Chronic pain-induced depression: Underlying mechanism revealed in mice, showing how ketamine acts as antidepressant in chronic pain

Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Understanding the underlying mechanism identifies a potential therapeutic target for treatment

Peer-Reviewed Publication

UNIVERSITY OF ALABAMA AT BIRMINGHAM

 

IMAGE: LINGYONG LI view more 

CREDIT: UAB

BIRMINGHAM, Ala. – Chronic pain often leads to depression, which increases suffering and is clinically difficult to treat. Now, for the first time, researchers have uncovered the underlying mechanism that drives those depressive systems, according to a study published in The Journal of Clinical Investigation.

The mechanism acts to cause hypersensitivity in a part of the brain called the anterior cingulate cortex, or ACC, and knowledge of this mechanism identifies a potential therapeutic target for the treatment of chronic pain-induced depression, say Lingyong Li, Ph.D., and Kimberley Tolias, Ph.D., co-leaders of the research.

“Chronic pain is a major, unmet health issue that impacts the quality of life,” said Li, an associate professor at the University of Alabama at Birmingham Department of Anesthesiology and Perioperative Medicine. “Unfortunately, patients suffering from chronic pain have limited effective treatment options.”

The research focused on a protein called Tiam1, which modulates the activity of other proteins that help build or unbuild the cytoskeletons of cells. Specifically, the research teams of Li and Tolias, a professor at Baylor College of Medicine, Houston, Texas, found that chronic pain in a mouse model leads to an activated Tiam1 in ACC pyramidal neurons, resulting in an increased number of spines on the neural dendrites. Dendrites are tree-like appendages attached to the body of a neuron that receive communications from other neurons.

This higher spine density increased the number of connections, and the strength of those connections, between neurons, a change known as synaptic plasticity. Those increases caused hypersensitivity and were associated with depression in the mouse model. Reversing the number and strength of connections in the model, by using an antagonist of Tiam1, relieved the mice of depression and diminished hypersensitivity of the neurons.

The ACC was already known as a critical hub for comorbid depressive symptoms in the brain. To investigate the mechanism for those symptoms, the team led by Li and Tolias first showed that Tiam1 in the ACC was activated in two mouse models of chronic pain with depressive or anxiety-like behaviors, as compared to controls.

To show that Tiam1 in the ACC modulates chronic pain-induced depressive-like behaviors, the researchers used molecular scissors to delete Tiam1 from the forebrain excitatory neurons of the mice. These mice were viable, and fertile, and displayed no gross alterations, and they still showed hypersensitivity to chronic pain. Strikingly, however, these Tiam1 conditional knockout mice did not display depressive- or anxiety-like behaviors in five different tests that gauge depression or anxiety.

When researchers specifically deleted Tiam1 from ACC neurons, they found the same results as the broader forebrain deletion. Thus, Tiam1 expressed in ACC neurons appears to specifically mediate chronic pain-induced depressive-like behaviors.

Other studies have established that an underlying cause of stress-induced depression and anxiety disorders is alterations in synaptic connections in brain regions involved in mood regulation, including the prefrontal cortex, the hippocampus and the amygdala. Li and Tolias found similar changes in dendritic neurons in the ACC for chronic pain-induced depressive-like behavior — they saw a significant increase in dendritic spine density and signs of increased cytoskeleton building. This was accompanied by increased NMDA receptor proteins and increased amplitudes of NMDA currents in the ACC neurons, both associated with hyperactivity.

These maladaptive changes were not seen in the Tiam1-knockout mice.

Researchers further showed that inhibiting Tiam1 signaling with a known inhibitor alleviated the chronic pain-induced depressive-like behaviors, without reducing the chronic pain hypersensitivity itself. The inhibition also normalized dendritic spine density, cytoskeleton building, NMDA receptor protein levels and NMDA current amplitudes.

Ketamine is a drug known to produce rapid and sustained antidepressant-like effects in chronic pain-induced depression, without decreasing sensory hypersensitivity. However, its mechanism is not fully understood. Li, Tolias and colleagues showed that ketamine’s sustained antidepressant-like effects in chronic pain are mediated, at least in part, by ketamine’s blocking the Tiam1-dependent, maladaptive synaptic plasticity in the mouse ACC neurons.

