Newly Discovered Gut Bacteria Linked to Rheumatoid Arthritis

By Meagan Chriswell, University of Colorado Medicine

Rheumatoid arthritis affects 1 in 100 people worldwide. It causes inflamed, painful and swollen joints, often in the hands and wrists, and can lead to loss of joint function as well as chronic pain and joint deformities and damage. What causes this condition has been unknown.

In our recently published study, my colleagues and I found an important clue to a potential culprit behind this disease: the bacteria in your gut.

Rheumatoid arthritis is an autoimmune condition, meaning it develops when the body’s immune system starts to attack itself. Proteins called antibodies, which usually help fight off viruses and bacteria, begin to attack the joints instead.

The origins of the antibodies that cause rheumatoid arthritis have been an area of study for many years. Some research has shown that these antibodies can start forming at sites like the mouth, lung and intestines over 10 years before symptoms arise. But until now, it was unclear why researchers were finding these antibodies in these particular areas.

We wanted to investigate what could trigger the formation of these antibodies. Specifically, we wondered if bacteria in the microbiome, a community of microorganisms that live in the intestines, might be the ones activating the immune response that leads to rheumatoid arthritis.

Since microbes commonly live at the same sites as the antibodies driving rheumatoid arthritis, we hypothesized that these bacteria could be triggering the production of these antibodies. We reasoned that though these antibodies were meant to attack the bacteria, rheumatoid arthritis develops when they spread beyond the intestines to attack the joints.

First, we sought to identify the intestinal bacteria targeted by these antibodies. To do this, we exposed the bacteria in the feces of a subset of people at risk for developing rheumatoid arthritis to these antibodies, allowing us to isolate just the bacterial species that reacted and bound to the antibodies.

We found that one previously unknown species of bacteria was present in the intestines of around 20% of people who were either diagnosed with rheumatoid arthritis or produce the antibodies that cause the disease.

As a member of the Cherokee Nation of Oklahoma, I suggested we name this species Subdoligranulum didolesgii (“didolesgii” means arthritis or rheumatism in Cherokee) as a nod to the contributions that other Indigenous scholars have made to science as well as the fact that rheumatoid arthritis affects Indigenous people at a higher rate than other populations.

Subdoligranulum didolesgii has not been detected in the feces of healthy people before, and it is currently unknown how prevalent this bacteria is in the general population.

We also found that these bacteria can activate specialized immune cells called T cells in people with rheumatoid arthritis. T cells drive inflammatory responses in the body, and have been linked to the development of different autoimmune diseases.

These findings suggest that these gut bacteria may be activating the immune systems of people with rheumatoid arthritis. But instead of attacking the bacteria, their immune system attacks the joints.

Why This Bacteria?

It is still unknown why people with rheumatoid arthritis develop an immune response to Subdoligranulum didolesgii. But we think it may be the culprit when it comes to rheumatoid arthritis because this bacteria is found only in the intestines of people with rheumatoid arthritis, and not in the intestines of healthy people.

While many immune responses happen in the intestines, they are usually self-contained and do not spread to other areas of the body. However, we believe that a particularly strong intestinal immune response against Subdoligranulum didolesgii could allow antibodies to bypass the intestinal “firewall” and spread to the joints.

To confirm our hypothesis, we gave mice an oral dose of Subdoligranulum didolesgii and monitored their reaction. Within 14 days, the mice began to develop joint swelling and antibodies that attacked their joints.

My colleagues and I hope this research can shed light on the origins of rheumatoid arthritis. Our next goal is to discover how common these bacteria are in the general population and test whether the presence of these bacteria in the gut may lead to the development of rheumatoid arthritis in people.

It’s important to note that antibiotics are unlikely to be helpful treatment for the microbiomes of patients with rheumatoid arthritis. Although Subdoligranulum didolesgii may be triggering an autoimmune response for some people with rheumatoid arthritis, antibiotics eliminate both helpful and harmful bacteria in the gut. Additionally, removing the bacteria won’t necessarily stop the immune system from attacking the joints once it has started.

Nevertheless, we believe that these bacteria can be used as tools to develop treatments for rheumatoid arthritis and hopefully ways to prevent disease from happening in the first place.

Meagan Chriswell is a MD/PhD Candidate in Immunology at the University of Colorado Anschutz Medical Campus. She does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article.

This article originally appeared in The Conversation and is republished with permission.

Brain Changes Found in Patients with Long-Term Lyme Disease

By Pat Anson, PNN Editor

Researchers at Johns Hopkins University have documented changes in the brains of patients with post-treatment Lyme disease that may explain symptoms such as brain fog, memory loss and other cognitive issues. The finding could also have implications for patients with long covid, fibromyalgia, multiple sclerosis, chronic fatigue and other health conditions who have cognitive problems.    

Lyme disease is a bacterial illness spread by ticks that causes a rash, flu-like aches and fever, joint pain and fatigue. Most patients fully recover when treated early with antibiotics, but up to 20% of those with post-treatment Lyme disease (PTLD) have long-term symptoms, including depression, insomnia and cognitive difficulties. There is usually no clinical or laboratory evidence to explain their ongoing issues.

“Objective biologic measures of post-treatment Lyme symptoms typically can’t be identified using regular MRIs, CT scans, or blood tests,” says John Aucott, MD., director of the Johns Hopkins Lyme Disease Clinical Research Center.

Aucott and his colleagues recruited 12 PTLD patients and 18 people without a history of Lyme to undergo functional MRI (fMRI) scans while performing a short-term memory task. The scans allow investigators to track blood flow and other changes in the brain in real time.

Their findings, published in the journal PLOS ONE, suggest that cognitive difficulties in PTLD patients are linked to functional and structural changes in the “white matter” of the brain, which is crucial for processing and relaying information. The imaging tests revealed unusual activity in the frontal lobe, an area of the brain responsible for memory recall and concentration. Patients with post-treatment Lyme needed longer periods of time to complete the memory task.

“We saw certain areas in the frontal lobe under-activating and others that were over-activating, which was somewhat expected,” said lead author Cherie Marvel, PhD, an associate professor of neurology at Johns Hopkins.

“However, we didn’t see this same white matter activity in the group without post-treatment Lyme.”

To confirm their finding, researchers used another form of imaging called diffusion tensor imaging (DTI) on all 12 patients with Lyme and 12 of the non-Lyme participants. DTI detects the direction of water movement within brain tissue. Water was diffusing, or leaking, in the the same white matter regions identified in the fMRI.

Researchers believe the increased activity they saw in white matter may reflect an immune system response in the PTLD patients, which may also explain cognitive issues in patients with other chronic health conditions.

PLOS ONE

“Results reported here may have implications for other diseases in which white matter pathology has been demonstrated (e.g., multiple sclerosis) or in illnesses in which cognitive complaints follow disease onset,” researchers said. “The use of multimodal neuroimaging methods, like the ones used in the current study, may be a viable approach for obtaining information on brain function and structure to identify biomarkers of disease burden.”

Researchers say larger studies with more patients will be needed to confirm their findings, as well as long-term tracking of brain changes from the initial Lyme infection through development of PTLD.

Nearly 500,000 people are believed to get Lyme disease each year in the United States. Diagnoses of Lyme have soared over the past 15 years, according to a recent analysis of insurance claims that found Lyme cases rose 357% in rural areas and 65% in urban areas. The highest rates of Lyme were in New Jersey, Vermont, Maine, Rhode Island and Connecticut.

