Experimental Implant Uses Coolant to Numb Nerve Pain

By Pat Anson, PNN Editor

Applying ice on inflamed tissues and sore muscles is one of the oldest ways to relieve pain and promote healing.  Researchers at Northwestern University are taking that tried-and-true method a step further, with the development of a small, flexible implant that can alleviate pain by literally cooling nerves.

Researchers believe the experimental implant could be most beneficial to patients who undergo surgeries, nerve grafts or even amputations. Surgeons could implant the device during the procedure to help patients manage post-operative pain on demand without the use of drugs.

“As engineers, we are motivated by the idea of treating pain without drugs — in ways that can be turned on and off instantly, with user control over the intensity of relief,” says John Rogers, PhD, Professor of Materials Science and Engineering at Northwestern and lead author of a study published in the journal Science.

“The technology reported here exploits mechanisms that have some similarities to those that cause your fingers to feel numb when cold. Our implant allows that effect to be produced in a programmable way, directly and locally to targeted nerves, even those deep within surrounding soft tissues.”

In experiments on laboratory rats, Rogers and his colleagues demonstrated that the implants can rapidly cool peripheral nerves to relieve neuropathic pain.

As thick as a sheet of paper, at its widest point the implant is 5 millimeters wide – about the size of the eraser on a pencil. One end is curled into a cuff that can softly wrap around a nerve, without the need for sutures to hold it in place.

“If you think about soft tissues, fragile nerves and a body that’s in constant motion, any interfacing device must have the ability to flex, bend, twist and stretch easily and naturally,” said Rogers.

NORTHWESTERN UNIVERSITY

To induce cooling, the device contains tiny microfluid channels. One channel contains a liquid coolant (perfluoropentane), while a second channel contains dry nitrogen. When the liquid and gas flow into a shared chamber, a reaction occurs that causes the liquid to evaporate and cool. A tiny sensor in the implant monitors the temperature of the nerve to ensure that it’s not getting too cold, which could cause tissue damage.

“As you cool down a nerve, the signals that travel through the nerve become slower and slower — eventually stopping completely,” said coauthor Matthew MacEwan, PhD, from Washington University School of Medicine in St. Louis. “We are specifically targeting peripheral nerves, which connect your brain and your spinal cord to the rest of your body. These are the nerves that communicate sensory stimuli, including pain. By delivering a cooling effect to just one or two targeted nerves, we can effectively modulate pain signals in one specific region of the body.”

An external pump allows patients to remotely activate the implant and increase or decrease its intensity. Because the device is biocompatible and water-soluble, it will naturally dissolve and absorb into the body over the course of days or weeks — bypassing the need for surgical extraction.

Other cooling therapies have been tested experimentally, but have limitations. Instead of targeting specific nerves, they cool large areas of tissue, potentially leading to side effects such as tissue damage and inflammation.

“You don’t want to inadvertently cool other nerves or the tissues that are unrelated to the nerve transmitting the painful stimuli,” MacEwan said. “We want to block the pain signals, not the nerves that control motor function and enables you to use your hand, for example.”

Experimental Injection Could Reverse Spinal Cord Injuries

By Pat Anson, PNN Editor

An experimental injection therapy that uses synthetic nanofibers to stimulate nerve cells could be used someday to reverse paralysis and repair damaged spinal cord tissues, according to a new study by researchers at Northwestern University.

In experiments on laboratory animals, the therapy successfully regenerated spinal cord nerves, reduced scar tissue and triggered the formation of new blood vessels. After a single injection, paralyzed mice regained the ability to walk within four weeks.

“Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease,” said lead author Samuel Stupp, PhD, an expert in regenerative medicine and founding director of the Simpson Querrey Institute for BioNanotechnology (SQI) at Northwestern.

“For decades, this has remained a major challenge for scientists because our body’s central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease. We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.”

Stupp and his colleagues used nanotechnology to develop synthetic nanofibers that mimic the natural environment around the spinal cord. Intensifying the motion of molecules within the nanofibers promotes the repair and regeneration of myelin, the insulating layer of axons that help nerve cells transmit electrical signals.

Researchers say the nanofibers biodegrade into nutrients for nerve cells within 12 weeks and completely disappear from the body without noticeable side effects. Their study, published in the journal Science, is the first in which researchers controlled the motion of molecules through changes in chemical structure to increase a therapy’s efficacy.

Nearly 300,000 people are currently living with a spinal cord injury in the United States. About 30% are hospitalized at least once a year after the initial injury and less than 3% of those with a severe injury ever recover basic physical functions. Life expectancy for patients with spinal cord injuries is significantly lower than healthy people and has not improved since the 1980s.

