How Neuroinflammation Causes Chronic Pain

Barby Ingle, Columnist

What is neuroinflammation and why does it cause severe burning pain even when there seems to be no injury?

Let me explain it as simply as I can. Say you sprain your ankle. Your ankle then hurts, swells, discolors, and the pain limits use. The swelling occurs because of “healing” chemicals that move into the affected area and work to repair any damage.

In a typical person, this process is successful and the healing chemicals trigger another set of chemicals to take the healing chemicals away. The swelling and discoloration go away and the person doesn’t have any additional issues healing from that trauma.

But sometimes the healing process doesn’t work correctly and the neuroinflammation becomes chronic, activating glial cells in our spine and brain. This poor healing process changes your spine and brain in ways that essentially leave your pain signals turned on.  

Glial cells are small nerve cell that fire off about every two minutes looking for any threats to the body. This is part of your fight or flight system. They are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for the brain's neurons. Glia is a Greek word meaning glue.

In the human brain, there is roughly one glia for every neuron, with a ratio of about two neurons for every three glia in the cerebral gray matter, according to the research article, Equal Numbers of Neuronal and Nonneuronal Cells Make the Human Brain an Isometrically Scaled-Up Primate Brain.”



The four main functions of glial cells are to surround neurons and hold them in place; supply nutrients and oxygen to neurons; insulate one neuron from another; and to destroy pathogens and remove dead neurons. They also modulate neurotransmission, according to the “D-amino acids in the brain: d-serine in neurotransmission and neurodegeneration" research paper. Therefore, glia is a lot more than just the “glue” of the nervous system.

Why should we pay attention to glia activated neuroinflammation? There needs to be much more research into this area and ways to control glial activation. What else activates glia? What deactivates it?

At a medical conference in 2008, I learned how neuroinflammation primes the nervous system in chronic pain patients. Let’s say that someone slaps you unexpectedly. Your body reacts with a fight or flight response. Then down the road a few months, maybe a year, someone slaps you again. Now your fight or flight response is on guard. Instead of firing every two minutes or so, the glial are on full time. This is a signal to your healing process that something is wrong. Your body wants to be ready to protect you in case you are slapped again.

The second “slap” can be any kind of any trauma: a torn ligament, broken bone or even a paper cut. It can be just as big or even smaller than the first slap. The first slap causes the priming, the second one confirms the risk (even if there is none), and now the body’s protection system is “on” just in case.

Looking at my case, I had a tear in two of my knee ligaments in 2001 and underwent surgery. I bounced back in a very short time and continued on with my athletic activities as a head Division IA collegiate cheerleading and dance coach.

About a year later, I was in a minor auto accident and had a brachia plexus injury which devastated my life. The harder I fought it, the worse I got physically. Was it priming? Was I exposed to something that set off the neuroinflammation process?

Fortunately, years later I was able to deactivate my glia and go into remission because of infusion therapy. That helped me to understand the importance of controlling glia activation and neuroinflammation.

I hope by sharing my story it starts more conversations to get medical practices to catch up to the science that already exists. Is deactivating the glia a cure? No, but it does go a long way in assisting with chronic pain management.

It got me from wheels to walking. And now that I am walking, I will keep talking until more lives are changed for the better. 

Barby Ingle suffers from Reflex Sympathetic Dystrophy (RSD) and endometriosis. Barby is a chronic pain educator, patient advocate, and president of the International Pain FoundationShe is also a motivational speaker and best-selling author on pain topics.

More information about Barby can be found at her website.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

Lyrica Linked to Birth Defects

By Pat Anson, Editor

A drug widely prescribed to treat fibromyalgia, neuropathy and other chronic pain conditions increases the risk of major birth defects, according to a new study published in Neurology, the medical journal of the American Academy of Neurology.