Experimental Vaccines Target Epstein-Barr Virus

By Liz Szabo, Kaiser Health News

Maybe you’ve never heard of the Epstein-Barr virus. But it knows all about you.

Chances are, it’s living inside you right now. About 95% of American adults are infected sometime in their lives. And once infected, the virus stays with you.

Most viruses, such as influenza, just come and go. A healthy immune system attacks them, kills them, and prevents them from sickening you again. Epstein-Barr and its cousins, including the viruses that cause chickenpox and herpes, can hibernate inside your cells for decades.

This viral family has “evolved with us for millions of years,” said Blossom Damania, a virologist at the University of North Carolina-Chapel Hill. “They know all your body’s secrets.”

Although childhood Epstein-Barr infections are typically mild, exposure in teens and young adults can lead to infectious mononucleosis, a weeks-long illness that sickens 125,000 Americans a year, causing sore throats, swollen glands, and extreme fatigue. And while Epstein-Barr spends most of its time sleeping, it can reawaken during times of stress or when the immune system is off its game. Those reactivations are linked to a long list of serious health conditions, including several types of cancer and autoimmune diseases.

Scientists have spent years trying to develop vaccines against Epstein-Barr, or EBV. But recently several leaps in medical research have provided more urgency to the quest — and more hope for success. In just the past year, two experimental vaccine efforts have made it to human clinical trials.

What’s changed?

First, the Epstein-Barr virus has been shown to present an even greater threat. New research firmly links it to multiple sclerosis, or MS, a potentially disabling chronic disease that afflicts more than 900,000 Americans and 2.8 million people worldwide.

The journal Science in January published results from a landmark 20-year study of 10 million military personnel that offers the strongest evidence yet that Epstein-Barr can trigger MS. The new study found that people infected with Epstein-Barr are 32 times as likely as people not infected to develop MS.

And shedding new light on the mechanisms that could explain that correlation, a separate group of scientists published a study in Nature describing how the virus can cause an autoimmune reaction that leads to MS.

The disease, which usually strikes between ages 20 and 40, disrupts communication between the brain and other parts of the body and is often marked by recurring episodes of extreme fatigue, blurred vision, muscle weakness, and difficulty with balance and coordination. At its worst, MS can lead to impaired speech and paralysis.

“Now that we know that Epstein-Barr is very tightly linked to MS, we could save a lot of lives if we develop the vaccine now.”

— Blossom Damania, Virologist

Amplifying that newfound urgency, several new studies suggest that reactivation of the Epstein-Barr virus also is involved with some cases of long covid, a little-understood condition in which patients experience lingering symptoms that often resemble mononucleosis.

And just as crucial to the momentum: Advances in vaccine science spurred by the pandemic, including the mRNA technology used in some covid vaccines, could accelerate development of other vaccines, including ones against Epstein-Barr, said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine. Hotez co-created a low-cost, patent-free covid vaccine called Corbevax.

Some researchers question the need for a vaccine that targets a disease like MS that, while debilitating, remains relatively rare.

Eliminating Epstein-Barr would require vaccinating all healthy children even though their risk of developing cancer or multiple sclerosis is small, said Dr. Ralph Horwitz, a professor at the Lewis Katz School of Medicine at Temple University.

Before exposing children to the potential risks of a new vaccine, he said, scientists need to answer basic questions about MS. For example, why does a virus that affects nearly everyone cause disease in a small fraction? And what roles do stress and other environmental conditions play in that equation?

The answer appears to be that Epstein-Barr is “necessary but not sufficient” to cause disease, said immunologist Bruce Bebo, executive vice president for research at the National MS Society, adding that the virus “may be the first in a string of dominoes.”

‘We Could Save a Lot of Lives’

Hotez said researchers could continue to probe the mysteries surrounding Epstein-Barr and MS even as the vaccine efforts proceed. Further study is required to understand which populations might benefit most from a vaccine, and once more is known, Hotez said, such a vaccine possibly could be used in patients found to be at highest risk, such as organ transplant recipients, rather than administered universally to all young people.

“Now that we know that Epstein-Barr is very tightly linked to MS, we could save a lot of lives if we develop the vaccine now,” Damania said, “rather than wait 10 years” until every question is answered.

Moderna and the National Institute of Allergy and Infectious Diseases launched separate clinical trials of Epstein-Barr vaccines over the past year. Epstein-Barr vaccines also are in early stages of testing at Opko Health, a Miami-based biotech company; Seattle’s Fred Hutchinson Cancer Center; and California’s City of Hope National Medical Center.

Scientists have sought to develop vaccines against Epstein-Barr for decades only to be thwarted by the complexities of the virus. Epstein-Barr “is a master of evading the immune system,” said Dr. Jessica Durkee-Shock, a clinical immunologist and principal investigator for NIAID’s trial.

Both MS and the cancers linked to Epstein-Barr develop many years after people are infected. So a trial designed to learn whether a vaccine can prevent these diseases would take decades and a lot of money.

Moderna researchers initially are focusing on a goal more easily measured: the prevention of mononucleosis, which doubles the risk of multiple sclerosis. Mono develops only a month or so after people are infected with Epstein-Barr, so scientists won’t have to wait as long for results.

Mono can be incredibly disruptive on its own, keeping students out of class and military recruits out of training for weeks. In about 10% of cases, the crippling fatigue lasts six months or more. In 1% of cases, patients develop complications, including hepatitis and neurological problems.

For now, the clinical trials for Epstein-Barr immunizations are enrolling only adults. “In the future, the perfect vaccine would be given to a small child,” Durkee-Shock said. “And it would protect them their whole life, and prevent them from getting mono or any other complication from the Epstein-Barr virus.”

The NIAID vaccine, being tested for safety in 40 volunteers, is built around ferritin, an iron-storage protein that can be manipulated to display a key viral protein to the immune system. Like a cartoon Transformer, the ferritin nanoparticle self-assembles into what looks like a “little iron soccer ball,” Durkee-Shock said. “This approach, in which many copies of the EBV protein are displayed on a single particle, has proved successful for other vaccines, including the HPV and hepatitis B vaccine.”

Moderna’s experimental vaccine, being tested in about 270 people, works more like the company’s covid shot. Both deliver snippets of a virus’s genetic information in molecules called mRNA inside a lipid nanoparticle, or tiny bubble of fat. Moderna, which has dozens of mRNA vaccines in development, hopes to learn from each and apply those lessons to Epstein-Barr, said Sumana Chandramouli, senior director and research program leader for infectious diseases at Moderna.

“What the covid vaccine has shown us is that the mRNA technology is well tolerated, very safe, and highly efficacious,” Chandramouli said.

But mRNA vaccines have limitations.

Although they have saved millions of lives during the covid pandemic, the antibody levels generated in response to the mRNA vaccines wane after a few months. It’s possible this rapid loss of antibodies is related specifically to the coronavirus and its rapidly evolving new strains, Hotez said. But if waning immunity is inherent in the mRNA technology, that could seriously limit future vaccines.

Designing vaccines against Epstein-Barr is also more complicated than for covid. The Epstein-Barr virus and other herpesviruses are comparatively huge, four to five times as large as SARS-CoV-2, the coronavirus that causes covid. And while the coronavirus uses just one protein to infect human cells, the Epstein-Barr virus uses many, four of which are included in the Moderna vaccine.

Earlier experimental Epstein-Barr vaccines targeting one viral protein lowered the rate of infectious mononucleosis but failed to prevent viral infection. Targeting multiple viral proteins may be more effective at preventing infection, said Damania, the UNC virologist.