“Currently, there are no therapeutics that trigger spinal cord regeneration,” Stupp said in a news release. “I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients.” 

The key behind Stupp’s breakthrough therapy is fine tuning the motion of molecules so that they can find and constantly engage with moving cellular receptors with bioactive signals. Injected as a liquid, the “dancing molecules” immediately form a gel in a complex network of nanofibers that mimic the extracellular matrix of the spinal cord.

“Receptors in neurons and other cells constantly move around,” Stupp said. “The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibers. By making the molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”

Stupp and his team found that fine-tuning the molecules’ motion within the nanofibers makes them more agile and results in greater therapeutic effect in paralyzed mice. They also confirmed that formulations of their therapy performed successfully in vitro tests with human cells, indicating increased bioactivity and cellular signaling.

Once connected to the nerve receptors, the dancing molecules trigger two cascading signals, both of which are critical to spinal cord repair. One signal induces myelin to rebuild around axons, which improves how nerve cells communicate with the brain. The second signal helps neurons survive after injury by promoting the regrowth of lost blood vessels that feed neurons and other cells for tissue repair. The therapy also reduces glial scarring, which acts as a physical barrier that prevents the spinal cord from healing. 

“The signals used in the study mimic the natural proteins that are needed to induce the desired biological responses. However, proteins have extremely short half-lives and are expensive to produce,” said first author Zaida Álvarez, a former research assistant in Stupp’s laboratory who is now a researcher scholar at SQI. “Our synthetic signals are short, modified peptides that — when bonded together by the thousands — will survive for weeks to deliver bioactivity. The end result is a therapy that is less expensive to produce and lasts much longer.”

While the new therapy could be used to treat paralysis after a major spinal cord injury, Stupp believes it could also be used to as a therapy for neurodegenerative diseases and strokes.

“The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinson’s disease and Alzheimer’s disease,” Stupp said. “Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets.”

You can learn more about Stupp’s research in this podcast and by watching this video:

Recent research at Yale University and Sapporo Medical University in Japan found that injections of mesenchymal stem cells (MSCs) in patients paralyzed by spinal cord injuries led to significant improvement in their motor functions. In a small study, more than half of the paralyzed patients showed substantial improvements in function within weeks of being injected with autologous MSCs derived from their own bone marrow.

Rare Autoimmune Disease Goes Into Remission After Stem Cell Therapy

By A. Rahman Ford, PNN Columnist

New research at Northwestern University and the Mayo Clinic confirms that we can heal ourselves with our own stem cells. A small study published in the journal Neurology found that treating a person with stem cells derived from their own blood or bone marrow can reverse a rare autoimmune disease called neuromyelitis optica (NMO).

Also known as Devic Disease, NMO is a chronic neurological disorder that causes inflammation in the optic nerve and spinal cord. Common symptoms are eye pain that can rapidly lead to blindness, and pain in the spine, legs or arms that can lead to paralysis. Bladder and bowel control may also be affected.

Neuromyelitis optica is often misdiagnosed as multiple sclerosis (MS). The normal course of treatment is high-dose corticosteroids and immunosuppressants.

In the study, 13 patients with NMO were first given drugs to suppress their immune system, followed by an infusion of hematopoietic stem cells (HSCT).

The results were significant and durable. After 57 months, most patients were in remission and were off all immunosuppressive drugs.

A biological marker in the blood that correlates with NMO disease activity also disappeared.

“There is marked difference between a transplant and the drug,” said lead author Dr. Richard Burt, a professor of medicine and chief of immunotherapy and autoimmune disease at Northwestern University Feinberg School of Medicine. “The transplant improved patients’ neurological disability and quality of life. They got better, and the disease maker disappeared for up to five years after transplant.”

Two of the patients relapsed after the HSCT infusion and had to go back on drug therapy.

According to Northwestern Now, Dr. Burt is a pioneer in the field of using autologous stem cells to treat autoimmune disease. Previous research by Burt has shown that HSCT can reverse relapsing-remitting multiple sclerosis, systemic sclerosis and chronic inflammatory demyelinating polyneuropathy.

When interviewed  by The Daily Northwestern about the implications of Burt’s work, Feinberg Associate Neurology Professor Dr. Roumen Balabanov predicted that chronic autoimmune diseases would be treated through “a single, radical approach” that would allow patients to live normal lives without being dependent on medications to control their symptoms.

“The point of this treatment being radical is that the patients will actually have normal lives,” Balabanov said. “They don’t have to take those lifelong medications.”

Those lifelong drugs can cost up to $500,000 per year. Conversely, the HSCT transplant costs about $100,000.

Dr. Burt is currently on sabbatical to teach his HSCT protocol at stem cell clinics around the country and to write a book. Actress Selma Blair recently had her multiple sclerosis treated by Burt’s clinic. She has been very public about her experience on social media and in interviews.