Women taking pregabalin were six times more likely to have a pregnancy with a major defect than women who were not taking the drug, the study found. The birth defects included heart defects and structural problems with the central nervous system (CNS) or other organs. Birth defects due to chromosomal abnormalities were not included in the results.

Pregabalin is the generic name of Lyrica, which is approved by the FDA to treat diabetic nerve pain, fibromyalgia, epilepsy, post-herpetic neuralgia caused by shingles and spinal cord injury. It is also prescribed “off label” to treat a variety of other conditions. Lyrica is Pfizer’s top selling drug, generates over $5 billion in annual sales, and is currently approved for use in over 130 countries.

The international study involved nearly 700 pregnant women in seven different countries. Four of the 125 women who took pregabalin during pregnancy had children with central nervous system defects, or 3.2 percent. That compares to a birth defect rate of just 0.5% in the 570 women who did not take pregabalin.

Of the women taking pregabalin, 115 were taking it to treat neuropathic pain, 39 were taking it for psychiatric disorders, including depression and anxiety, five were taking it for epilepsy, and one for restless leg syndrome.

Most of the women started taking pregabalin before they became pregnant. All of them stopped taking the drug at an average of six weeks into their pregnancies.

A small number of women also took another anti-seizure drug during their pregnancy. Women in that group had a 6 percent chance of a major birth defect, compared to 2 percent of the women who did not take another anti-seizure medication.

“We can’t draw any definitive conclusions from this study, since many of the women were taking other drugs that could have played a role in the birth defects and because the study was small and the results need to be confirmed with larger studies, but these results do signal that there may be an increased risk for major birth defects after taking pregabalin during the first trimester of pregnancy,” said study author Ursula Winterfeld, PhD, of the Swiss Teratogen Information Service and Lausanne University Hospital in Lausanne, Switzerland.

“Pregabalin should be prescribed for women of child-bearing age only after making sure that the benefits of the drug outweigh the risks and after counseling them about using effective birth control. In cases where women have taken pregabalin during pregnancy, extra fetal monitoring may be warranted.”

A spokesman for Pfizer said the study was small and the findings could have been influenced by other factors.

"As the authors agree, the study has significant limitations and cannot be used to draw definitive conclusions," Steven Danehy said in an email to Pain News Network. "The study was small, did not account for other medical conditions or medications, and the women taking Lyrica had higher rates of smoking and diabetes, all of which can negatively affect pregnancy outcomes."  

Because women are more likely than men to have a chronic pain condition such as fibromyalgia, they are the biggest consumers of Lyrica.

The FDA warning label for Lyrica does not specifically warn pregnant women not to take the drug. But it does caution them to consult with a doctor if they are pregnant or plan to become pregnant.

“It is not known if Lyrica will harm your unborn baby. You and your healthcare provider will have to decide if you should take Lyrica while you are pregnant. If you become pregnant while taking Lyrica, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry,” the label says.

The label also cautions men to see a doctor if they plan to father a child while taking Lyrica. 

“Animal studies have shown that pregabalin, the active ingredient in Lyrica, made male animals less fertile and caused sperm to change. Also, in animal studies, birth defects were seen in the offspring (babies) of male animals treated with pregabalin. It is not known if these problems can happen in people who take Lyrica,” the warning label states.

What Does Your Pain Feel Like?

By Pat Anson, Editor

Does your chronic pain feel like you’ve been hit with a hammer, a bad sunburn that won’t go away, or ants crawling under your skin?

Those are some of the choices patients have in a new campaign launched in Ireland to change the way patients describepain to their physicians.   

Accurately assessing pain is difficult because pain is so subjective. For many years doctors have relied on various versions of the Wong Baker Pain Scale – a series of sad and smiling faces a patient chooses from to help their doctor understand how much pain they are in. The scale is so simple it was originally developed for children, but is now used around the world for adults.

The “Mypainfeelslike…” campaign aims to improve on that method by using more descriptive images and phrases to help doctors understand and diagnose their patient’s pain. The campaign focuses on neuropathic pain, but can be used for many other types of chronic pain. The initiative is sponsored by Grunenthal Group, a German pharmaceutical company.