“If you close one door, the other door is still open,” Damania said. “You have to block infection in all cell types to have a successful vaccine that prevents future infections.”

Kaiser Health News is a national newsroom that produces in-depth journalism about health issues.

Nearly Half of Adults Think U.S. Healthcare System Is Failing

By Pat Anson, PNN Editor

Almost half of American adults (44%) give the U.S. healthcare system poor or failing grades, according to a new Gallup survey that found most respondents concerned about rising medical costs and growing healthcare inequality. Overall, the healthcare system was given a barely passing grade of C-minus.

"After years of higher prices, growing inequities, skipping treatments, getting sicker, or borrowing money to pay medical bills, it's no wonder so many Americans view the health system so poorly," said Timothy Lash, President of West Health, a group of healthcare non-profits that commissioned the survey.

The survey of nearly 5,600 Americans in all 50 states was conducted in June, with a nationally representative sample reflecting racial and ethnic backgrounds.

The worst overall grade on the healthcare report card – a D-minus – was given to the cost of care. One in four adults (26%) did not seek treatment due to cost in the last three months; while one in three (35%) are concerned they will be unable to afford healthcare in the next 12 months.  

Healthcare in America Report Card

source: west health-Gallup

The affordability issue is worse for those living with chronic health conditions. About 1 in 5 skipped care to pay for other household expenses, compared to about one in eight of those without chronic conditions.

“When members of my family have needed surgeries or medications [they] have to really consider how much medical debt they’re willing to go into. Our healthcare system forces us to try and make calculations between financial security and health just because of how expensive things are, and that’s even with health insurance, so I can’t imagine if you didn’t have health insurance how fraught that would be,” said survey participant Stef Schloo, 28, who lives in Pennsylvania

“I am single and so all of that falls down on me. And the only thing that would concern me is if I really developed a major health situation or, God forbid, if I was in a major accident or had to have long-term care, that’s a great concern to me,” said Patricia Slough, 67, who lives in Massachusetts.

Quality of care was the only aspect of the healthcare system that received more positive than negative marks, although it was still only able to earn an overall grade of C-plus. Women were less likely to give good grades for quality than men (38% vs. 57%); and Black and Hispanic Americans were also less likely to give a good grade for quality than the general population (36% each vs. 47%).

“You can have some of the best doctors in the world practicing here. I’m not saying that other countries don’t have great doctors, but I think our healthcare professionals can be second to none depending on where you go in America,” said Andrew Kerner, 30, who lives in North Carolina.

Healthcare Access and Equity

The grades for access to care and equitable care also broke down along racial lines. Two-thirds of Black Americans (66%) and Asian Americans (64%) selected a grade of D or F for health equity, which is the ability of every person to get quality care regardless of race and ethnicity. By comparison, Hispanic Americans (55%) and White Americans (53%) gave a poor or failing grade to equity,

Women, Blacks, Hispanics and Asian Americans were also more critical when it came to access to care. More than 40% in each of these groups gave access D’s and F’s, compared to about a third of White Americans and men.

“For the richest country on earth I think we have the most deplorable healthcare system... due to its inequity, mainly due to the way it all depends on how much money somebody has whether they get good healthcare or not,” said Anne Courtney Davis, 71, who lives in Ohio.

The survey also found that most younger and middle-aged adults are worried that Medicare and Social Security will not be available to them when they become eligible. That sentiment cuts across political lines, with 71% of Democrats, 66% of independents and 62% of Republicans worried or extremely worried about not having access to Medicare. When it comes to Social Security, there is even more agreement — 77% of Democrats, 75% of independents and 73% of Republicans are worried it won’t be there for them when they grow older.

Under an 11-point plan by Sen. Rick Scott (R-FL), chair of the National Republican Senatorial Committee, funding for Social Security, Medicare and other so-called entitlements would have to be put to a vote in Congress every five years.

“When I witness these individuals say that Medicare should be renewed every five years, it kind of makes me nervous [it’s] not going to be there for individuals when we get older,” said Nick Lembo, 27, of Indiana. “That’s startling to me because you should want to take care of those who are older than you because eventually... you’re going to be at that age.”

New Treatment Offers Hope for Lupus Patients

By Dr. Eric Morand, Monash University, Australia

When real patients have unprecedented positive outcomes to a new treatment, it’s tempting to talk about it as “breakthrough” for medical science. This describes the excitement around a new report from researchers in Germany of a radical new treatment for lupus.

The patients in the study – five people with severe lupus – went into remission following pioneering CAR T-cell treatment, which uses genetically altered cells.

What is lupus, why is this such big news, and what could it mean for other patients and diseases?

Around 5 million people are affected by some form of lupus worldwide. The most common form of lupus is technically known as systemic lupus erythematosus. Though not widespread, it is more common than multiple sclerosis (MS). Both are “autoimmune” diseases where the immune system attacks its owner instead of the germs it is supposed to fight.

MS is an autoimmune disease where the immune system attacks nerve tissue. In contrast, lupus can affect any organ in the body. Treatments for lupus have been so poor for so long that even wealthy and famous people with the disease – like pop star and actor Selena Gomez – have had organ failure resulting in the need for a kidney transplant. A lot of complicating factors have made it hard to improve outcomes for people with the disease.

Firstly, the variety of tissues lupus can affect means no two patients are exactly alike. Diagnosis is hard and often delayed. This also means we researchers have to deal with a lot of complexity as we try to work out what is causing the disease. This clinical variability makes measuring improvement in response to treatment difficult, and many clinical trials have likely failed due to measurement issues.

Second, there is variation between patients in which part of the immune system goes wrong. This means different patients will need different treatments – and we still do not know with certainty how to get this right. But progress is happening fast.

Innate and Adaptive Immunity

The immune system is in two parts, innate and adaptive.

The “innate” immune system responds fast but non-specifically to viruses and other germs that hit the body with a slug of germ-killing inflammatory proteins. The “adaptive” immune system is slower but more precise. It swings into action after the innate immune system and provides long lasting defense against the invading germ.

When you are vaccinated against a disease (such as COVID), the fever and aches you might get in the first day or two is your innate immune system at work. But the long-lasting protection from antibodies is provided by a part of your adaptive immune system, a key part of which is delivered by cells called “B cells”.

In lupus, both parts of the immune system are involved, and both have been successfully used to develop medicines. Earlier this year, the Therapeutic Goods Administration approved anifrolumab, a drug which blocks “interferon”, a crucial protein made by the innate immune system.

Another drug which works on B cells of the adaptive immune system, called belimumab, was approved a few years ago. Unfortunately, neither drug is on Australia’s Pharmaceutical Benefits Scheme yet, so access is extremely limited.

However, we now know that interferon and B cells are both important, and so very strong treatments that almost completely eradicate either could be useful. That is where this potential new treatment comes in.

Already Used to Treat Cancer

Treatments to destroy B cells are used in cancers like lymphoma. The most powerful of these uses CAR-T cells, which train a type of natural cell to be an assassin of the B cell.

CAR-T medicines are highly complex to make, and extremely expensive – but they work.

T cells are collected from the blood, then re-engineered in a special laboratory.

Now, this new report shows targeting B cells using this approach could be effective in lupus too. Building on a first-ever patient treated in this way by the same group a year ago, doctors in Germany created a “homemade” CAR-T treatment and used it in five patients with severe lupus.

Remarkably, all five patients had near complete eradication of disease, allowing them to stop conventional medicines, like steroids, with potentially harmful side effects.