“Our work demonstrates the critical role Tiam1 plays in the pathophysiology of chronic pain-induced mood dysregulation and the sustained antidepressant-like effects of ketamine, revealing it as a potential therapeutic target for the treatment of comorbid mood disorders in chronic pain,” Li said.

Co-first authors of the study, “TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain,” are Qin Ru and Yungang Lu, Baylor College of Medicine.

Co-authors with Li, Tolias, Ru and Lu are Ali Bin Saifullah, Francisco A. Blanco and Changqun Yao, Baylor College of Medicine; Juan P. Cata, MD Anderson Cancer Center, Houston, Texas; and De-Pei Li, University of Missouri School of Medicine, Columbia, Missouri.

Support came from United States Department of Defense grants W81XWH-20-10790 and W81XWH-21-10742, the Mission Connect/TIRR Foundation, and National Institutes of Health grant NS062829.

At UAB, Anesthesiology and Perioperative Medicine is a department in the Marnix E. Heersink School of Medicine.

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JOURNAL

Journal of Clinical Investigation

DOI

10.1172/JCI158545 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

TIAM1-mediated synaptic plasticity underlies comorbid depression-like and ketamine antidepressant-like actions in chronic pain

Most antidepressants ineffective for common pain conditions

Overview adds to mounting evidence challenging the use of medicines for pain

Peer-Reviewed Publication

BMJ

Some antidepressant drugs are effective for some pain conditions, but most are either ineffective or the evidence is inconclusive, despite being used for a range of pain conditions, finds an overview of the latest evidence published by The BMJ today.

Researchers call for a more nuanced approach when prescribing antidepressants for pain.

The use of antidepressants doubled in OECD countries from 2000 to 2015 and their off-label (unapproved) use to treat common pain conditions such as fibromyalgia, persistent headaches, and osteoarthritis is thought to be part of this increase.

To explore this further, a team of researchers led by Giovanni Ferreira at the University of Sydney carried out an overview of the effectiveness, safety, and tolerability of antidepressants for pain according to condition.

They searched databases for systematic reviews comparing any antidepressant with placebo for any pain condition in adults and found 26 eligible evidence reviews published between 2012 and 2022 involving 156 separate trials and over 25,000 participants.

These reviews reported on the effectiveness of eight classes of antidepressant covering 22 pain conditions (42 distinct antidepressant versus placebo comparisons). Almost half (45%) of the trials in these reviews had ties to industry.

Using data from each review, the researchers estimated relative risks of pain or average differences in pain between groups on a 0-100 point scale, taking account of dose, treatment duration, and number of trials and participants.

They also assessed safety and tolerability (withdrawals due to adverse events), certainty of evidence, and risk of bias. Findings were then classified from each comparison as effective, not effective, or inconclusive. 

No review provided high certainty evidence on the effectiveness of antidepressants for pain for any condition. 

Nine reviews provided evidence that some antidepressants were effective compared with placebo for nine conditions in 11 distinct comparisons. 

For example, moderate certainty evidence suggested that serotonin-norepinephrine reuptake inhibitors (SNRIs) were effective for back pain (average 5.3 points lower on the pain scale than placebo), postoperative pain, fibromyalgia, and neuropathic pain.

Low certainty evidence suggested that SNRIs were effective for pain linked to breast cancer treatment, depression, knee osteoarthritis, and pain related to other underlying conditions.

Low certainty evidence also suggested that selective serotonin reuptake inhibitors (SSRIs) were effective for people with depression and pain related to other conditions; and that tricyclic antidepressants (TCAs) were effective for irritable bowel syndrome, neuropathic pain, and chronic tension-type headache. 

For the other 31 comparisons, antidepressants were either not effective (five comparisons) or the evidence was inconclusive (26 comparisons).

Most safety and tolerability data were imprecise, indicating that the safety of antidepressants for several conditions is still uncertain.

This was a well designed review based on a thorough literature search and the researchers took steps to minimise the impact of issues such as differences in study design and quality, imprecision, and publication bias.