Instead of an unhappy face, patients can choose from a dozen images, ranging from a burning flame to a rope tied in knots to a set of ice cubes. They also fill out a questionnaire and select different phrases to describe their pain, such as “a hot iron on my skin” or “a volcano erupting.”

Patients are also asked to fill out a questionnaire to select different phrases to describe their pain, such as “a hot iron on my skin” or “a volcano erupting.” And there's a list of multiple choice answers to describe how pain affects their ability to work, exercise and socialize.

It may take a few minutes to complete the questionnaire, but the idea is to get patients to “invest more time and accurateness in thinking about their symptoms, describing them more precisely, and preparing for doctors’ appointments.”

“Doing so forces us to reconsider our chronic pain, and the different ways that we feel it. This improves our self-awareness, allows us to better communicate our situation, and helps us get the most value out of the very short time that we usually have during doctors’ appointments,” the website says.

To take the questionnaire, click here.

According to a survey by Grunenthal, over half of Irish pain sufferers feel frustrated when trying to communicate their pain to a doctor. Over a quarter say they delay discussing their pain because they’re not sure how to do it.

“Living with chronic or nerve pain affects people’s well-being, their ability to be independent, their productivity and relationships, which can lead to feelings of depression," John Lindsay, chair of Chronic Pain Ireland told the Irish Independent.  “The ‘Mypainfeelslike’ campaign will help raise awareness of the impact of chronic pain and give people living with this disease the tools to re-evaluate their pain management plans.”

Neuropathy More Damaging Than Previously Thought

By Pat Anson, Editor

A tingling, sometimes painful sensation in the hands and feet – the early stages of small fiber neuropathy -- may be more damaging to the peripheral nervous system than previously thought, according to new research published in JAMA Neurology.

A 3-year study by Johns Hopkins neurologists found that patients with small fiber neuropathy showed unexpected deterioration over the entire length of sensory nerve fibers, not just nerve fibers at the surface of the skin.

“I liken small fiber neuropathy to the canary in the coal mine,” says senior author Michael Polydefkis, MD, professor of neurology at the Johns Hopkins University School of Medicine and director of the Cutaneous Nerve Lab. “It signals the beginning of nerve deterioration that with time involves other types of nerve fibers and becomes more apparent and dramatically affects people’s quality of life. The results of this new study add urgency to the need for more screening of those with the condition and faster intervention.”

Nearly 26 million people in the United States have diabetes and about half have some form of neuropathy, according to the American Diabetes Association.  Small fiber neuropathy can also be caused by lupus, HIV, Lyme disease, celiac disease or alcoholism.

Diabetic peripheral neuropathy causes nerves to send out abnormal signals. Patients feel pain or loss of feeling in their toes, feet, legs, hands and arms. It may also include a persistent burning, tingling or prickling sensation. The condition can eventually lead to injuries, chronic foot ulcers and even amputations.

Polydefkis and his colleagues found that small fiber nerve damage occurs even in patients with prediabetes, and the early symptoms of burning pain may be less benign than most clinicians think. Routine nerve tests, like nerve conduction, often fail to identify nerve damage because they mostly assess injury to large diameter nerve fibers.

In an effort to measure nerve damage more accurately, Johns Hopkins researchers took small samples of skin — the size of a large freckle — from 52 patients diagnosed with small fiber neuropathy and from 10 healthy controls. Skin samples were taken from the ankle, the lower thigh near the knee and the upper thigh. Three years later, samples from the same area in the same patients were taken for comparison.

Microscopic analysis of the skin samples showed that patients with small fiber neuropathy initially had fewer nerve fibers on the ankle compared to the upper thigh, demonstrating the most nerve damage was further down the leg. But after three years, researchers found that longer nerve fibers were also lost from the lower and upper thighs, something that was not expected.