What This Means for Other Patients

So what does it mean for patients in Australia? Well, most centres aren’t able to make their own CAR-T treatments, so delivering this potential treatment will require a commercial approach.

However, it might be quicker to market than other treatments in development as it takes a proven approach into a new disease, rather than being new from the ground up.

One day we might even be able to extend such treatments to other autoimmune diseases, like MS, where B cell-directed treatments have been helpful, as well as in lupus.

This would need to be balanced against risk. Importantly, short term side effects of CAR-T treatment (which include brain and bone marrow problems) can be severe. For this reason, such a treatment would only be used for the most severe cases in which standard treatments have failed, like the patients in the German trial.

Long-term side effects are also unknown at this time, and of course suppressing the immune system so profoundly in the setting of a pandemic is not without major risks.

Formal trials of a commercial CAR-T medicine for lupus are in the advanced planning stages already, and Australia is likely to be front and centre of these due to our lupus expertise and trial-friendly regulatory environment. With all these advances, we can at last tell our patients, and our friends and family with lupus, that there is light at the end of what has been a very long tunnel.

Eric Morand, MD, is a clinical rheumatologist and Head of the School of Clinical Sciences at Monash Health, Monash University in Australia.  Dr. Morand consults with companies involved in lupus drug development, including Novartis and AstraZeneca. He receives funding from Australia’s National Health and Medical Research Council and Lupus Research Alliance US, and is a Director of Rare Voices Australia.

This article originally appeared in The Conversation and is republished with permission.

How Intractable Pain Causes Brain Tissue Loss

By Dr. Forest Tennant, PNN Columnist

The brain not only controls pain but the endocrine, cardiovascular, metabolic, respiratory and gastrointestinal systems. Any or all of these biologic systems may malfunction if there is brain tissue loss.

Beginning in 2004, brain scan studies began to document that brain tissue loss can be caused by intractable pain. Today, almost 20 years later, this important fact appears to be either unknown or a mystery to both the public and medical professionals.

Basic science researchers have unraveled the complex process of how and why this pathological phenomenon may occur. A good understanding of how this pathology develops is critical to properly care for and treat persons who develop intractable pain whether due to a disease or an injury.

What Causes Tissue Loss?

Tissue loss anywhere in the body is caused by inflammation, autoimmunity, or loss of blood supply due to trauma or disease. The brain scan studies done since 2004 that documented brain tissue loss were not done in persons who had a stroke or head trauma, but in pain patients experiencing inflammation and autoimmunity (i.e., collagen deterioration). It turns out that both biologic mechanisms may operate to cause brain tissue loss in intractable pain patients.

In the pursuit of understanding brain tissue loss and its accompanying malfunctions, it has been discovered that the brain and spinal cord (central nervous system or CNS) contain cells called microglia. They are closely akin to the immune protective cells in the blood stream which are called a “lymphocytes.”

The microglia in the CNS lay dormant until a harmful infection, toxin or bioelectric magnetic signal enters its domain, at which time it activates to capture and encapsulate the danger or produce inflammation to destroy the offender.

If the microglia are overwhelmed by some danger, such as a painful disease that isn’t cured, it produces excess inflammation that destroys some brain tissue which can be seen on special brain scans. Some viruses such as Epstein Barr may hibernate in microglia cells and create an autoimmune response, which magnifies inflammation and brain tissue loss.

Intractable pain diseases such as adhesive arachnoiditis (AA), reflex sympathetic dystrophy (CRPS/RSD), and genetic connective tissue diseases such as Ehlers-Danlos syndrome may incessantly produce toxic tissue particles and/or bioelectromagnetic signals that perpetuate microglial inflammation, tissue loss and CNS malfunctions.

This is the reason why proper pain management must have two targets: the pain generator and CNS inflammation.

How To Know You Have Lost Brain Tissue

If your pain is constant and never totally goes away, it means you have lost some brain tissue and neurotransmitters that normally shut off pain. If you have episodes of sweating, heat or anxiety, you probably have inflammation that is flaring. Naturally, if you feel you have lost some reading, calculating or memory capacity, it possibly means you have lost some brain tissue. MRI’s may also show some fibrous scars.

Fortunately, studies show that if a painful disease or injury is cured or reduced, brain tissue can regenerate. While we can’t guarantee that brain tissue will be restored, we offer here our simple, immediate and first step recommendations using non-prescription measures.

First, do you know the name and characteristics of the disease or injury that is causing your pain? Are you engaging in specific treatments to reduce or even cure your disease, or are you simply taking symptomatic pain relief medications? 

Start at least two herbal-botanical agents that have some clinical indications that they reduce inflammation in the brain and spinal cord: serrapeptase-palmitoylethanolamide (PEA) and astragalus-curcumin-luteolin-nanokinase. You can take different agents on different days. 

Increase the amount of protein (meat, fish, poultry, eggs) in your diet. Consider a collagen supplement. Limit starches and sugars. 

Start taking these vitamins and minerals:

• Vitamin C - 2,000mg in the AM & PM

• Vitamin B-12, Vitamin D

• Minerals: Magnesium and selenium

We recommend vitamins daily and minerals 3 to 5 days a week. 

The above will help you stop additional tissue loss and hopefully regenerate brain tissue.  

Forest Tennant, MD, DrPH, is retired from clinical practice but continues his research on the treatment of intractable pain and arachnoiditis. This column is adapted from bulletins recently issued by the Arachnoiditis Research and Education Project and the Intractable Pain Syndrome Research and Education Project.

The Tennant Foundation gives financial support to Pain News Network and sponsors PNN’s Patient Resources section.   

Why Antibiotics Can Lead to a C. Diff Infection

By Madora Pennington, PNN Columnist

Got antibiotics? Then you may be on your way to a dangerous and potentially deadly infection. When antibiotics alter the balance of intestinal flora, a bacteria that causes diarrhea and inflammation of the colon -- clostridioides difficile -- can take over and result in a C. diff infection.

That is what happened to Kristy Collins. It took two rounds of antibiotics to clear up her severe ear and sinus infection. A few days later, a lunchtime salad left Kristy with a strangely upset stomach. She thought it was nothing more than a bit of food poisoning, but soon she was having malodorous belches and the foulest smelling diarrhea. She also became severely dehydrated.

At first, her doctor suspected a stomach virus. But when her stomach troubles didn’t relent, a stool test revealed that Kristy had C. diff.  Luckily, she was diagnosed and treated within a few days.

Because she has Ehlers-Danlos Syndrome (EDS), an inherited chronic illness, Kristy is a seasoned patient with a medical team in place. But having EDS also makes her more like to get C. diff. Thus far, she has had 19 surgeries for EDS-related problems. Most surgical procedures require a round of antibiotics to prevent infection and more if an infection occurs after surgery.

After her bout with C. diff, Kristy needed another surgery. She and her doctors were very concerned about a possible C. diff recurrence, as about 1 in 5 patients will get another infection. Kristy’s doctors tested her after surgery to ensure it had not returned.

Kristy worries whenever she needs antibiotics and questions her doctors if they are truly necessary. She already follows a very healthy diet, which helps manage her chronic illness and suspects this may be part of why she has not had a C. diff recurrence. She also follows her doctors’ advice.

“It was the first time doctors told me to take probiotics,” Kristy says, which she did while taking antibiotics. Probiotics are living microorganisms that enhance intestinal health. They are found in fermented food like yogurt and sauerkraut or made into supplements.