But they acknowledge that most comparisons had a limited number of trials, and results may not apply to antidepressants prescribed for symptoms linked to pain conditions, such as fatigue or sleep disturbance. Caution is also needed in interpreting these findings because 45% of the trials forming the evidence for this review had ties to industry, they add.

In conclusion, they say: “Some antidepressants were efficacious for some pain conditions; however, efficacy appears to depend on the condition and class of antidepressant. The findings suggest that a more nuanced approach is needed when prescribing antidepressants for pain.”

These findings suggest that for most adults living with chronic pain, antidepressant treatment will be disappointing, say researchers in a linked editorial.

They acknowledge that clinicians continue to prescribe medicines for which the evidence is poor because they see that some people respond to them, albeit modestly, but say other less potentially harmful options, such as exercise and support with mobility and social isolation, can help people to live well with pain. 

For people with pain, compassionate and consistent relationships with clinicians remain the foundations of successful care, they write. 

Studies must also involve people living with pain to ensure, among many other things, that pain research is meaningful to those living with pain and helps them and their clinicians make better shared decisions about treatments, they conclude.

 

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-072415 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic review

ARTICLE PUBLICATION DATE

1-Feb-2023

Antidepressants use for chronic pain on the rise, but are they effective?

More thoughtful approach to prescribing for pain needed

Peer-Reviewed Publication

UNIVERSITY OF SYDNEY

Many people are unaware that some antidepressants (medications used to treat people living with depression) are also being prescribed to treat certain chronic pain conditions.

One in five people experience chronic pain in Australia and globally, and treatment of chronic pain is often suboptimal, with commonly used medicines having limited or unknown benefits. The use of antidepressants to help manage a person’s pain is on the rise, even when they do not have a mood disorder like depression.

An international team of researchers has found that some classes of antidepressants were effective in treating certain pain conditions in adults, but others were either not effective, or the effectiveness was unknown.

Published in The BMJ, the study reviewed the safety and effectiveness of antidepressants in the treatment of chronic pain.

The researchers say the results show that clinicians need to consider all the evidence before deciding to prescribe antidepressants for chronic pain management. 

“This review, for the first time, brings together all the existing evidence about the effectiveness of antidepressants to treat chronic pain in one comprehensive document,” said lead author Dr Giovanni Ferreira from The Institute for Musculoskeletal Health and Sydney Musculoskeletal Health at the University of Sydney.

The review examined 26 systematic reviews from 2012 to 2022 involving over 25,000 participants. This included data from 8 antidepressant classes and 22 pain conditions including back pain, fibromyalgia, headaches, postoperative pain, and irritable bowel syndrome.

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants such as duloxetine were found to be effective for the largest number of pain conditions, such as back pain, knee osteoarthritis, postoperative pain, fibromyalgia, and neuropathic pain (nerve pain).

By contrast tricyclic antidepressants, such as amitriptyline, are the most commonly used antidepressant to treat pain in clinical practice, but the review showed that it is unclear how well they work, or whether they work at all for most pain conditions.

The use of antidepressants as a treatment for pain has recently gained attention globally. A 2021 guideline for chronic primary pain management published by The National Institute for Health and Care Excellence (NICE) recommends against using pain medicines with the exception of antidepressants. The guideline recommends different types of antidepressants, such as amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine or sertraline for adults living with chronic primary pain.

Dr Ferreira said a more nuanced approach to prescribing antidepressants for pain is needed.

“Recommending a list of antidepressants without careful consideration of the evidence for each of those antidepressants for different pain conditions may mislead clinicians and patients into thinking that all antidepressants have the same effectiveness for pain conditions. We showed that is not the case.”

Co-author Dr Christina Abdel Shaheed from The School of Public Health and Sydney Musculoskeletal Health at the University of Sydney said:

“The findings from this review will support both clinicians and patients to weigh up the benefits and harms of antidepressants for various pain conditions so that they can make informed decisions about whether and when to use them.”

Dr Ferreira said that there are multiple treatment options for pain, and people should not rely solely on pain medicines for pain relief.