Recently the Scottish Health Technologies Group recommended HSCT be approved in Scotland to treat relapsing-remitting multiple sclerosis.

A. Rahman Ford, PhD, is a lawyer and research professional. He is a graduate of Rutgers University and the Howard University School of Law, where he served as Editor-in-Chief of the Howard Law Journal.

Rahman lives with chronic inflammation in his digestive tract and is unable to eat solid food. He has received stem cell treatment in China. 

The information in this column 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.

Can Sugar Pills Relieve Chronic Pain?

By Pat Anson, PNN Editor

“Sugar pills relieve pain for chronic pain patients”

That is the actual headline in a news release issued this week by the Feinberg School of Medicine at Northwestern University. If you’re a pain sufferer and that doesn’t make you laugh or get your blood boiling – then the rest of this article probably will.

So be forewarned.

In an age when many chronic pain patients are being urged to try yoga, meditation, acupuncture and plain old aspirin, Northwestern researchers have concluded that many could find pain relief in a sugar pill.

That conclusion is based on a lengthy but small study of 63 patients with chronic back pain.  Twenty patients were given no treatment, while the rest were given a placebo – a sugar pill that they were told was pain medication. No one was given an actual painkiller.

Over the course of 8 weeks, participants tracked their pain on a smartphone app, MRI brain images were taken, and psychological profiles of each patient were made.

The study, published in the journal Nature Communications, found that about half the patients who took the placebo had a 30 percent reduction in pain, a level considered just as effective as a real painkiller.

Researchers said patients who responded to the sugar pills had a similar brain anatomy and psychological traits. The right side of their emotional brain was larger than the left, and they had a larger sensory area than people who did not respond to the placebo. The placebo responders also were more emotionally self-aware, sensitive to painful situations and mindful of their environment.

“This is the first brain imaging RCT (randomized controlled trial) specifically designed to study chronic pain patients receiving placebo pills compared to a no treatment arm,” said senior study author A. Vania Apkarian, PhD, a professor of physiology at Northwestern University Feinberg School of Medicine.  

“Daily pain ratings from a smart phone revealed that patients receiving placebo pills showed stronger pain reduction and a higher response rate compared to patients in the no treatment arm, indicating that placebo pills successfully induced analgesia that could not be explained by the natural history of the patient or the mere exposure to the study.”

Doctors ‘Should Seriously Consider’ Placebos

Although his study is small and needs to be replicated, Apkarian thinks doctors should put his findings to work.

"Clinicians who are treating chronic pain patients should seriously consider that some will get as good a response to a sugar pill as any other drug," he said. "They should use it and see the outcome. This opens up a whole new field."

Giving pain patients sugar pills would not only save healthcare costs, Apkarian says they would eliminate the risk of addiction and other side-effects from pharmaceutical drugs.

"It's much better to give someone a non-active drug rather than an active drug and get the same result," Apkarian said. "Most pharmacological treatments have long-term adverse effects or addictive properties. Placebo becomes as good an option for treatment as any drug we have on the market."

The medical community has long known about the potency of the placebo effect and put it to use. Doctors as far back as the late 18th century used placebo treatments “more to please than benefit the patient.”

Today, the gold standard of clinical trials is a “placebo-controlled study” in which some participants are given sugar pills and sham treatments. The medication or therapy being studied has to be found more effective than the placebo for the study to be considered a success.

Time magazine recently published a cover story on placebos, sharing the stories of real patients who find relief in placebo pills even though they know they’re fake.

You don’t need to enroll in a clinical study to take placebos. You can buy a bottle of Zeebo’s “honest placebo pills” for $14.95 on Amazon. Some of the reviews for Zeebo are hilarious.

“I have not bought this product, but just reading about it brightened my day. And the comfort of knowing that if I ever needed a good placebo, its right here available with free shipping and two day delivery. I feel better already!” said one reviewer.

“The pills do every thing promised, which is nothing,” wrote another reviewer. “I purchased them in the forlorn hope that they would fool my demented wife that they helped to relieve her chronic pain. I didn't expect much going in and I wasn't disappointed.”

Study: Some Brains ‘Hardwired’ for Chronic Pain

By Pat Anson, Editor

Why do some people develop chronic pain from an injury or illness, while others do not?

The answer to that question may really be all in our heads.

A groundbreaking study by scientists at Northwestern University and the Rehabilitation Institute of Chicago (RIC) found that some people are genetically predisposed to chronic pain because of brain “abnormalities” that raise their risk of developing chronic pain. The findings challenge long-standing views on the science of pain, which emphasize treating pain at the site of the initial injury.