Antibiotics tend to alter that flora in the colon, creating an environment where C diff can flourish. Many people have immune systems that can handle a C. diff infection without symptoms, but others get very ill with watery diarrhea that may contain blood or mucus, or cause nausea, vomiting, loss of appetite, abdominal pain, and bloating. At its worst, C. diff can cause a loss of blood circulation, sepsis, perforated bowel, or swelling so severe it shuts down the colon.

It is not just antibiotics that can cause a C. diff infection. Other possibilities are chemotherapy treatment, proton pump inhibitor medications (usually used to treat acid reflux), kidney or liver disease, malnutrition, or simply being an older person. C. diff infects approximately half a million Americans annually, according to the CDC. 

C. diff can also be fatal. In the U.S., nearly 30,000 people die every year from a C. diff infection. Diagnosis is usually made by testing a stool sample. It is treated with antibiotics, monoclonal antibodies, or, in severe cases, surgery.

How to Prevent C. Diff

Good hygiene practices can help prevent its spread. For C. diff, hand washing with soap and water is more effective than using alcohol-based hand sanitizers. It is also essential to limit the use of antibiotics to situations when they are truly necessary, to avoid disrupting the balance of bacteria in the colon. Many doctors recommend repopulating the beneficial bacteria with probiotic supplementation during or after antibiotic treatment.

Recovering from a C. diff infection can be mysterious as well as complicated. Many patients are not advised on how or what to eat or drink. Food can seem like the enemy, and meals can feel traumatizing.

To address this unmet need, the Peggy Lillis Foundation, a non-profit advocacy organization created in honor of a beloved kindergarten teacher whose life was taken suddenly by C. diff, recently published a nutrition and lifestyle guide.

 “This guide begins to address the dearth of information by combining medical expertise, dietary guidance, and first-hand knowledge from C. diff survivors,” says Executive Director Christian John Lillis.

The guide is sponsored by probiotic manufacturer Bio-K Plus and put together by the PLF’s Scientific Advisory Council. It covers tips on managing the acute phase of a C. diff infection, preventing a recurrence, improving gut health, dealing with the emotional implications of C. diff, and recipes. It is available to download free by clicking here.

Madora Pennington is the author of the blog LessFlexible.com about her life with Ehlers-Danlos Syndrome. She graduated from UC Berkeley with minors in Journalism and Disability Studies. 

Lyme Disease Cases Soar in U.S.

By Pat Anson, PNN Editor

Diagnoses of Lyme disease in the United States have soared over the past 15 years, primarily in rural areas in the Northeast, according to a new analysis of private insurance claims by FAIR Health, a nonprofit that tracks healthcare costs and insurance trends.   

Lyme disease is a bacterial illness spread by ticks. Left untreated, it can lead to chronic fatigue, muscle and joint pain, cognitive issues and other long-term symptoms that are often misdiagnosed as fibromyalgia, neuropathy or autoimmune disorders.

In its analysis of over 36 billion insurance claims from 2007 to 2021, FAIR Health said that claims with a Lyme disease diagnosis rose 357 percent in rural areas and 65 percent in urban areas. The highest rates of Lyme disease were in New Jersey, Vermont, Maine, Rhode Island and Connecticut.

“Lyme disease remains a growing public health concern. FAIR Health will continue to use its repository of claims data to provide actionable and relevant insights to healthcare stakeholders seeking to better understand the ongoing rise of Lyme disease cases,” FAIR Health President Robin Gelburd said in a press release.

The FAIR Health study found that malaise, fatigue and soft-tissue-related symptoms were significantly more common in Lyme patients than in the overall patient population.

Other early symptoms of Lyme disease include fever, chills, headache, and swollen lymph nodes. A delayed rash often appears at the site of the tick bite. The rash grows in size and sometimes resembles a bulls-eye.

Although Lyme disease is treatable with antibiotics, some patients develop long-term symptoms known as Lyme disease syndrome or chronic Lyme disease.

About 30,000 Lyme cases are reported annually by state health departments. The CDC estimates the actual number of cases is probably much higher and that about 300,000 Americans may become infected every year.

Most reported cases of Lyme disease occur in the Northeast, mid-Atlantic and upper Midwest, especially during the summer months when more people spend time outdoors. Recent studies show Lyme is spreading to neighboring states and is no longer just a seasonal disease, possibly due to the effects of climate change.

Gut Bacteria Identified as Cause of IBS

By Pat Anson, PNN Editor

Canadian researchers have identified one of the primary causes of Irritable Bowel Syndrome (IBS), a frustrating intestinal condition that causes abdominal pain, cramps, bloating, gas and diarrhea.

The culprit appears to be Klebsiella aerogenes, a strain of bacteria that causes white blood cells to produce excess amounts of histamine, a chemical that triggers a painful immune system response. Gut bacteria have long been suspected as a likely cause of IBS, but this is the first time a specific bacterial strain has been identified.  

Researchers at McMaster University and Queen’s University studied stool samples from both Canadian and American IBS patients, and found Klebsiella aerogenes in about 25 percent of them.

“We followed up these patients for several months and found high levels of stool histamine at the time when the patients reported severe pain, and low stool histamine when they were pain-free,” said senior author Premysl Bercik, MD, a gastroenterologist and professor at McMaster’s Michael G. DeGroote School of Medicine.

Further tests on laboratory mice that were colonized with gut microbes from IBS patients showed that several types of bacteria produced histamine, but Klebsiella aerogenes was a “super-producer.” The chemical is produced when histidine, an essential amino acid in animal and plant protein, is converted into histamine, triggering pain and inflammation.

“Now that we know how the histamine is produced in the gut, we can identify and develop therapies that target the histamine producing bacteria,” said first author Giada de Palma, an assistant professor of medicine at McMaster.

Researchers found that when mice colonized with histamine producing bacteria were fed a diet low in carbohydrates, histamine production dramatically decreased. That would explain the benefits of diets low in carbohydrates and high in dietary fiber, which are often recommended to IBS patients. Allergy medications that block histamine production may also be useful in treating IBS.

“Many but not all IBS patients will benefit from therapies targeting this histamine driven pathway,” said co-first author David Reed, assistant professor of medicine at Queen’s University.

The McMaster-Queens study was funded by the Canadian Institutes of Health Research and published in the journal Science Translational Medicine.

How Emojis Could Enhance Pain Care

By Pat Anson, PNN Editor

Because pain is subjective and varies from patient to patient, there has long been a debate in the medical community about the best way to measure it.

The two most widely used methods, the numeric 0 to 10 pain scale and the Wong-Baker scale, both rely on patients to self-report their pain levels by assigning a number or a face to it. Someone in severe pain, for example, might rate it an “8” or point to an unhappy, grimacing face to help their doctor understand how much pain they are in.

Not exactly cutting-edge science, is it?

In an effort to find a more useful way to measure pain in the digital age, researchers at Massachusetts General Hospital (MGH) asked 109 patients to rate their pain on a numerical scale and by using an electronic device to select one of six emoji faces modeled after the Wong-Baker scale. The patients suffered from abdominal, chest, back or extremity pain, and were admitted for emergency care or surgery at MGH.

JAMA IMAGE

The study findings, published in JAMA, showed no discernible difference between the numerical and emoji scales – suggesting that digital emojis can be useful in collecting patient health data, particularly for young children and individuals with different cultural, language and cognitive abilities.

"By demonstrating concordance between emoji and the numerical pain rating scale, we've validated the use of emoji as an accurate, open-source and economical alternative to popular visual analog pain scales such as Wong-Baker," first author Shuhan He, MD, an MGH emergency department attending physician, said in a press release.

