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.”

Tiny Experimental Implant Could Treat Neuropathic Pain

By Pat Anson, PNN Editor

A tiny wireless implant that stimulates peripheral nerves from within blood vessels shows potential as a treatment for neuropathic pain, according to a proof-of-concept study by a team of Texas researchers published in the journal Nature Biomedical Engineering.

The implants have only been tested in laboratory animals, but researchers say they could replace larger and more invasive devices currently used to treat Parkinson’s disease, epilepsy, chronic pain, hearing loss and paralysis.

The MagnetoElectric Bio ImplanT -- ME-BIT for short -- is slightly larger than a grain of rice. It’s designed to be placed in a blood vessel near the nerve targeted for stimulation. The implant requires no surgery or batteries, and draws its power and programming from an electromagnetic transmitter worn outside the body.

“Because the devices are so small, we can use blood vessels as a highway system to reach targets that are difficult to get to with traditional surgery,” said lead author Jacob Robinson, PhD, Associate Professor of Electrical and Computer Engineering at Rice University.

RICE UNIVERSITY

“We’re delivering them using the same catheters you would use for an endovascular procedure, but we would leave the device outside the vessel and place a guidewire into the bloodstream as the stimulating electrode, which could be held in place with a stent.”

The ability to power the implant remotely eliminates the need for electrical leads through the skin and other tissues. Leads used for devices like pacemakers can cause inflammation and sometimes need to be replaced. Battery-powered implants may also require additional surgery to replace the batteries.

Researchers say ME-BIT’s wearable charger could even be misaligned by several inches and still provide sufficient power and programming to the implant, without irritating surrounding tissues.

“We’re getting more and more data showing that neuromodulation, or technology that acts directly upon nerves, is effective for a huge range of disorders – depression, migraine, Parkinson’s disease, epilepsy, dementia, etc. – but there’s a barrier to using these techniques because of the risks associated with doing surgery to implant the device, such as the risk of infection,” said co-author Sunil Sheth, MD, Associate Professor of Neurology and director of the Vascular Neurology Program for McGovern Medical School at UTHealth Houston.

“If you can lower that bar and dramatically reduce those risks by using a wireless, endovascular method, there are a lot of people who could benefit from neuromodulation.”

Electrical stimulation can reduce pain when doctors target the spinal cord and dorsal root ganglia (DRG), a bundle of nerves that carry sensory information to the spinal cord. But existing DRG stimulators require invasive surgery to implant a battery pack and pulse generator.

By using blood vessels, researchers say they can place the ME-BIT implant strategically in a minimally invasive way and have more predictable outcomes.

“One of the nice things is that all the nerves in our bodies require oxygen and nutrients, so that means there’s a blood vessel within a few hundred microns of all the nerves,” Robinson explained. “With a combination of imaging and anatomy, we can be pretty confident about where we place the electrodes.

In a previous study, Robinson and his colleagues demonstrated the viability of the implants by placing them beneath the skin of laboratory rodents that were fully awake and free to roam about their enclosures. The rodents preferred to be in parts of the enclosures where a magnetic field activated the implant, which provided a small voltage to the reward center of their brains.

Researchers need to conduct more animal studies and eventually human trials before seeking FDA approval for the implants.

“We’re doing some longer-term studies to ensure this approach is safe and that the device can stay in the body for a long time without causing problems,” said Sheth, who estimates the process will take a few years.

Tiny Implant Could Revolutionize Stimulators

Pat Anson, PNN Editor

Engineers at Rice University have created a tiny implant – about the size of a grain of rice -- that can electrically stimulate the brain and central nervous system without using a battery or wired power supply.

The magnetically powered implant generates the same kind of high-frequency signals as much larger battery-powered stimulators used to treat chronic pain, epilepsy, Parkinson's disease and other medical conditions. It could be implanted almost anywhere in the body in a minimally invasive procedure.

Researchers demonstrated the viability of the implants by placing them beneath the skin of laboratory rodents that were fully awake and free to roam about their enclosures. The rodents preferred to be in portions of the enclosures where a magnetic field activated the stimulator, which provided a small voltage to the reward center of their brains.