"While simple, the logic of addressing problems at the site of an injury to remove pain has resulted in only limited success," said senior study author Marwan Baliki, PhD, a research scientist at RIC and an assistant professor of physical medicine and rehabilitation at Northwestern University Feinberg School of Medicine.

"The central processes of chronic pain have largely been ignored, so our research team set out to better understand the brain's role."

Baliki and his colleagues conducted the first longitudinal brain imaging study, which tracked 159 patients for three years following an acute back injury, along with 29 healthy control subjects.  

MRI brain scans were conducted on all of the participants five times during the course of the study.

The researchers found that patients who developed chronic pain from their back injury had a smaller hippocampus and amygdala compared to those who recovered from the injury and the healthy control subjects.

The hippocampus is the primary brain region involved in memory formation and retention, while the amygdala is involved in the processing of emotions and fear. In addition to size variations, these brain regions also showed differences in connections to the rest of the brain, particularly to the frontal cortex, an area involved in judgment.

Together, the researchers estimate that these brain differences accounted for about 60% of the chronic pain felt by participants.

Most importantly, the study also revealed that the volumes of the amygdala and hippocampus did not change over the course of the study, suggesting that those who developed chronic pain were genetically predisposed to it.  

"Here we establish that the gross anatomical properties of the corticolimbic brain, not the initial back pain, determine most of the risk for developing chronic pain," said first author Etienne Vachon-Presseau, PhD, a visiting postdoctoral fellow in physiology at Feinberg.

“As the anatomical risk factors were stable across 3 years, they were presumably hardwired and present prior to the event initiating back pain. These results pave the way for the development of novel and distinct approaches to prevention and treatment of chronic pain.”

The Northwestern and RIC study will be published in the June edition of the journal Brain.

Researchers Say Chronic Pain Rewires Brain

By Pat Anson, Editor

Researchers at Northwestern University say a brain region that controls whether we feel happy or sad is rewired by chronic pain.

Their research on laboratory rats, published in the journal Nature Neuroscience, may have also uncovered a new treatment strategy that restores the brain and dramatically lessens pain.

'It was surprising to us that chronic pain actually rewires the part of the brain controlling whether you feel happy or sad," said corresponding author D. James Surmeier, chair of physiology at Northwestern University Feinberg School of Medicine. "By understanding what was causing these changes, we were able to design a corrective therapy that worked remarkably well in the models. The question now is whether it will work in humans."

The new treatment combines a Parkinson's drug, L-dopa, and a non-steroidal anti-inflammatory drug (NSAID), both of which are FDA approved. The combined drugs target brain circuits in the nucleus accumbens and completely eliminated chronic pain behavior when administered to rodents. The key is administering the drugs together and soon after an injury.

The scientists hope to begin a clinical trial on humans to further test their theory.

"The study shows you can think of chronic pain as the brain getting addicted to pain," said A. Vania Apkarian, a professor of physiology at Feinberg. "The brain circuit that has to do with addiction has gotten involved in the pain process itself."

The researchers found that a group of neurons thought to be responsible for negative emotions became hyper-excitable within days after an injury that triggers chronic pain. This change was triggered by a drop in dopamine, a neurotransmitter.

"These results establish chronic pain cannot be viewed as a purely sensory phenomenon but instead is closely related to emotions," Apkarian said.

When scientists gave the rats the NSAID and L-dopa, which raises dopamine levels, the changes in the brain were reversed and the animals' chronic pain behavior stopped. That suggests supplementing anti-inflammatories with a medication that activates dopamine receptors or raises dopamine levels might be an effective way of treating chronic pain or preventing the transition from acute to chronic pain.

Scientists also treated the rats with another Parkinson's drug, pramipexole, which activates dopamine receptors and mimics dopamine's effect. That drug also decreased the animals' pain-like behavior.

"It is remarkable that by changing the activity of a single cell type in an emotional area of the brain, we can prevent the pain behavior," said Marco Martina, an associate professor of physiology at Feinberg.

In addition to Parkinson’s, L-Dopa is used to combat anxiety and depression, and to improve the ability to concentrate and focus. L-Dopa is sold under the brand names Levodopa, Sinemet, Madopar, Stalevo, and Prolopa.

A recent study by British researchers also found that brain chemistry is changed by chronic pain.

Researchers at the University of Manchester used PET scans to measure the spread of opioid receptors in the brains of 17 arthritis sufferers and nine healthy control subjects. The number of opioid receptors was highest in the arthritis sufferers, suggesting their brain chemistry had changed and made them more resilient to pain. That could explain why some people are better able to cope with pain than others.

The University of Manchester study is being published in Pain, the official journal of the International Association of the Study of Pain.