“Some pain medicines may have a role in pain management, but they need to be considered as only part of the solution. For some pain conditions, exercise, physiotherapy, and lifestyle changes may also help. Speak to your health professional to learn more about what alternatives might be appropriate for you,” Dr Ferreira said.

Professor Christopher Maher, Co-Director of Sydney Musculoskeletal Health at the University of Sydney, said, “This review distilled the evidence from over 150 clinical trials into an accessible summary that clinicians can use to help them make better decisions for their patients with chronic pain.”

The current status of antidepressants in Australia and globally

Most antidepressant prescriptions for pain are ‘off-label’, which is when antidepressants have not been approved to be prescribed for pain.

Many antidepressants are thought to help with pain by acting on chemicals in the brain that can assist with pain relief, such as serotonin. However, it is unknown exactly why some antidepressants improve pain. In Australia, the only antidepressant approved for treating pain is duloxetine, which is approved for diabetic neuropathic pain (nerve pain caused by diabetes).

Amitriptyline is approved in the United Kingdom for some pain conditions, such as neuropathic pain (nerve pain), tension-type headaches and migraines, but it is not approved for treating any pain conditions in Australia.

The use of antidepressants has doubled in OECD countries from 2000 to 2015, and the use of ‘off-label’ prescriptions of antidepressants for pain is considered a contributing factor to this increase. Data from Canada, the United States, the United Kingdom and Taiwan, suggest that among older people, chronic pain was the most common condition leading to an antidepressant prescription, even more so than depression.

Currently, no data from Australia shows how many antidepressant prescriptions are for pain.

-ENDS-

 

Note:  Antidepressants are prescription-only medicines. Do not use antidepressants unless advised by a doctor. It is very important not to abruptly cease treatment with antidepressant medicines. This can lead to withdrawal effects which can be distressing and sometimes present as serious health issues. These withdrawal effects include dizziness, nausea, anxiety, agitation, tremor, sweating, confusion, and sleep disturbance.

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-072415 

METHOD OF RESEARCH

Systematic review

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Efficacy, safety, and tolerability of antidepressants for pain: an overview of systematic reviews

ARTICLE PUBLICATION DATE

1-Feb-2023

 You can unlearn chronic back pain

Chronic pain is a leading cause of disability worldwide. But new research shows that people can be taught to retrain their brains and reverse the pain.

Chronic pain affects millions of people worldwide

Daniel Waldrip was mowing the lawn in his hometown of Boulder, Colorado, just like any other Saturday.

But the next day, Waldrip, then in his late 20s, was struck with back pain so severe he couldn't get out of bed. He blamed the mowing.

It was the start of 18 years of chronic pain and countless unsuccessful treatments, including physical therapy, chiropractors, acupuncture and massage.

The World Health Organization says that lower back pain is the single leading cause of disability in 160 countries. Most psychological treatments only reduce pain rather than eliminate it and pain medication only provides temporary relief.

"There were times when it felt like I was paralyzed, just so much pain, and there were other times when it was kind of manageable and it was okay — but it was always there, it was a constant part of my life," Waldrip told DW.

The 49-year-old lived with chronic pain until his mid 40s, when he heard about a clinical trial for a new treatment that was happening in his hometown. The treatment was called Pain Reprocessing Therapy (PRT).

PRT aims to rewire neural pathways in the brain to deactivate pain and train the brain to respond to signals from the body more appropriately, using what's called pain education.

Ultimately, the goal is to reduce a patient's fear of certain movements, so that when they do move in those ways, they are confident that it won't cause them any pain.

Each participant in the trial got one telehealth session with a physician and eight psychological treatment sessions over four weeks.

About one month after the study, Waldrip was 100% pain free.

"It's been three or four years now and I haven't had a single issue with my back since I completed the treatment — it completely changed my life," said Waldrip.

What is pain and how does it become chronic?

Pain is like an alarm system that alerts us when we may have hurt ourselves or become injured. 

But regardless of where a person hurts themselves physically, their sense of pain is formed in the brain.

Nerves send signals to the brain to let it know that something has happened in the body and the brain then decides whether to produce a pain sensation, and that depends on whether the brain thinks there is danger.