"Doing that proof-of-principle demonstration is really important, because it's a huge technological leap to go from a benchtop demonstration to something that might be actually useful for treating people," said Jacob Robinson, PhD, a member of the Rice Neuroengineering Initiative and corresponding author of a study published in the journal Neuron.

"Our results suggest that using magnetoelectric materials for wireless power delivery is more than a novel idea. These materials are excellent candidates for clinical-grade, wireless bioelectronics."

The implant has a thin film of magnetoelectric material that converts magnetic energy into electricity. Lead author Amanda Singer created the film by joining together two layers of very different materials.

The first layer, a magnetostrictive foil of iron, boron, silicon and carbon, vibrates at a molecular level when it's placed in a magnetic field. The second layer, a piezoelectric crystal, converts mechanical stress directly into an electric voltage.

This method avoids the drawbacks of radio waves, ultrasound, light and other wireless methods to power stimulators, which can interfere with living tissue or produce harmful amounts of heat.

RICE UNIVERSITY

"The magnetic field generates stress in the magnetostrictive material," Singer explained. "It doesn't make the material get visibly bigger and smaller, but it generates acoustic waves and some of those are at a resonant frequency that creates a particular mode we use called an acoustic resonant mode."

Acoustic resonance in magnetostrictive materials is what causes large electrical transformers to audibly hum.

"A major piece of engineering that Amanda solved was creating the circuitry to modulate that activity at a lower frequency that the cells would respond to," Robinson said. "It's similar to the way AM radio works. You have these very high-frequency waves, but they're modulated at a low frequency that you can hear."

Tiny implants capable of modulating the brain and central nervous system could have wide-ranging implications. They could replace battery-powered implants used to treat epilepsy and reduce tremors in patients with Parkinson's disease. Neural stimulation could also be useful for treating depression, obsessive-compulsive disorders and chronic intractable pain.

Singer said creating a signal that could stimulate neurons without harming them was a challenge, as was miniaturization.

"When we first submitted this paper, we didn't have the miniature implanted version," she said. "When we got the reviews back after that first submission, the comments were like, 'OK, you say you can make it small. So, make it small.’

"So, we spent another a year or so making it small and showing that it really works. That was probably the biggest hurdle. Making small devices that worked was difficult, at first."

In all, the study took more than five years to complete, largely because Singer had to make virtually everything from scratch.

How Far Will You Go for Pain Relief?

By Carol Levy, Columnist

In 1991, my surgeon ran out of options on how to help me. I’d had most of the procedures available for trigeminal neuralgia. Even the ones that helped were always short lived.

In a last ditch effort, he tried a dorsal column stimulator implant. It was successful in stopping about 85 percent of my pain. I was still disabled by severe eye pain, but I no longer had the spontaneous pain that could be caused by a simple touch.

Unfortunately, I lost the implant to an infection. A second implant did not help at all and also became infected.

The doctor told me there was nothing else he could do. There was so much scar tissue in my neck, where both implants had been placed, that surgically implanting another stimulator was impossible.

I was inconsolable. This was it.

No medications were helping and I dreaded a new neurosurgical attempt. But how could I refuse, if it might relieve the pain? Pain is different than most other symptoms. We are biologically ordained to do almost anything we can to be free of it.

The doctor understood this. To my astonishment, he had not given up. One day he came to me and said, “I have an idea.” It would be another implant, in the sensory cortex area of my brain,

The surgery would be 100% experimental. Only 12 other people in the world had it. Most of those were for pain in a different area of the brain than trigeminal neuralgia.

But I was in pain. Daunting, intolerable and disabling pain. Of course I said, “Yes.”

Recovering from the surgery was horrendous. I was anesthetized, but repeatedly awakened so they could ask, “Where is the pain? Where is it now?”

Over and over again; awake, torture, sleep, awake, torture, sleep. Finally, there was blessed sleep only.

