical messenger in the nocebo response. Initially, this molecule was discovered to play a role in digestion, and later, it was found to be involved in the modulation of anxiety and panic disorders. In a study, researchers tested a harmless stimulus and measured the pain experienced. Results show that intense pain was accompanied by increased cholecystokinin activity. When they blocked the cholecystokinin pathway, this heightened pain perception almost vanished. It suggests that when someone takes a placebo, the cholecystokinin can increase the perception of pain.¹² 

Brain-imaging studies show that areas associated with fear and anxiety are more active during a nocebo response. These regions, such as the hippocampus and medial prefrontal cortex, can make the pain pathways sensitive, rather than calming them down.¹³ 

The released chemical compounds and the active brain regions together make the muscles tighten, and people become hypersensitive to any stimulus. It is how even a sugarpill can cause a painful experience. 

FAQs

Are there individual differences in the placebo and nocebo effects of pain perception?

Yes, there are differences among individuals in both the placebo and nocebo responses in pain perception. Personality traits and expectations play essential roles in someone’s reaction to taking a medication or placebo.^14,15 Biological factors are also important, including the various genetic traits that can lead to placebo or nocebo effects. This is called the placebome, the genetic and molecular factors that influence how an individual responds to placebos.¹⁶

Can someone be aware of taking a placebo and still have a placebo or nocebo effect?

Yes, even if someone is aware of taking a placebo, they can still respond positively or negatively to an inactive substance. This phenomenon was observed in both ways, in placebo pain relief and nocebo pain experience.^17,18

Summary

The placebo effect is the positive influence of the mind over the body, when an inactive substance can cause improvements in a condition. In contrast, the nocebo response is a negative influence of the mind, where taking an inactive chemical compound can generate side effects. These two different reactions are common in pain perception. Positive expectations can lead to the release of various neurotransmitters, such as endorphins, dopamine, and endocannabinoids. Brain regions responsible for pain perception are deactivated, while others associated with expectations are active. These changes can generate a placebo effect, decreasing the perceived pain level. Negative expectations activate the stress management system, leading to the release of cortisol and cholecystokinin. In the brain, fear regions become more active, which can keep the body in a hypersensitive state, making even a harmless stimulus a painful experience.