“We are all taught in medical school that the longest nerves degrade first, and we show that this isn’t always the case,” says lead author Mohammad Khoshnoodi, MD, assistant professor of neurology at Johns Hopkins,

Patients with prediabetes or diabetes had at least 50 percent fewer small nerve fibers in their ankles initially than those participants with an unknown cause for their small fiber neuropathy, indicating these patients started the study with more damage to their small nerve fibers.

The patients with prediabetes continued to have worsening damage to their small nerve fibers over the course of the study, losing about 10 percent of their nerve fiber density each year at all sites tested along the leg. Patients with diabetes also lost similar rates of nerve fibers along the three sites of the leg.

“I expected that people with diabetes would do worse, but I didn’t really expect people with prediabetes to experience a similar rate of degradation of their small nerve fibers,” says Polydefkis.

Researchers caution that their study was small, and that other factors such as high blood sugar, smoking, high blood pressure and high cholesterol, may also have contributed to the decline in nerve fibers.

CRPS Patients Needed for Clinical Study

By Pat Anson, Editor

About 80,000 Americans each year are diagnosed with Complex Regional Pain Syndrome (CRPS), a poorly understood condition caused by injury or trauma that leads to throbbing and burning pain that never goes away. It often takes years and multiple doctors before a patient is diagnosed with CRPS – and by then the pain has often migrated to other parts of the body and has become chronic.

That’s the dilemma now faced by Axsome Therapeutics (NASDAQ: AXSM), a biopharmaceutical research company that hopes to win FDA approval for an experimental, non-opioid drug that would be the first medication of any kind approved for treating CRPS --- also known as Reflex Sympathetic Dystrophy (RSD).

Axsome is conducting a Phase 3 clinical study of the drug --- called AXS-02 --- in the United States, Canada, the United Kingdom and Australia.

The challenge? Although Axsome only needs about 190 patients for the CREATE-1 study, it’s having trouble finding enough eligible patients. They’re looking for patients who suffered their initial injury in the last year and who were diagnosed with CRPS in the last six months.

“We’re trying to find patients very early in the stages of CRPS,” says Randall Kaye, MD, chief medical officer of Axsome.  

It typically takes a year or more for a patient to get a CRSP diagnosis because its early symptoms are not all that different from acute pain caused by surgery, a broken bone or some other type of trauma. It takes an experienced doctor to recognize the early signs.

“These are patients who continue to have pain that just doesn’t quite follow the routine course. Even after about a week or two, something is different. The pain is too much or the quality of the pain is just different. They describe a burning sensation or there’s exquisite sensitivity to temperature,” says Kaye. “What happens to these patients is that they continue to see a variety of physicians before they’re given that label of CRPS.”



“I wish it was easy to diagnose Complex Regional Pain Syndrome,” says Barby Ingle, president of the International Pain Foundation (iPain), who was diagnosed with RSD/CRPS two years after a car accident that injured her shoulder. “I went from having RSD in my face and shoulder. It then spread to my right arm and hand, then my entire right side. By the time I was properly diagnosed I had full body including organ involvement.”

“I have personally spoken to thousands of patients who have been diagnosed with RSD/CRPS. Out of all of them, two were diagnosed within the first 3 months, most took over a year. For me, I saw 43 providers before receiving a proper diagnosis. Most pain providers were not educated and although providers are getting better education now, there are still major delays.”

Opioids and other pain medications only dull the pain of CRPS, but Axsome is hoping that AXS-02 can also treat the underlying condition that causes the disorder.

“I hope so,” says Kaye. “Instead of just relieving pain, we’re getting right at the underlying pathophysiology of the condition.”

AXS-02 is an oral formulation of zoledronic acid, an injectable bisphosphonate that inhibits the production of compounds that cause bone pain. Bisphosphonates have long been used to treat osteoporosis and Kaye believes they might also stop the progression of CRPS.