I was not convinced the implant helped, until it failed 20 years later. Then I realized it had slightly reduced the level of my phantom pain. Not much, but enough that once it stopped working, the pain increased.  It did nothing for the eye pain, but any relief is to be celebrated.

I thought the doctor who took over my surgeon’s practice could fix it, but that was not feasible. The implant was so old the replacement parts were no longer available.

In two weeks he will take the implant out so that I can get an MRI, to see if there is anything else he can do to try and help me (I cannot have an MRI because of the implant).

The funny thing is I’ve asked him, more than once: “Can't you use the newer version and just put the implant back?”  

The answer is always no.

It didn’t occur to me that I was asking him to put me through the torture of the procedure all over again.  Worse still, once I realized repeating the surgery meant repeating the torture, I still found myself entertaining the thought: Maybe I could tolerate it if he would do it.

I cannot imagine putting myself through that horror again - when I think about it sensibly. But, when I think about it from a pain standpoint and how I may get some relief, it seems like a sensible idea.

Thankfully, he's refused so the debate within myself is purely hypothetical. I wonder though, what exactly will we do or entertain if it offers the possibility of ending the pain? How far are we willing we go?

That, in its own way, may be as petrifying as the pain itself.

Carol Jay Levy has lived with trigeminal neuralgia, a chronic facial pain disorder, for over 30 years. She is the author of “A Pained Life, A Chronic Pain Journey.” 

Carol is the moderator of the Facebook support group “Women in Pain Awareness.” Her blog “The Pained Life” can be found here.

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

Magnetic Implant Could Someday Deliver Medication

By Pat Anson, Editor

Over the years scientists have developed a variety of drug delivery systems designed to help patients take medications more safely – from pumps to implants to pills made with abuse-deterrent formulas.

Researchers at the University of British Columbia have now developed one of the strangest ones yet -- a magnetic drug implant -- that could offer an alternative for pain patients who don’t like pills or injections and fear the idea of having a pain pump installed.

“This could one day be used for administering painkillers, hormones, chemotherapy drugs and other treatments for a wide range of health conditions. In the next few years we hope to be able to test it for long-term use and for viability in living models,” said Mu Chiao, PhD, a professor of mechanical engineering at UBC.

COURTESY UBC

The magnetic device – a silicone sponge with magnetic carbonyl iron particles wrapped in a polymer layer – is just six millimetres (about a quarter of an inch) in diameter. The drug is injected into the device and then surgically implanted in the area being treated.

Researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. They found that it was able to deliver the drug on demand even after repeated use. The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, proving that drugs stored in the device remain effective.

Passing a magnet over the patient’s skin activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue.

The University of British Columbia released this short video to show how it works:

“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths. Many other implants lack that feature,” said Ali Shademani, a PhD student in the biomedical engineering program at UBC, who was lead author of a study published in the journal Advanced Functional Materials.

Implants such as Probuphine – which was approved last year by the Food and Drug Administration to treat opioid addiction -- cannot be adjusted to deliver different medication levels once they are implanted.

The UBC researchers say actively controlling drug delivery is important not only for treating pain, but for conditions like diabetes, where the required dose and timing of insulin varies from patient to patient.

“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” said co-author John Jackson, a research scientist in UBC’s faculty of pharmaceutical sciences.

Opioid Implant Raises Safety Questions

(Editor’s Note: Our story about an opioid implant that could someday be used to treat chronic pain struck a nerve with a lot of readers. One of them was Mary Maston, a pain sufferer and  patient advocate, who wrote in expressing concern about the safety and risks associated with implants and other medical devices.)

By Mary Maston, Guest Columnist

Why is everything going to implants? Implants seem to have an initial success rate and I can't argue with the fact that they do work for some, but it seems that class action lawsuits for side effects and internal injuries invariably come about down the line.

Transvaginal mesh was touted as the "next big thing." I had a doctor try to convince me that it would solve all of my female problems. Luckily, I didn't bite. We all know how that ended up.

