This article is part of the Expert Guide “Understanding Pain”.

When the Brain Can Take Back Control: Understanding the Placebo Effect Without Misconceptions

Why this article?

For a long time, the placebo effect was regarded as a purely psychological phenomenon. When a person’s pain decreased after receiving an inactive substance, many saw it as proof that “it was all in their head.”

Today, however, neuroscience tells a different story. Thanks to brain imaging, it is now possible to observe the brain while a person is experiencing pain or receiving a treatment. This research has revealed an unexpected finding: in people who respond to a placebo, some of the same brain regions activated by an actual opioid analgesic treatment are also engaged. This is particularly the case for the rostral anterior cingulate cortex, whose activity covaries with that of the brainstem in a similar way during opioid analgesia and placebo analgesia (Petrovic et al., 2002). A second study showed that placebo analgesia is accompanied by decreased activity in pain-sensitive regions (thalamus, insula, anterior cingulate cortex). It is also accompanied by increased prefrontal activity during the anticipation of pain (Wager et al., 2004). A meta-analysis of 25 imaging studies subsequently confirmed the consistency of these findings across the literature (Atlas & Wager, 2014).

The placebo effect is therefore neither an illusion of pain nor imaginary relief: it corresponds to measurable changes in the way the nervous system processes and modulates pain. This discovery has thus profoundly changed our understanding of the brain. Indeed, the brain is not merely an observer of the events occurring in the body: it actively participates in their regulation.

The brain networks engaged by a treatment and by a placebo. Brain imaging shows that the pain-modulation activity engaged by a placebo partly overlaps with brain systems engaged during some forms of analgesia, notably opioid analgesia, illustrating the existence of endogenous biological mechanisms of pain control.

The brain is not passive: it anticipates

The previous articles in this guide have shown that pain results from the interaction between tissues and the nervous system. It also involves the body’s adaptive capacities and adaptive loops that can gradually become self-sustaining. The brain thus helps coordinate this whole, in constant interaction with the information coming from the body and the environment.

Indeed, its role is not limited to receiving information from the body. It continuously interprets sensory signals, compares them with past experiences, assesses the context, and builds a prediction of what is likely to happen. This capacity for anticipation is today one of the major models in contemporary neuroscience, often referred to as predictive coding. In these models, the brain is described as continuously generating predictions and adjusting them based on the sensory information it receives (Friston, 2010; Clark, 2016). Normally, this capacity allows the body to react quickly to danger, adapt behavior, and optimize its responses. Pain is also part of this adaptive logic: it too can be anticipated, amplified, or dampened depending on what the brain predicts about the context.

A genuine biological modulation system

When the brain judges that a situation is better under control, it can activate its own regulatory systems. This is the case, for example, when a treatment is administered, when a trusted person steps in, or when the context simply becomes reassuring. These mechanisms are now well identified. They notably involve the prefrontal cortex, which contributes to expectations and to the appraisal of context, as well as the anterior cingulate cortex, which is involved in pain control. They also rely on the periaqueductal gray, a center for modulating pain pathways. Finally, there are the endogenous opioid systems, which can reduce the transmission of nociceptive signals.

Moreover, these networks belong to the descending pain modulation system, which is now extensively documented (Fields, 2004; Tracey & Mantyh, 2007). One study showed that administering naloxone, an opioid antagonist, reduces both the behavioral effect of the placebo and the associated brain responses. This reduction extends all the way to brainstem structures involved in descending pain modulation — the periaqueductal gray and the rostral ventromedial medulla (RVM) (Eippert et al., 2009). This study is particularly compelling: it shows that placebo-induced activation extends all the way to the structures that directly modulate the transmission of the pain signal. The placebo therefore does not create a special mechanism: it engages biological systems that already exist in the brain, and that partly overlap with those engaged during opioid analgesia.

The descending pain modulation system. The descending modulation pathways allow the brain to reduce or amplify the transmission of nociceptive signals depending on the context and the body’s needs.

A placebo does not replace a treatment

This discovery does not mean, however, that a placebo can heal a fracture, free a compressed nerve, clear up an infection, or treat cancer. Lesions remain. Mechanical stresses persist. Inflammatory processes follow their own course.

In fact, the placebo acts elsewhere: it mainly changes the way the nervous system processes and modulates pain-related information. In other words, it influences the perception and regulation of pain, without necessarily removing its cause. The authoritative reviews on the subject emphasize this point: the placebo mainly modulates the perception of pain. It does not directly treat the cause of tissue damage (Benedetti, 2014; Colloca & Barsky, 2020).

This distinction is essential. It explains why an effective treatment should always seek to correct the mechanism responsible for the pain — as do the main families of treatment already presented in this guide. At the same time, however, it is important to take into account the brain’s natural capacity to participate in the recovery process.

The opposite effect also exists: the nocebo effect

If positive expectations can reduce pain, negative expectations can produce the opposite effect. Fear, uncertainty, worrying explanations, or unfavorable past experiences can increase the vigilance of the nervous system and amplify the perception of pain: this is known as the nocebo effect.

Here again, however, this is not an imaginary phenomenon. A landmark study showed that worrying words spoken before a painful procedure are enough to activate identifiable biological networks and to increase the sensitivity of the nervous system (Benedetti et al., 2007). In other words, negative expectations are not mere states of mind: they have a measurable physiological expression. A review on the clinical relevance of the nocebo effect also points out that the way possible side effects are presented can contribute to increasing their perception or reporting in some people (Colloca & Miller, 2011). The therapeutic context thus becomes a genuine biological actor in care, in either direction.

Placebo and nocebo: two opposite responses of the same predictive brain. The predictive brain can mobilize the natural pain-modulation mechanisms (placebo) or, conversely, heighten vigilance and amplify pain (nocebo), depending on the context and expectations.

A new way of understanding care

This view thus naturally aligns with all the mechanisms described in this guide. Chronic painChronic painPain is called chronic when it persists or recurs for more than three months. It may accompany an identified disease or be a condition in its own right.Read the full entry : Chronic pain often results from the interaction of several adaptive loops: persistent mechanical stresses, sensitization of the nervous system, behavioral changes, gradual loss of physical capacity, and disruption of many biological mechanisms. Treatments seek to act on these different components — but they also act within a human context.

The quality of the information given to the person, their understanding of their pain, and their confidence in the proposed treatment all contribute to mobilizing the body’s natural regulatory mechanisms. The same applies to the consistency of the explanations, the feeling of gradually regaining control of the situation, and the positive experience of the first improvements. Pain education — explaining to a person what is actually happening in their body — is part of this logic. It does not claim to demonstrate a specific placebo mechanism, but it aims to act on understanding and expectations, two levers that influence the perception of pain (Moseley & Butler, 2015). Far from being opposed to biological treatments, these dimensions accompany them and can enhance their effectiveness.

From tissue to brain: the living organism as an adaptive system. In summary, the various mechanisms presented in this guide converge on a single idea. Pain results from the interaction between tissues, the nervous system, and the brain, within a single adaptive system.

The studies that shaped the current understanding of placebo

Note: this content presents general knowledge drawn from neuroscience and does not constitute a diagnosis or a prescription. It should not be interpreted as an invitation to replace a prescribed treatment with a placebo: any treatment decision should be made with a healthcare professional.

© Gil Ayache. The concepts, diagrams, terminology, and principles presented on this page constitute a work protected by copyright. They are made available to Blue Portance under an intellectual property license agreement, without transfer of economic rights or of authorship.