“It’s pretty straightforward. Patients take one tablet once a week for six weeks and they’re done,” Kaye told Pain News Network. “We don’t think there will be a reoccurrence based on the mechanism of action. But we want to be sure.”

Proving that AXS-02 can do more than just relieve symptoms of CRPS will take time. If it can find enough patients, Axsome hopes to finish the CREATE-1 study in mid-2017. Additional studies may then be needed. If the clinical results are positive, the Food and Drug Administration has granted “fast track” and “orphan drug” designation for AXS-02, which will speed up the application and approval process.

CRPS patients interested in applying for the CREATE-1 study should click here.    

Cellphone Towers Amplify Pain in Amputees

By Pat Anson, Editor

For many years there has been a debate about the possible health effects of cell phone towers, power lines and other transmission devices that create electromagnetic fields (EMFs). These magnetic and electromagnetic frequency waves pass right through us, raising concern that they might cause cancer and other adverse health effects.

A new study by researchers at The University of Texas at Dallas suggests that cellphone towers may trigger neuropathic pain, especially in amputees that suffer from phantom limb pain.

"Our study provides evidence, for the first time, that subjects exposed to cellphone towers at low, regular levels can actually perceive pain," said Dr. Mario Romero-Ortega, senior author of the study and an associate professor of bioengineering in the University's Erik Jonsson School of Engineering and Computer Science. "Our study also points to a specific nerve pathway that may contribute to our main finding."

Most of the previous research into the possible health effects of cellphone towers has been conducted on individuals with no diagnosed, pre-existing conditions. This is one of the first studies to look at the effects of EMFs on amputees.

For years, retired Maj. David Underwood noticed that whenever he drove under power lines or near other electromagnetic fields, he would feel a buzz in what remained of his left arm. When traveling by car through Texas' open spaces, the buzz often became more powerful.

"When roaming on a cellphone in the car kicked in, the pain almost felt like having my arm blown off again," said Underwood, an Iraq War veteran who was injured by an improvised explosive device (IED). His injuries resulted in 35 surgeries and the amputation of his left arm.

"I didn't notice the power lines, cellphones on roam or other electromagnetic fields until I first felt them in my arm," says Underwood.

After learning about Underwood’s experiences, Romero-Ortega decided to study the phenomena.

He and his colleagues thought that neuromas -- inflamed peripheral nerve bundles that often form due to injury – could be more sensitive to EMFs. To test their theory in a laboratory, they assigned 20 rats into two groups -- one receiving a nerve injury that simulated amputation, and the other group receiving a sham treatment.

Researchers then exposed the rats to a radiofrequency electromagnetic antenna for 10 minutes, once per week for eight weeks. The antenna delivered a power density similar to what a human would be exposed to 125 feet away from a cellphone tower.

By the fourth week, 88 percent of the rats in the nerve-injured group demonstrated a behavioral pain response, while only one rat in the sham group exhibited pain. After growth of neuroma and resection -- the typical treatment in humans with neuromas who are experiencing pain -- the pain responses persisted.

"Many believe that a neuroma has to be present in order to evoke pain. Our model found that electromagnetic fields evoked pain that is perceived before neuroma formation; subjects felt pain almost immediately," Romero-Ortega said. "My hope is that this study will highlight the importance of developing clinical options to prevent neuromas, instead of the current partially effective surgery alternatives for neuroma resection to treat pain."

Romero-Ortega says since the research produced pain responses in rats similar to those in anecdotal reports from humans such as Major Underwood, the results "are very likely" generalizable to humans.

"There are people who live in caves because they report to be hypersensitive to radiomagnetism, yet the rest of the world uses cellphones and does not have a problem. The polarization may allow people to disregard the complaints of the few as psychosomatic," he said. "In our study, the subjects with nerve injury were not capable of complex psychosomatic behavior. Their pain was a direct response to man-made radiofrequency electromagnetic energy."

