Showing posts sorted by relevance for query PAIN. Sort by date Show all posts
Showing posts sorted by relevance for query PAIN. Sort by date Show all posts

Thursday, February 02, 2023

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

Lingyong Li 

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.

Wednesday, September 07, 2022

 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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Wednesday, April 07, 2021

 

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."

Thursday, August 18, 2022

Pain, pain go away, help our children run and play

Pain management techniques for young children

Peer-Reviewed Publication

UNIVERSITY OF SOUTH AUSTRALIA

Like it or not, bumps and bruises are an unavoidable part of childhood. But while no parent wants their child to feel pain, teaching children about pain when they’re young can help them better understand and respond to pain when they’re older.

In a new study from the University of South Australia researchers identified five key approaches that parents and caregivers can use when talking with young children about ‘everyday’ pain, and that can help their recovery and resilience after injury.

In Australia, as many as one in four children, and one in five adults experience chronic pain, making it a vital topic for public health.

In this study, researchers investigated ‘everyday’ pains in young children (aged 2-7 years-old), asking experts from child health, psychology, development, resilience, as well as parents and educators, what they thought would promote children’s recovery and resilience after minor pains or injury.

With 80 per cent consensus across all experts, the most important messages were to:

  • Teach children about the meaning of pain – pain is our body’s alarm system.
  • Validate children’s pain – ensure they feel safe, heard, and protected, but don’t make a fuss.
  • Reassure children after an injury - let them know that their body will heal, and the pain will pass.
  • Support children’s emotions – let them express themselves but encourage them to regulate.
  • Involve children in their recovery – encourage them to manage their pain (eg. get a bandaid).

Lead researcher, UniSA’s Dr Sarah Wallwork, says parents and caregivers likely play a critical role in helping children learn about pain.

“Whether it’s falling from a bike or dealing with the often-dreaded vaccinations, everyday pain experiences are opportunities for parents to promote positive pain-related beliefs and behaviours,” Dr Wallwork says.

“While it’s important to teach children that pain is our body’s alarm system and that it’s there to protect us, it’s equally important to understand that pain and injury do not always align.

“As adults, one of the greatest pain management challenges is that we hold fundamental, life-long beliefs about how pain and recovery works. Often, when we get an injury, we believe that pain must follow; and conversely, if we feel pain, then we must have an injury - but as research shows, this isn’t always the case.

“In children, pain can be influenced by their emotions – for example, fear, hunger, or tiredness can exacerbate symptoms, even though this is not pain itself.

“Teaching children that they can have some control over their pain - and that how they feel on the inside can influence this - empowers them to actively engage with their own pain management. 

“This can be age-appropriate too. So, for a very young child, empowerment might be getting a bandaid or a wet cloth, rubbing the area and distracting them, then telling them their injury is protected by the bandaid and that it is now safe to move on and play. For an older child, the process can be more involved.

“The key is to demonstrate that the child is the healer and they that are actively involved in the healing process.

“By helping children learn about pain when they are young, we’re hoping to promote lifelong ‘helpful’ pain behaviours that will actively encourage recovery and prevent future pain problems.”

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