Neuromodulation: Is it the solution to everything?/ by sylvia kronstadt
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|Fri, 09-13-2013 - 9:14am|
Everything in Modulation
Don't worry. Be happy☺.
In a recent post, I documented the desperate -- even ruthless -- effort to gain acceptance of vagus nerve stimulation for the treatment of depression. The medical-device industry is investing millions in order to reap billions in the burgeoning field of neuromodulation. But if you're not depressed: "Don't worry. Be happy!" Before long, they'll be peddling something that may change your life, too. Your brain is their playground.
If you have any of these conditions (among others), just be patient. The finest minds in science are at work as we speak: Anxiety, sleep apnea, depression, Alzheimer’s, epilepsy, Tourette's syndrome, addiction, "phantom pain," obsessive-compulsive disorder, tremor, Parkinson's and other movement disorders, obesity, tinnitus, incontinence, fibromyalgia, hearing loss, bladder dysfunction, migraine, IBS, asthma, eating disorders, chronic pain, heart disease, systemic inflammation, and autoimmune diseases, including rheumatoid arthritis. They will also perk up your memory and cognition. All you'll feel is a little tingle.
But the more you know about the industry, the more uneasy you'll feel about them messing with your mind.
My participation in Cyberonics' clinical trial for vagus nerve stimulation (VNS) gave me a rather too up-close-and-personal glimpse into how this frenetically competitive new industry is gearing up to be The Next Big Thing, in the health-care system and among profit-hungry investors (http://kronstantinople.blogspot.com/2013/09/what-happens-in-my-vagus-stays-in-my.html).
Even so, I decided to write about neuromodulation because I had become intrigued by its extraordinary potential to improve the quality of life for people around the world. I felt hopeful.
Silly me! I can't believe how readily I was taken in by the beautiful pictures and prose that the medical device industry is using to entice patients.They portray sleek, futuristic technologies that infuse our neurons with sparkly, radiant relief from our physical and mental dysfunctions.
What began as a heartwarming tale of human genius laboring humbly for the betterment of mankind quickly devolved into the usual scenario: When money and ambition are involved, scandal ensues.
To make matters worse, our neurological systems -- including our brains -- are the unfortunate raw material of this industry, which really doesn't know what it's doing. Researchers are barely beginning to understand what happens when one site or another is electrically stimulated. Will they cure your incontinence, or make you fall down, or cause you to acquire a British accent? Or all three? If they are attempting to normalize your appetite or elevate your mood, couldn't they electrocute your creativity or kill a skill? If they are trying to elicit your bonding instincts, could they accidentally unleash aggression or turn you into an alcoholic? Could they change your sex drive, or even your sexual orientation? In an effort to erase your traumatic memories, what else might they erase? Could all this experimental tinkering and mucking about in the delicate, mysterious realm of our neurological infrastructures leave us wondering who we truly are? Do we have a fundamental Self that the mad scientists can't take away from us -- or not?
It's a crap shoot. And those who are in enough distress to serve as study subjects for unproven technologies are the crap.
Billions of dollars are at stake. Patients are used, in some cases damaged or defrauded, and then left to fend for themselves.
And that's how a saga of hope and dreams turned into investigative reporting, with a side dish of disgust. Fasten your seatbelts.
THE ELECTRA COMPLEX
For generations, physicians have been "intrigued by the possibility of harvesting the power of electrical impulses in the human body for therapeutic benefit," according to the International Neuromodulation Society website. I was surprised to learn that the "modern" era of neuromodulation began (albeit in a rather primitive way) in the early 1960s, with the use of deep brain stimulation (DBS) to resolve chronic and intractable pain, and evolved to include spinal cord stimulation by the end of the decade.
Which begs the question: After all these years, why are they still screwing up so badly?
In a companion article, I will describe the financial, regulatory and ethical aspects of this wild and crazy industry, which has potential applications for virtually every physical and psychological ailment, and is thus expected to see explosive growth in coming decades. In this post, I'll examine some of the products that it is developing.