At one point in the study, members of the research group showed Underwood video of subjects in the experiment and their response to radiofrequency electromagnetic fields.

"It was exactly the same type of movements I would have around cellphones on roam, power lines and other electromagnetic fields," said Underwood.

Until the study was published online in PLOS ONE, there was no scientific evidence to back up the anecdotal stories of people like Underwood, who reported neuropathic pain around cellphone towers and other technology that produce EMFs. .

Phantom limb pain is a common and painful disorder that many amputees feel after their limbs are removed. The origin of the pain and sensations from the missing limb are not well understood. There are nearly 2 million amputees in the United States, according to the Centers for Disease Control and Prevention.

My Life as a Teen with Chronic Pain

By Stacy Depew Ellis, Guest Columnist

School, sports, music, catching up on the latest gossip. That is what I wish I could say my teenage years were filled with.

Don’t get me wrong, I had a great life. However, I was more concerned with being at school, when my last dose of medicine was, and how I was going to get up the stairs.

When I was in eighth grade, I had a traumatic accident in my dance class. After being misdiagnosed and put in a cast for almost three months, I was diagnosed with a chronic pain syndrome called Reflex Sympathetic Disorder (RSD) or CRPS.

I was sent to yet another doctor to see about treatment. It was decided that I would continue taking pain medication and start receiving lumbar injections. Little did I know that sleepless nights and several emergency room trips would also be included. I would be given more than the recommended amount of painkillers and would still be screaming in pain. Every trip back there offered more questions about a teenager being addicted to prescription drugs. Every doctor in town had seen me.

I started high school as a homebound student. I was going to school for my elective classes and seeing a teacher at my house for core classes. A lot of kids my age got hurt, most of them had a cast at some point. But my illness wasn’t visible; you couldn’t see anything wrong with me. I began losing friends and rumors spread like wildfire throughout my community and school. The worse my pain was, the worse the rumors were. It was tough, but I got through school.



After my 33rd spinal injection, I put a stop to the poking and prodding. The doctor hit a nerve and I was paralyzed from my shoulder to my finger tips for two days. Forty-eight hours of not moving an arm. Even more doctors came to see me and I started what would become the first of many steroid treatments.

Time went by and nothing got better. I had headaches, achiness, and started having trouble putting my thoughts into sentences. I saw a neurologist who once again started a smorgasbord of tests. Using my body as a human cushion was normal. What seemed like years of MRIs, spinal taps, and some things I have never heard of, led to the diagnosis of multiple sclerosis.

MS? Really? I was 21 years old.  My first round of treatment was a huge dose of steroids. I took 150 Prednisone pills followed by three days of IV steroids. My flare ups were bad, leaving me in the hospital for weeks at a time. I was a guinea pig for these pharmaceutical companies, injecting myself with a different medicine every month to see which worked best.

It was relieving to finally have a diagnosis and know what was wrong, but having MS is almost worse than not knowing. Heaven forbid I get sick and need to see a doctor. No one wants to treat someone with something like MS. Doctors immediately go to “it’s just the MS” and real problems get overlooked and never fixed. Honestly, the dentist even has trouble being your doctor.

I have been on medicine almost my whole life. I have been seen for depression and spent my paychecks on medical bills. There may never be a cure for multiple sclerosis and I may always be popping pills and injecting things into my stomach, but I am happy to say that I do my hardest to not let my disability hinder me. I try to not let it even be a part of me and I live my life to the fullest.

I will be on anti-anxiety medicine forever but I also believe that I can do anything that I desire. That is something that no doctor can ever take from me.

Stacy Depew Ellis lives in Alabama with her husband. Stacy proudly supports the Alabama-Mississippi National Multiple Sclerosis Society and the Ronald McDonald House Charity, which provided housing for Stacy and her mother when she was in a treatment program in Philadelphia.

Pain News Network invites other readers to share their stories with us.  Send them to:

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represent the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.