Pain draws a person's attention to potential harm and diminishes when that warning signal is no longer needed. This is called acute pain. It is a sudden sensation that occurs in response to something specific, like a burn, injury, surgery or dental work.

But pain that persists for more than three months despite treatment is considered chronic.

"It's really important that people are able to experience pain. It's critical for survival, and yet some people [continue to have] pain even though their bodies have recovered," said James McAuley, a psychologist and professor at the University of New South Wales (UNSW).

While scientists have their theories, it is still unclear what causes chronic pain or how acute pain becomes chronic, said McAuley.

But they do know that some changes occur in the brain when pain goes from acute to chronic.

"The nerves are misfiring and advising the brain that the patient is having pain or is at a risk of damage," said Steven Faux, director of the Rehabilitation Unit at St Vincent's Public Hospital.

Studies correct communication between brain and body

That study in Boulder, Colorado, published in the Journal of the American Medical Association (JAMA) in January 2022, involved 151 patients with chronic back pain.

It compared PRT to a placebo control group and a "usual care" group, where people continued what they normally did to manage their pain, such as physical therapy or medication. 

"What was particularly striking about the outcomes was that two thirds of people in the PRT group were pain free or nearly pain free at the end of treatment as compared to 20% of controls," said lead study author Yoni Ashar, a clinical psychologist and neuroscientist at the University of Colorado.

Functional MRI scans of people's brains before and after the trial showed PRT changed how people's brains processed the pain.

"We saw reduced activity in a number of pain processing brain regions, showing that this treatment changes the brain and changes how the brain processes pain," Ashar told DW.

Another study published in JAMA in August 2022 also had success in treating patients' chronic back pain. The approach, developed by McAuley at UNSW in Australia, improved communication between the back and the brain.

The study divided 276 participants into two groups: One group did a 12-week course of sensorimotor retraining, and the other received a 12-week course of sham treatments.

20% of the participants fully recovered from their chronic pain, meaning they rated their pain as zero or one out of 10, for one year.

The words we use to describe pain can affect recovery

Central to both studies is giving people the confidence that they can move without thinking they will hurt themselves, or make their pain worse. Some of that involves the words we associate with chronic pain.

When high quality scanning machines were developed in the 1980s, health professionals were able to see the spines of people with back pain clearly for the first time. They saw ossifications, vertebrae that looked like they were disintegrating, and bulging or slipped discs. 

"We found all of that stuff and we thought: 'Well, we've found the reason why people get back pain,'" McAuley said.

It was only later that doctors realized that a patient could have a bulging spine and not get chronic pain.

But by then "the horse had bolted," as McAuley put it. It became common for some people to perceive they would get pain even when that wasn't necessarily the case — all because of the words we used.

Some studies have found that negative language, including the word pain itself, can cause people to rate their pain as higher on a so-called pain scale.

That was highlighted in a study from 2019 that found that people experienced more pain when pain-related and negative words were used before introducing a harmful stimulus compared to when neutral words were used.

So imagine a person indeed had chronic back pain, and they heard these words, and then saw their spine on an X-ray scan — that could keep them trapped in a pain loop, unless they get help to retrain their brain to think differently.

"It does feel like we're on the cusp of a completely new way of thinking about and treating chronic pain," McAuley said.

The latest pain science is showing that the communication between the brain and the body can be corrected and that patients who have spent years, sometimes decades, of their life in pain, can finally overcome it.

Edited by: Zulfikar Abbany

THE BENEFITS OF PHYSICAL TOUCH
Setting the tone
Our skin is often the starting point for how we perceive situations and interact with one another. Researchers have found that people can detect certain emotions, like love, anger, gratitude and disgust, from touch. Regular positive touch has been shown to reduce aggression and increase pro-social behavior. It also helps us form and maintain emotional bonds in relationships.
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Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits

 

Research identifies gender bias in estimation of patients' pain

A new study suggests that when men and women express the same amount of pain, women's pain is considered less intense based on gender stereotypes.

UNIVERSITY OF MIAMI

Research News

 

"On a scale of one to 10, how much pain are you in?"