BABY'S GOT BACK, BUT THE PAIN IS AN AFFRONT
One of the most highly touted and desperately needed neuromodulation therapies is spinal cord stimulation (SCS), a pacemaker-like device which inserts stimulating electrodes into the epidural area, between the vertebrae, to block pain signals from reaching the brain. Because it claims to treat low back pain, and pain down the legs, it sounds particularly appealing to me, because I have two herniated lumbar discs and bilateral sciatica. I hurt all the time. Just looking at the pictures of this device, radiating its soothing pulses, makes me long to get one.
Since the millions of people who suffer from chronic back pain rarely do the research required to access clinical-trial data, they are readily seduced by device-makers' ravishing sales pitches. I will review the sweeping claims made by these companies a bit farther down, but first I will share some patients' perspectives.
the expensive and risky step of having a stimulator implanted in their spines, and it backfired.
The activists among them urge an uprising of SCS victims, instructing them to report their experiences to the FDA's MedWatch site, in the hope that approval will be revoked and others won't have to endure the disappointment and anguish that they have.
I scrutinized this site but was unable to find any FDA web page that lists the complaints -- so that prospective implant patients could be informed about what kind of problems they might experience -- and there was no indication how many complaints had been received or whether/when any action would be taken. Knowing the FDA, I assume no one has even read the complaints, much less acted on them.
A number of them have had infections, rejection of the device by the body, and autoimmune reactions. Some have lost bladder control while adjusting the intensity of the stimulation or have had their legs give way as they were walking. One woman, who maintains a blog about her SCS journey, said she never expected to get more than a 30-40 percent reduction in pain relief, and that's as good as its gotten. She still takes medication and gets acupuncture treatments for her back pain. Some patients still have to use a morphine pain pump, even after SCS surgery. A registered nurse wrote, "I had the permanent spinal stimulator implant inserted in August of 2010. It has never worked right and I am now being scheduled to have it removed." She's not the only one: Many patients are seeking funds to have the device removed.
"This has been my worst nightmare," one young man wrote. "I hoped I could return to athletics if my back got better, and now I can hardly even move my legs."
A more detailed list of unintended effects appears at the bottom of this post.
The most common complaint is that SCS simply does not relieve lower back pain, despite the exhilarating promises that were made. People who had been so hopeful are devastated.
HEY JUDE: DON'T MAKE IT BAD
("And anytime you feel the pain, hey Jude, refrain!)
St. Jude Medical claims that its Medical Neuromodulation Division has developed new technologies to manage chronic pain and other neurological disorders for more than 30 years.
Given the saga of its ill-fated Eon Mini in 2008 -- among other disasters -- its use of the term "proven method" becomes worse than hyperbolic -- it's a bald-faced lie.
"Even with its small size, the Eon Mini has the longest-lasting battery life of any rechargeable spinal cord stimulation (SCS) device in its class. It is the only small rechargeable neurostimulator to receive a 10-year battery longevity approval by the FDA. For patients this means the device should provide sustainable therapy and maintain a reasonable recharge interval for 10 years of use at high settings."
Remember what all those message board people were saying about "sustainable therapy"?
Following a routine overview of the production facility in 2009, the FDA wrote, "Inspection revealed that these devices are adulterated within the meaning of section 501 (h) of the Act, 21 U.S.C. § 351 (h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements."
The letter continued: "...we encourage your company to contact our Recall Coordinator. While initiating Corrective and Preventive Actions (CAPAs) to correct the various quality issues, these CAPAs did not address the gaps in your company's design and production controls that caused the quality problems. The Agency is not satisfied with your response."
The letter goes on to demand that St. Jude address the violations, which it enumerates in detail.
(Soon, St. Jude would also be coping with massive recalls of its new-and-improved, FDA sanctioned heart-device leads, which were burning through their insulation.)
Regarding the spinal-stimulation debacle: As usual, St. Jude had set itself up with grandiose claims (pride goeth before the fall): "The Eon Mini design is based on the field-proven platform of the Eon® neurostimulator and almost three years of performance data and improvements to the device. It will be available in both the U.S. and Europe in the third quarter of 2008."