Bladder slings come to mind too. Some IUD’s have caused issues. People have had major problems with hip and knee replacements. Spinal cord stimulators are being pushed on patients in record numbers, and the bomb is eventually going to drop on those too.

While there are success stories, there are some pretty horrific stories floating around online about implanted devices in general. Some will argue collateral damage: "Just think of the ones they've helped. The many outweigh the few.”

But I can promise you that the ones that have been harmed by these implants see things much differently.

Here's the thing: anything implanted in the body is going to be seen as a foreign object. What does the body tend to do when there's a foreign object inside it? It attacks it, trying to force it out. That's why your eyes water when you get something in them, that's why you vomit when you ingest something that's harmful, and that's why you go to the bathroom -- so the body can rid itself of waste.

When it can’t force the implants out, the body rebels with side effects, infections and pain. The surgeries required to implant these things damage nerves and create scar tissue, which also contribute to pain.

courtesy titan pharmaceuticals

If they're planning on this new implant being simply injected into the arm instead of being surgically implanted, that's going to have to be one heck of a big needle! The size of a match stick? Ouch!!

Then there is the issue of tolerance. Pain medication is not a "one size fits all" fix like the makers of this implant are implying. It comes with a preloaded dose of buprenorphine. How can they guarantee that the dosage they put in it is going to work for the majority of the people it's implanted in? 

What if it stops working in a month or two, or doesn't work at all? Do they have that one taken out and another one put in, or is the old one left in and a new one with a stronger dose implanted?

Will the patient be able to go back to taking oral pain medication? What if it causes side effects in the patient after a few days or weeks that they can't handle, or they end up being allergic to the medicine? How long would they have to live with those issues before it is removed?

Some people metabolize medications faster than others, so saying that it's going to work for a full six months for the implant or an entire month for the injection in everyone isn't practical. What about breakthrough pain? If someone had the implant, but showed up in the ER in pain because of their condition, would they be treated respectfully and in a timely manner, or dismissed because they had the implant and "that should take care of all of your pain."

There needs to be a very specific and compassionate treatment protocol set up for patients before this scenario happens, and all doctors need to be required to follow it.

I can understand and appreciate some of the pros listed in the article. Not having to make trips to the pharmacy, not having to remember to take pills and waiting for them to kick in to feel better. Possibly and hopefully not having to go to the doctor every month and being subjected to random drug screens and pill counts.

Doctors would certainly benefit because they wouldn't be prescribing pain medications nearly as much or maybe not at all. That would definitely get them off the hook with the DEA and I can see how that would make them want to push it onto all of their patients.

I understand that addiction and chronic pain go hand in hand for some people. Not all, but some. But as a chronic pain patient, I don't want to be lumped into the same category as addicts, because I am not an addict, never have been and never will be.

This raises serious questions that I think should be considered before we shout to the heavens how wonderful this new implant is going to be for addicts and legitimate chronic pain patients alike.

I understand there is still a lot of work to be done, and that it's going to take time and testing to answer a lot of these questions. Oral medications certainly have their own set of problems and aren't without risks either. However, history tells us that jumping on a bandwagon isn't necessarily a good thing down the road in a lot of cases.

I'm not saying that the thought of being pain free for an extended amount of time isn't appealing. Honestly, I would probably be more apt to try this than a spinal cord stimulator. But I hope that the manufacturers and the FDA will address the questions I've posed. I guarantee you I'm not the only one that will ask them.

Mary Maston suffers from a rare congenital kidney disease called Medullary Sponge Kidney (MSK), along with Renal Tubular Acidosis (RTA) and chronic cystitis. She is an advocate for MSK and other chronic pain patients, and helps administer a Facebook support group for MSK patients.

Mary has contributed articles to various online media, including Kidney Stoners, and is an affiliate member of PROMPT (Professionals for Rational Opioid Monitoring & Pharmaco-Therapy).

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

Implant Could Be ‘Game Changer’ in Pain Treatment

By Pat Anson, Editor

Imagine going to your doctor’s office and getting an implant put in your arm that delivers a steady flow of pain medication for six months.

