Placebo pain relief occurs where the brain expects it

Pain is not just a signal from skin or nerves. It is a decision made by your brain after weighing context, experience, and expectation, and a new study now shows that decision can be tuned to specific body parts.

Researchers found that placebo pain relief does not spread everywhere. It shows up mainly where your brain expects it.

Dr. Lewis S. Crawford of the University of Sydney’s School of Medical Sciences and Brain and Mind Centre (BMC) led the work. His team used ultra-high field functional magnetic resonance imaging (fMRI) to watch tiny brainstem hubs while people reported their pain.

Pain relief follows body map

Your brainstem sits between the brain and the spinal cord and helps regulate breathing, heart rate, and pain control. It routes signals to and from the body and houses chemical systems that set our internal state.

The team found that pain relief followed a spatial pattern. Facial pain relief linked to activity in higher brainstem regions while arm and leg relief tracked lower ones.

Trained spots show less pain

Ninety-three healthy volunteers received heat pulses to the face, forearm, or leg. A sham cream labeled as a numbing agent was applied and the heat was quietly turned down during training so the cream seemed to work.

During scanning, the same heat was applied to the sham site and a control site with identical settings. Many people still reported less pain on the trained site, which reflects placebo analgesia.

Response rates differed by location. Significant pain reductions appeared in 49 percent for face, 48 percent for arm, and 61 percent for leg.

Importantly, the relief stayed local. When a hidden cream was placed on a separate body site during scanning, the effect did not generalize to that new spot.

Brainstem zones guide placebo signals

Two brain regions did most of the work, the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM). These areas form a descending control system that can quiet incoming pain signals before they reach conscious awareness.

A recent review maps how different periaqueductal gray subregions support defensive actions and pain control. The new results fit that picture by showing location-specific changes for face versus limbs.

The periaqueductal gray appears to organize pain relief in a rostral to caudal gradient. The rostral end aligned with face-related relief and the caudal end with body-related relief.

The rostral ventromedial medulla showed a matching pattern. It linked rostral zones to face relief and more caudal zones to limb relief.

Placebo in pain relief

The periaqueductal gray has columns that support different strategies. The lateral column is tied to active coping and short-lasting, targeted analgesia, while the ventrolateral column is more associated with whole body opioid-driven analgesia.

This study points to the lateral column when placebo relief is spatially precise. That suggests a different chemistry may be at work than standard opioid circuits.

Cannabinoid signaling is one candidate within the periaqueductal gray. Evidence shows cannabinoids can reduce pain when engaged in this region.

A human and animal report summarizes how cannabinoids in the periaqueductal gray influence antinociception and may contribute to descending control.

Expectations and placebo response

Expectations set during conditioning shaped the brainstem response. Relief appeared where people believed the cream would help and activity shifted in matching brainstem zones.

Ultra-high field scanning at 7 Tesla MRI made it possible to resolve these small nuclei. That level of detail is rare in human imaging and helped separate face-related and limb-related signals.

The effect was not all-or-nothing. Some participants did not show a measurable placebo response at a given site, which is consistent with known variability in placebo sensitivity.

Those who did respond showed changes in both periaqueductal gray and rostral ventromedial medulla that lined up with the trained body region.

Why this matters for patients

If the brain controls pain with a map, treatment could be tuned to the right spot rather than blasting the whole system. This could reduce side effects and keep people alert and functional.

“This is the first time we’ve seen such a precise and detailed pain map in the human brainstem, showing us that it tailors pain relief to the specific part of the body that’s experiencing it,” said Dr. Crawford.

Opioid medications can quiet pain but often act broadly and carry risks when used long term. According to Dr. Crawford, a map-based approach could guide non-opioid strategies that target the right microcircuit.

“This could lead to more precise treatments for chronic pain that don’t rely on opioids and work exactly where the brain expects pain relief to occur.”

Why pain relief varies with placebo

Why did almost half of participants fail to show a significant placebo effect at some sites? Individual differences in learning, attention, and expectations likely play roles, along with subtle physiology in the descending system.

A timely commentary from the National Library of Medicine notes that identifying somatotopy in brainstem pain modulation could help in the management of chronic pain, where localized symptoms are common.

Researchers also need to determine which neurotransmitters drive the precise mapping. Opioids probably contribute in some circuits, while cannabinoids and other transmitters may shape lateral column effects.

Behavioral training that tunes expectations to match specific sites could enhance clinical results. Devices or medicines might then amplify that targeted control.

Future tests of placebo effects

Non-invasive stimulation methods could be tested to nudge the correct brainstem nodes while patients practice site specific expectation training. Imaging could confirm whether the right periaqueductal gray and rostral ventromedial medulla zones are engaged during therapy.

Drug development could also change. If a medicine claims to help a knee or jaw, imaging can check whether the matching brainstem segment lights up as expected.

Clinicians may one day combine modest doses of systemic drugs with local expectation training to get focused relief. The goal is steady function without heavy sedation or widespread side effects.

Patients with chronic, localized pain might benefit most from this approach. They could receive treatment plans that respect the map.

“The brain’s natural pain relief system is more nuanced than we thought,” said Dr Crawford. “Essentially, it has a built-in system to control pain in specific areas. It’s not just turning pain off everywhere; but working in a highly coordinated, anatomically precise system.”     

The study is published in the journal Science.

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