In a recent study published by the Journal of Pain, co-authored by Elizabeth Losin, assistant professor of psychology and director of the Social and Cultural Neuroscience lab at the University of Miami, researchers found that a patient's pain responses may be perceived differently by others based on their gender.

According to "Gender biases in estimation of others' pain," when male and female patients expressed the same amount of pain, observers viewed female patients' pain as less intense and more likely to benefit from psychotherapy versus medication as compared to men's pain, exposing a significant patient gender bias that could lead to disparities in treatments.

The study consisted of two experiments. In the first, 50 participants were asked to view various videos of male and female patients who suffered from shoulder pain performing a series of range of motion exercises using their injured and uninjured shoulders. Researchers pulled the videos from a database that contains videos of actual shoulder injury patients, each experiencing a range of different degrees of pain. The database included patients' self-reported level of discomfort when moving their shoulders.

According to Losin, the study likely provides results more applicable to patients in clinical settings compared to previous studies that used posed actors in their stimuli videos.

"One of the advantages of using these videos of patients who are actually experiencing pain from an injury is that we have the patients' ratings of their own pain," she explained. "We had a ground truth to work with, which we can't have if it's a stimulus with an actor pretending to be in pain."

The patients' facial expressions were also analyzed through the Facial Action Coding System (FACS)--a comprehensive, anatomically based system for describing all visually discernible facial movements. The researchers used these FACS values in a formula to provide an objective score of the intensity of the patients' pain facial expressions. This provided a second ground truth for the researchers to use when analyzing the data.

The study participants were asked to gauge the amount of pain they thought the patients in the videos experienced on a scale from zero, labeled as "absolutely no pain," and 100, labeled as "worst pain possible."

In the second experiment, researchers replicated the first portion of this study with 200 participants. This time, after viewing the videos, perceivers were asked to complete the Gender Role Expectation of Pain questionnaire, which measures gender-related stereotypes about pain sensitivity, the endurance of pain, and willingness to report pain.

Perceivers also shared how much medication and psychotherapy they would prescribe to each patient and which of these treatments they believed would be more effective in treating each patient.

The researchers analyzed the results of the participants' responses to the videos compared to the patient's self-reported level of pain and the facial expression intensity data. The ability to analyze observers' perceptions relative to these two ground truth measures of the patients' pain in the videos allowed the researchers to measure bias more accurately, Losin explained. That is because bias could be defined as different ratings for male and female patients despite the same level of responses.

Overall, the study found that female patients were perceived to be in less pain than the male patients who reported, and exhibited, the same intensity of pain. Additional analyses using participants' responses to the questionnaire about gender-related pain stereotypes allowed researchers to conclude that these perceptions were partially explained by these stereotypes.

"If the stereotype is to think women are more expressive than men, perhaps 'overly' expressive, then the tendency will be to discount women's pain behaviors," Losin said. "The flip side of this stereotype is that men are perceived to be stoic, so when a man makes an intense pain facial expression, you think, 'Oh my, he must be dying!' The result of this gender stereotype about pain expression is that each unit of increased pain expression from a man is thought to represent a higher increase in his pain experience than that same increase in pain expression by a woman."

What's more, psychotherapy was chosen as more effective than medication for a higher proportion of female patients compared to male patients.

Additionally, the study concluded that the gender of the perceivers did not influence pain estimation. Both men and women interpreted women's pain to be less intense.

The idea to study disparities in the perception of pain based on a patient's gender was derived from previous research, Losin said, that found women are often prescribed less treatment than men and wait longer to receive that treatment as well.

"There's a pretty wide literature showing demographic differences in pain report, the prevalence of clinical pain conditions, and then also a demographic difference in pain treatments," Losin pointed out. "These differences manifest as disparities because it seems that some people are getting undertreated for their pain based on their demographics."

Moving forward, Losin and her fellow researchers hope this study is a step in identifying and addressing gender disparities in health care. Co-authors of the study included the study's lead author, Lanlan Zhang, Guangzhou Sport University; Yoni K. Ashar, Weill Cornell Medical College; Leonie Koban, Paris Brain Institute; and senior author Tor D. Wager, Dartmouth College.