"Because emoji are open source and digital, they could encourage collection of data on a patient's condition over days, weeks, or months—information that could then be integrated into electronic health records and documented on patients' charts."

Rather than just an online fad, Dr. He and his colleagues say colorful emoji symbols could be a practical and imaginative way to break down communication barriers in the hospital setting.

"If a clinician doesn't understand the patient due to a language barrier or disability, it's tantamount to no treatment at all," said senior author Jarone Lee, MD, vice chief of Critical Care and Trauma Emergency Surgery at MGH. "Among populations that could benefit are patients in the intensive care unit who may have difficultly speaking, such as those on mechanical ventilators who need an alternative way to characterize their pain to caregivers."

Digital emojis originated in Japan over a decade ago. Of the 3,500 emoji symbols approved for use by the Unicode Consortium -- a nonprofit that maintains uniform text standards for computers — only 50 are relevant to medicine.

The first medical emojis, introduced in 2015, were the syringe and the pill. Emojis have since been added to represent disability, a stethoscope, bone, teeth, heart and lungs. Dr. He is working with professional medical societies to develop more emojis – including ones to represent pain -- with the goal of getting them approved by the Unicode Consortium.

He believes medical emojis could become mainstream tools for enhancing diagnosis and treatment. In emergency room cases where timing is critical, emojis could lead to a point-and-tap form of communication that bridges language gaps and speeds clinical decisions.

"As physicians, our job is to know how patients feel," Dr. He said, "and the use of emoji allows us to make that process more equitable and thus improve healthcare delivery for all patients in a very meaningful way."

What’s Missing in ‘Elvis’ Movie: The King’s Chronic Illness

By Pat Anson, PNN Editor

There’s a scene towards the end of the new “Elvis” movie when you know the end is coming soon. Presley, as depicted by actor Austin Butler, collapses in a hallway minutes before being scheduled to take the stage at the International Hotel in Las Vegas.

Instead of rushing an unconscious Elvis to a hospital, manager Tom Parker --- played by a surprisingly villainous Tom Hanks -- declares that the show must go on and summons “Dr. Nick” to make it right. After a quick injection of stimulant drugs, Elvis recovers just enough to sing, dance and entertain an adoring crowd in a packed showroom.   

That one scene sums up how the real Elvis Presley spent his final years before dying of an apparent heart attack in 1977 at the young age of 42. Popping pills. Slurring his words. Deeply depressed. And driven to continue performing by “Colonel” Parker and others.

“They really tried to push Elvis beyond his capacity in the last few years of his life. He was disabled,” says Dr. Forest Tennant, a retired physician and pain management expert who is one of the last people alive to be intimately familiar with Elvis’ drug use and medical problems.

In 1981, Tennant was hired by an attorney for Dr. George Nichopoulos (Dr. Nick), who faced criminal charges in Presley’s death. Tennant reviewed the autopsy report, medical records and a confidential 161-page private investigation, and testified as a defense witness for Nichopoulos, who would be acquitted of charges of overprescribing drugs.

After the trial, Tennant remained curious about Elvis’ medical problems and continued his research while treating people with intractable pain. The knowledge and experience Tennant gained in the last 50 years led to his recent book, appropriately titled “The Strange Medical Saga of Elvis Presley.”  

Elvis did indeed suffer from heart problems aggravated by an excessive use of drugs, but Tennant believes the ultimate cause of his death was a connective tissue disorder called Ehlers-Danlos syndrome (EDS), a major cause of intractable pain and other chronic health problems.

A diagnostic screening tool for EDS didn’t exist when Elvis was alive and few physicians were even aware of the condition. But Tennant thinks Presley had all the symptoms of EDS, including an unusual degree of flexibility and double jointness that allowed him to swing his hips and gyrate wildly. Those sexy dance moves helped make Elvis famous, but they also foretold what lay in store for him.

“EDS is a genetic connective tissue collagen disorder, and what that means is that you are genetically predetermined to have your collagen in certain tissues either disappear or deteriorate or become defective, and to put it bluntly, you can have a rectal problem and an eye problem at the same time due to the same cause because your collagen is deteriorating in these tissues,” Tennant told my colleague Donna Gregory Burch in a 2021 interview. “If you get a severe case like Elvis Presley, your life is going to be very miserable, and you're going to die young unless you get vigorous treatments.”      

The day before he died, a dentist gave Presley codeine for an aching tooth, not realizing how sick he was or that codeine could cause his heart to stop. Elvis collapsed in the bathroom 24 hours later. His sudden death led to rumors that he died from an overdose or even a horrible case of constipation. The truth is more complex.

“Nothing happened to Elvis Presley that we don't have a good logical, scientific explanation for now. But certainly back in those days we didn't,” Tennant explained. “Elvis Presley had multiple diseases. He was terribly ill, and he died accidentally in some ways with a dentist giving him codeine for his bad tooth, and his bad teeth were also part of the same disease that gave him a bad colon and a bad eye and a bad liver. They were all connected.

“He had all these metabolic defects due to his genetics, and so the codeine built up in his system. He had this terrible heart, so he died suddenly, within seconds, as he was trying to sit on the commode.”

Fortunately, the “Elvis” movie spares us any final scenes like that – ending instead with actual clips from one of Presley’s last concerts. They show a tired and very sick man, aged beyond his years and sweating profusely. But he still sang like “The King.”

All proceeds from sales of “The Strange Medical Saga of Elvis Presley” go the Tennant Foundation, which gives financial support to Pain News Network and sponsors PNN’s Patient Resources section.

‘My Pain Was No Big Deal’: Obese Patients Often Stigmatized by Doctors

By Lauren Sausser, Kaiser Health News

When Melissa Boughton complained to her OB-GYN about dull pelvic pain, the doctor responded by asking about her diet and exercise habits.

The question seemed irrelevant, considering the type of pain she was having, Boughton thought at the time. But it wasn’t unusual coming from this doctor. “Every time I was in there, she’d talk about diet and exercise,” said Boughton, who is 34 and lives in Durham, North Carolina.

On this occasion, three years ago, the OB-GYN told Boughton that losing weight would likely resolve the pelvic pain. The physician brought up diet and exercise at least twice more during the appointment. The doctor said she’d order an ultrasound to put Boughton’s mind at ease.

The ultrasound revealed the source of her pain: a 7-centimeter tumor filled with fluid on Boughton’s left ovary.

“I hate that doctor for the way she treated me — like my pain was no big deal,” Boughton said. “She seemed to make a decision about me based off of a very cursory look.”

Research has long shown that doctors are less likely to respect patients who are overweight or obese, even as nearly three-quarters of adults in the U.S. now fall into one of those categories. Obesity, which characterizes patients whose body mass index is 30 or higher, is pervasive in the South and Midwest, according to the Centers for Disease Control and Prevention. The state with the highest rate is Mississippi, where 4 in 10 adults qualify as obese.

Obesity is a common, treatable condition linked to a long list of health risks, including Type 2 diabetes, heart disease, and some cancers. Despite obesity’s prevalence, it carries a unique stigma.

‘Almost Like Malpractice’

Doctors often approach the practice of medicine with an anti-fat bias and struggle to communicate with patients whose weight exceeds what’s considered the normal range. Some obesity experts blame a lack of focus on the subject in medical schools. Others blame a lack of empathy.

To counter that, the Association of American Medical Colleges plans to roll out in June new diversity, equity, and inclusion standards aimed at teaching doctors, among other things, about respectful treatment of people diagnosed as overweight or obese.