No more pills. No more trips to the pharmacy. No more worries about your pain medication getting lost or stolen.

That’s the scenario a New Jersey drug maker envisions for its Probuphine implant – tiny rods about the size of a matchstick designed to be inserted subcutaneously under the skin of the upper arm.

Probuphine was developed by Braeburn Pharmaceuticals under a license agreement with Titan Pharmaceuticals (OTC: TTNP), which holds the rights to the implant technology. Both companies have applied to the Food and Drug Administration to have Probuphine approved to treat opioid addiction, but Braeburn’s long term goal is to also have the implant approved for chronic pain.

COURTESY TITAN PHARMACEUTICALS

“We are definitely interested in talking to the FDA about the use of Probuphine in pain,” said Behshad Sheldon, President and CEO of Braeburn.

The active ingredient in Probuphine is buprenorphine, a weaker opioid that’s long been used as an addiction treatment drug sold under the brand name Suboxone. Buprenorphine is also used to treat chronic pain and comes in various forms – pills, patches and film strips – but none as long-acting as an implant.

The advantages of an implant are many. The dosage is controlled and there’s hardly any risk of abuse, diversion, or accidental overdose. You also never have to remember to take a pill.

“We believe a buprenorphine implant could be a really great clinical tool to treat pain,” Sheldon told Pain News Network. “There’s just a peace of mind aspect for the patients. The medicine’s on board and they don’t have to worry about it.”

“I personally would want a Lipitor implant, because I can’t manage to take it three days in a row,” she joked.

Probuphine’s path to the marketplace hasn’t been a smooth one. Braeburn and Titan were stunned in 2013 when the FDA denied approval of the implant and asked for a new clinical study of Probuphine’s effectiveness in treating opioid addiction.

Braeburn recently reported the results of a six month, double-blind clinical trial of Probuphine on 177 patients, which found that the implant was more effective than buprenorphine tablets in treating addiction. The company said the implant insertion and removal were "generally well tolerated," although nearly one in four patients had a "mild" adverse event at the implant site.

“The data from this trial are encouraging and underscore the benefit of longer term medical treatments for patients with opioid addiction. I am confident that the implant, if approved by FDA, will be at least as effective as a sublingual formulation and have the added benefits of reducing problems related to compliance, misuse and abuse,"  said Richard Rosenthal, MD, Professor of Psychiatry and Medical Director of Addiction Psychiatry at the Icahn School of Medicine at Mount Sinai.

Braeburn and Titan plan to resubmit a New Drug Application (NDA) for Probuphine to the FDA in the second half of this year.

Long Term Injection for Pain

Braeburn has formed another partnership with Camurus, a Swedish drug company, to develop an injectable buprenorphine drug to treat addiction and chronic pain -- a single injection that lasts as long as a month. Camurus has already completed successful Phase I and II studies on the drug and both companies hope to start a Phase III trial later this year -- with the goal of seeking regulatory approval in 2016.

“There have been many conversations with expert clinicians and they’ve told us that they think buprenorphine in general, in a non or less abuse-able form of buprenorphine, in either an implant or an injection could really be game changing,” said Sheldon. “It is part of our plan to move into pain because pain and opioid addiction are so interconnected and we think there are ways, by treating patients with a less abuse-able formulation, you could actually help alleviate the addiction problem.”

Sheldon admits a lot more work needs to be done before a buprenorphine implant or injection is available to treat chronic pain.

“We haven’t studied it yet in pain and we haven’t had any conversations yet with the FDA. So there’s a lot more to do to get to that point,” she said.

Another formulation of buprenorphine to treat pain may be coming to the market relatively soon. Endo International (NASDAQ: ENDP) and BioDelivery Sciences (NASDAQ: BDSI) have submitted a new drug application for a buprenorphine film patch to the FDA. The companies are hoping for FDA approval by October of this year.

Although the patch contains much smaller doses than buprenorphine tablets or patches already on the market, the companies say the film is very effective in treating pain because the drug is absorbed through the inside lining of the cheek and enters the blood stream faster.