"I think one critical piece of information that could be conveyed in medical curricula is that people, even those with medical training in other studies, have been found to have consistent demographic biases in how they assess the pain of male and female patients and that these biases impact treatment decisions," Losin remarked. "Critically, our results demonstrate that these gender biases are not necessarily accurate. Women are not necessarily more expressive than men, and thus their pain expression should not be discounted."

 

Placebo pain relief works differently across human body, study finds

University of Sydney

• New research finds the human brain has a built-in pain map that activates in different areas when relieving face, arm or leg pain.

• But placebo pain relief only works where the brain expects it.

• Further research may help to unlock safer, targeted pain treatments.

 

Researchers from the University of Sydney have used placebo pain relief to uncover a map-like system in the brainstem that controls pain differently depending on where it’s felt in the body. The findings may pave the way for safer, more targeted treatments for chronic pain that don’t rely on opioids. 

Like a highway, the brainstem connects the brain to the spinal cord and manages all signals going to and from the brain. It produces and releases nearly all the neurochemicals needed for thinking, survival and sensing. 

Published in Science, the study used 7-Tesla functional magnetic resonance imaging (fMRI) – one of the most powerful brain scanners available, with only two in Australia – to pinpoint how two key brainstem regions manage pain through placebo effects. 

Dr Lewis Crawford, lead author and research fellow at the School of Medical Sciences and the Brain and Mind Centre, said: “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.” 

The study builds on decades of work by one of the authors, Professor Kevin Keay, Deputy Head of the School of Medical Sciences and a mentor to Dr Crawford.

How placebo pain relief works

Researchers exposed 93 healthy participants to heat pain on different body parts and applied a placebo pain relief cream while secretly lowering the temperature, conditioning them to believe the cream was alleviating their pain. 

The temperature used was individually adjusted to be moderately painful as perceived by each participant. Researchers used a self-report scale, where 0 was no pain and 100 was the worst pain imaginable, and sought a temperature between 40-50 for each participant. 

Later, the same pain stimulus was applied to the placebo-treated area as well as a separate untreated area for comparison. Up to 61 percent of participants still reported less pain in the area where the placebo cream was originally applied, typical of a true placebo response.

“We found that upper parts of the brainstem were more active when relieving facial pain, while lower regions were engaged for arm or leg pain,” said Dr Crawford.

Two key brainstem regions are involved in this process: the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM). These areas showed distinct patterns of activity depending on where pain relief was directed, with the upper parts of the PAG and RVM more active for facial pain, while lower parts were more active for arm or leg pain.

“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.”     

A new way to target pain relief 

Understanding which brainstem areas are linked to different parts of the body may open new avenues for developing non-invasive therapies that reduce pain without widespread side effects.  

“We now have a blueprint for how the brain controls pain in a spatially organised way,” said Professor Luke Henderson, senior author and Professor in the School of Medical Sciences and the Brain and Mind Centre. “This could help us design more effective and personalised treatments, especially for people with chronic pain in a specific area of their body.”

The study also challenges long-held assumptions about how placebo pain relief works. Instead of relying on the brain’s opioid system, experts say a different part of the brainstem – the lateral PAG – is not only responsible but works without using opioids and could instead be linked to cannabinoid activity. 

“Opioid-based pain relief typically activates central areas of the brain and can affect the whole body, whereas the cannabinoid circuit that we identified appears to operate in more targeted regions of the brainstem,” said Dr Crawford. “This supports the idea that cannabinoids may play a role in localised, non-opioid pain control.”

“Knowing exactly where pain relief is happening in the brain means we can target that area or assess whether a drug is working in the right place,” said Dr Crawford. “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 – a huge step forward for pain management.” 

 

-ENDS-

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Journal

Science

DOI

10.1126/science.adu8846 

Method of Research

Experimental study

Subject of Research

People

Article Title

Somatotopic organization of brainstem analgesic circuitry

Article Publication Date

28-Aug-2025

COI Statement

The research was approved by the University of Sydney Human Research Ethics Committee (2019/037) and all participants gave written informed consent. The authors declare no competing interests.