That’s not happening for many patients, said Dr. Scott Butsch, director of obesity medicine at the Cleveland Clinic’s Bariatric and Metabolic Institute. “This is almost like malpractice. You have these physicians or clinicians — whoever they are — relating everything to the patient’s obesity without investigation,” Butsch said. “The stereotypes and misperceptions around this disease just bleed into clinical practice.”

The problem, Butsch argued, is that too little attention is paid to obesity in medical school. When he trained and taught at Harvard Medical School for several years, Butsch said, students received no more than nine hours of obesity education spread over three days in four years.

In 2013, the American Medical Association voted to recognize obesity as a disease. But, Butsch said, doctors often approach it with a one-size-fits-all approach. “Eat less, move more” doesn’t work for everyone, he said.

Parents and medical providers need to take special care when talking to children who have been diagnosed with obesity about their weight, psychologists have warned. The way parents and providers talk to kids about their weight can have lifelong consequences and in some cases trigger unhealthy eating habits. For children who are obese, obesity experts agree, weight loss isn’t always the goal.

“There are many different forms of obesity, but we’re treating them like we’re giving the same chemotherapy to all kinds of cancer,” Butsch said.

Doctors Poorly Trained About Weight

All but four of the country’s 128 M.D.-granting medical schools reported covering content related to obesity and bariatric medicine in the 2020-21 academic year, according to curriculum data provided to KHN by the Association of American Medical Colleges, which does not represent osteopathic schools.

Even so, research suggests that many physicians haven’t been sufficiently trained to address weight issues with patients and that obesity education in medical schools across the world is “grossly neglected.” A survey completed by leaders at 40 U.S. medical schools found that only 10% felt their students were “very prepared” to manage patients with obesity.

Meanwhile, “half of the medical schools surveyed reported that expanding obesity education was a low priority or not a priority,” wrote the authors of a 2020 journal article that describes the survey’s results.

Butsch wants Congress to pass a resolution insisting that medical schools incorporate substantive training on nutrition, diet, and obesity. He acknowledged, though, that the medical school curriculum is already packed with subject matter deemed necessary to cover.

Dr. David Cole, president of the Medical University of South Carolina, said plenty of topics should be covered more comprehensively in medical school but aren’t. “There’s this massive tome — it’s about this big,” Cole said, raising his hand about a foot off the top of a conference table in Charleston. “The topic is: Things I never learned in medical school.”

The bigger issue, he said, is that medicine has historically been taught to emphasize memorization and has failed to emphasize culturally competent care. “That was valid 100 years ago, if you were supposed to be the fount of all knowledge,” Cole said. “That’s just not valid anymore.”

The Association of American Medical Colleges is trying to tackle the problem in two ways.

First, it developed a professional readiness exam for aspiring medical school students, called PREview, designed to assess an applicant’s cultural competence, social skills, and listening skills, as well as their ability to think through situations they may encounter in medical school and clinical settings.

“We call them softer skills, but they’re really the harder ones to learn,” said Lisa Howley, an educational psychologist and senior director of strategic initiatives at the association. More than a dozen medical schools now recommend or require that applicants submit their PREview test scores with their Medical College Admission Test scores.

Second, the medical college association will roll out new competency standards for existing medical students, residents, and doctors related to diversity, equity, and inclusion in June. Those standards will address racism, implicit bias, and gender equality and will aim to teach doctors how to talk with people who are overweight.

“The bias toward those individuals is way too high,” Howley said. “We have a lot more work to do in this space.”

After the source of Melissa Boughton’s pelvic pain was discovered, the OB-GYN who had recommended diet and exercise to ease her symptoms told Boughton the tumor was no big deal. “She acted like it was the most normal thing in the world,” Boughton said.

Boughton sought a second opinion from a doctor who marketed her practice as a “Healthy at Every Size” office. That doctor referred Boughton to a surgical oncologist, who removed the tumor, her left ovary, and part of a fallopian tube. The tumor was large, but it wasn’t cancerous. And although the surgery to remove it was considered successful, Boughton has since had trouble conceiving and is undergoing fertility treatment as she tries to have a baby.

“It’s an emotional roller coaster,” she said. “I feel very young at 34 to be going through this.”

Boughton — who describes herself as someone who doesn’t “fit into the BMI box” — said the experience taught her to choose her doctors differently.

“You can ask me if I diet and exercise like once,” she said. Any more than that, and she starts shopping for a different doctor.

Kaiser Health News is a national newsroom that produces in-depth journalism about health issues.  

Anti-Inflammatory Drugs May Contribute to Chronic Pain

By Pat Anson, PNN Editor

Anti-inflammatory drugs that are widely used to treat short-term acute pain disrupt the body’s natural healing process and increase the chances of developing chronic pain, according to a provocative new study by an international team of researchers.

If true, it means that ibuprofen, naproxen, diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) used by millions of people every day for the temporary relief of acute pain may contribute to long-term pain that is even harder to treat.    

“For many decades it’s been standard medical practice to treat pain with anti-inflammatory drugs. But we found that this short-term fix could lead to longer-term problems,” said co-author Jeffrey Mogil, PhD, Professor of Pain Studies and the Canada Research Chair in the Genetics of Pain at McGill University in Montreal.

In a series of studies, Mogil and his colleagues first analyzed genes and immune cells in the blood of 98 patients with acute lower back pain (LBP), noting which patients became free of pain and which ones developed chronic pain after three months.  

In patients who became pain free, there was an early inflammatory response to acute pain that activated neutrophils -- a type of white blood cell that helps the body fight infection.

In patients with chronic pain, there was no inflammatory immune response. This suggests that neutrophils play an active role in resolving pain and protecting patients from transitioning to chronic pain.

“Neutrophils dominate the early stages of inflammation and set the stage for repair of tissue damage. Inflammation occurs for a reason, and it looks like it’s dangerous to interfere with it,” said Mogil.

The study findings, published in Science Translational Medicine, were replicated in a cohort of patients with temporomandibular disorder (TMD), a painful inflammation of the jaw.

Researchers also tested their theory on laboratory animals, giving mice with acute pain the anti-inflammatory steroid dexamethasone or the NSAID diclofenac. While the drugs were initially effective, researchers found that blocking neutrophils in mice ultimately prolonged their pain up to ten times the normal duration. Three other analgesics without anti-inflammatory properties (gabapentin, morphine and lidocaine) produced short-term pain relief without affecting the overall duration of pain in mice.

These findings were also supported by a separate analysis of health records for 500,000 people in the United Kingdom with acute LBP. Those that took NSAIDs were nearly twice as likely to still have pain 2 to 6 years later than those who did not take NSAIDs. Patients who took acetaminophen (paracetamol) or antidepressants – neither of which are anti-inflammatory --  were not at higher risk of transitioning to chronic LBP.

“Our findings suggest it may be time to reconsider the way we treat acute pain. Luckily pain can be killed in other ways that don’t involve interfering with inflammation,” said co-author Massimo Allegri, MD, Head of Pain Service at Policlinico of Monza Hospital in Italy and Ensemble Hospitalier de la Cote in Switzerland.

Researchers say their findings should be followed up with larger clinical trials directly comparing the long-term effects of anti-inflammatory drugs to other pain relievers that don’t disrupt inflammation.

“Together, our results suggest that active immune processes confer adaptation at the acute pain stage, and impairment of such inflammatory responses in subjects with acute LBP (or TMD) increases the risk of developing chronic pain. These adaptive inflammatory responses are intrinsically transcriptionally driven, probably modified by both genetics and environmental factors, and can be inhibited by steroids and NSAIDs,” researchers said.

“Our conclusions may have a substantial impact on medical treatment of the most common presenting complaints to health care professionals. Specifically, our data suggest that the long-term effects of anti-inflammatory drugs should be further investigated in the treatment of acute LBP and likely other pain conditions.”

NSAIDs are widely used to treat everything from fever and headache to low back pain and arthritis. They are in so many different pain relieving products, including over-the-counter cold and flu medications, that many consumers may not be aware how often they use NSAIDs. At high doses, studies have found that NSAIDs increase the risk of a heart attack or stroke.

The current draft revision of the CDC opioid guideline recommends that NSAIDs should be used for low back pain, painful musculoskeletal injuries, dental pain, postoperative pain, kidney stones and acute pain caused by episodic migraine.

Acetaminophen also has its risks. Long-term use has been associated with liver, kidney, heart and blood pressure problems. Acetaminophen overdoses are involved in about 500 deaths and over 50,000 emergency room visits in the U.S. annually.

High-Frequency Spinal Cord Stimulators Provide More Pain Relief

By Pat Anson, PNN Editor

Spinal cord stimulators are often considered the treatment of last resort for patients with intractable or severe chronic pain. The surgically implanted devices emit low levels of electricity that reduce pain signals, but have high failure rates and often have to be removed because they’re ineffective, cause infections or need new batteries.

Two new studies suggest there are ways to improve the success rate of spinal cord stimulators (SCS) through improved patient selection and the use of high-frequency devices.

Low-frequency SCS (50 Hz) was first approved by the Food and Drug Administration for intractable back and leg pain in 1989. Six years later, the FDA approved high-frequency devices (10,000 Hz), that deliver pulses of electrical stimulation that are shorter in duration, lower in amplitude and do not cause paresthesia, an irritating sensation of tingling or prickling.

In a retrospective study of 237 patients who received stimulators between 2004 and 2020, researchers at the University of California San Diego School of Medicine reported that high-frequency devices were more effective at reducing pain and opioid use than low-frequency ones.

The study findings, published in the journal Bioelectronic Medicine, also show that male patients benefit more than women from high-frequency neuromodulation.

"Our work was sparked by a growing literature that demonstrate sex specific immune pathways differentially contribute to chronic pain processes," said senior author Imanuel Lerman, MD, an associate professor of anesthesiology at UC San Diego Health. "The observed parameter-specific (high versus low frequency) sex-based differences in spinal cord stimulation efficacy and opiate use are definitely intriguing.”

It’s not clear why men benefit more than women, but researchers believe it may be due to the male hormone testosterone having a modulating effect on pain signals. The sex differences may also be due to males and females processing chronic pain differently.

"Clearly more work needs to be done to carefully characterize sex specific pain regulatory pathways that may prove responsive to specific types of neuromodulation and or pharmaceutical therapies," said Lerman.

Improved Patient Selection  

Although most patients are required to undergo psychological testing and a trial treatment before getting a SCS, failure rates for the devices remain high at around 25 to 30 percent. With about 50,000 stimulators implanted in the U.S. every year, that means thousands of patients are getting poor results.

To improve patient outcomes, researchers at Florida Atlantic University developed machine-learning algorithms to help predict which patients may benefit from SCS. Working with a cohort of 151 SCS patients, they evaluated 31 features or characteristics in each patient.  

Researchers found two distinct clusters of patients which differ significantly in age, duration of chronic pain, preoperative pain levels and pain catastrophizing scores. They used computers to fine-tune the results, identifying the 10 most influential features that contribute the most to a successful SCS implant.

Results of the study, published in the journal Neurosurgery, demonstrate for the first time the ability of machine-learning algorithms to predict long-term patient response to SCS placement. The next step is to validate the data in future patients to ensure that the algorithm is useful in real-world situations, not just computer models.

"Our study resulted in the development of a model to predict which patients would benefit from spinal cord stimulation," said lead author Julie Pilitsis, MD, dean and vice president of medical affairs at Florida Atlantic University's Schmidt College of Medicine.  "After we validate this work, our hope is that this machine-learning model can inform a clinical decision support tool to help physicians better choose which patients may be most appropriate."

SCS is no longer limited to patients with intractable back and neck pain. Last year the FDA expanded the use of SCS to include lower limb pain from diabetic neuropathy.  Stimulators are also being used on patients with Complex Regional Pain Syndrome (CRPS).

A decision to get a SCS shouldn’t be taken lightly. A 2018 study by a team of investigative journalists found that stimulators have some of the worst safety records of medical devices tracked by the FDA. A 2020 FDA review of adverse events involving SCS found that nearly a third were reports of unsatisfactory pain relief. The review also identified nearly 500 deaths linked to the devices, along with nearly 78,000 injuries and 30,000 device malfunctions.

Steroids Raise Risk of Hospitalization for Sickle Cell Patients

By Pat Anson, PNN Editor

People with sickle cell disease who are prescribed a corticosteroid – an anti-inflammatory medicine often used to treat pain – are significantly more likely to be hospitalized with a severe pain episode, according to a new study.

Sickle cell disease (SCD) is a genetic disorder that causes red blood cells to form in a crescent or sickle shape, which creates painful blockages in blood vessels known as vaso-occlusive episodes (VOE), which can lead to infections, strokes and organ failure. About 100,000 Americans live with SCD, primarily people of African or Hispanic descent.

“Individuals living with SCD often suffer crippling episodes of pain, which can greatly impair their quality of life,” said Ondine Walter, MD, of Toulouse University Hospital in France, lead author of the study published in the journal Blood.

Walter and her colleagues looked at medical data for over 5,100 patients with SCD in the French National Health Insurance Database between 2010 and 2018. Patients had to have at least one hospitalization for VOE to be included, and their corticosteroid exposure was identified using outpatient prescribing records.

Researchers found that patients exposed to a corticosteroid in the month prior to a pain flare were nearly four times more likely to be hospitalized for VOE than those who did not get a steroid. The median time between filling a prescription for a corticosteroid and hospitalization was just five days.

Nearly half the patients (46%) were prescribed a corticosteroid during the study period, an indication of just how common steroid treatment is for SCD. Walter said the results demonstrate the need for better education of clinicians and patients about the potential risks of corticosteroids, especially when there isn’t a clear reason to use them.

“Based on our data, corticosteroids are commonly prescribed for conditions unrelated to their underlying SCD. Vaso-occlusive events and related hospitalization appear to follow corticosteroid prescription fairly quickly. This evidence suggests corticosteroids may be contributing to the events and should be avoided as much as possible in these patients,” Walter said. “Corticosteroids are mostly easy to avoid, and in circumstances when they are necessary, it’s important to start them in collaboration with an SCD expert and to take all appropriate precautionary measures to administer them safely.”

The American Society of Hematology’s Clinical Practice Guideline recommends against using corticosteroids for acute pain in SCD patients.

The French research team also found that SCD patients taking the drug hydroxyurea had about half the risk of being hospitalized for VOE than those not taking it, which may indicate the drug has a protective effect. Hydroxyurea is often prescribed to SCD patients to reduce the number of pain flares and the need for blood transfusions. Men benefited from hydroxyurea more than women and children.

It’s not uncommon for someone with SCD to visit an emergency room a few times each year due to acute pain or complications such as anemia. Many are disappointed by the experience. A 2021 survey of SCD patients in the U.S. found that nearly two-thirds felt ER staff were rude, ignorant or misinformed about sickle cell disease, didn’t take their pain seriously or believed they were drug seekers.