Before long, internal batteries were exploding, and leads were deteriorating.There were more stern FDA memos, which never seem to scare anyone very much. There were thousands of warning letters sent to patients. And then there were the recalls. And now there are the class-action lawsuits.
Poor St. Jude. What is wrong with those people? I sent them a list of very polite questions, but they ignored it.
Now, after its purported 30 years in this field, its website is eerily vague. It presents no actual products, but tries to lure you with the vague concept of SCS to eradicate your pain.
Having no device of its own to offer, this Giant in the Industry, "with some of the finest minds in science" on its payroll, came up with a clever "fix": Buy a company that knows (or seems to know) what it's doing.
In June of this year, St. Jude made a $40 million equity investment in Spinal Modulation, a company that has developed Axium, an "innovative neuromodulation therapy that provides a new pain management option for patients with chronic, intractable pain," a company press release revealed. (Ironically, Axium is funded in part by arch-rival Medtronic.)
"The agreement provides St. Jude Medical with an exclusive option to distribute the Axium™ Neurostimulator System, developed and manufactured by Spinal Modulation, in international markets where it is approved for sale. Additionally, St. Jude Medical will have the exclusive option to acquire the company for up to $300 million plus certain revenue-based milestones following U.S. commercialization."
The Axium Neurostimulator System delivers a form of spinal cord stimulation (SCS) targeting the dorsal root ganglion (DRG)."
"BACK" TO THE FUTURE: ANOTHER THRILLING FLOP
Medtronic, like the other major device makers, has had persistent problems with its products and with regulators. As I researched this article, I submitted an inquiry to the company, asking for clarification on a number of issues, including its efforts to improve and expand the uses for its neurostimulation and deep brain stimulation systems. The company declined to provide any information.
Since Medtronic developed neurostimulation therapy in partnership with physicians in the 1980s, nearly 250,000 people worldwide have received Medtronic neurostimulation therapy for the treatment of chronic, intractable pain, according to the company's promotional materials. No breakdown is provided on the type of therapy, the numbers by country, or the percentage of those who have continued to use these implanted devices, which prove to be ineffective in many patients and which lose effectiveness over time in others. Replacement costs, which are incurred every several years, can be prohibitive.
When Medtronic received FDA approval for its RestoreUltra spinal stimulation system in 2008, its clinical trials had produced results that would seem surprisingly weak, if one were not familiar with the flawed (to put it kindly) FDA process.
The Medtronic study compared SCS therapy plus conventional medical management to conventional medical management alone for treating chronic neuropathic back and leg pain. Investigators found that at six months, less than half of the 24 SCS patients had gotten a 50 percent or better pain relief in their legs. Back pain was characterized as "improved," and as a secondary benefit, without further elaboration.
This is a shocking outcome, which was ignored in the aggressive promotion of this product to doctors, and to patients whose primary complaint was chronic back pain. If this device significantly relieved back pain, that would have been reflected in the data.
The product's performance is so weak, it should not even have been approved to treat leg (sciatic) pain.
(A study published in the November 2012 issue of Neuromodulation -- and funded by a competitor, Nevro Corp. -- refers to this defect. The authors, who are promoting a new SCS device, write: "Despite advances in SCS technology.... pain relief for patients with predominant chronic back pain has been elusive, and patients with predominantly neuropathic leg pain are still widely accepted to be the best candidates for SCS." )
This observation is corroborated by numerous studies over the past decade at least, but SCS devices continue to be marketed as an effective treatment for chronic back pain, which is by far the larger market. As far as I'm concerned, this is fraud.
To make matters worse, 27 Medtronic SCS test subjects (32 percent) experienced device-related complications at the 12 months follow-up, the authors noted.
Does this success rate (and device failure rate) merit FDA approval? It appears the therapy is not very safe and not very effective. But Medtronic qualified for reimbursement from Medicare and Medicaid when the approval was secured, ensuring a handsome cash flow as thousands flocked to obtain pain relief.
And when the company flooded the media with the announcement of its FDA approval, it did not include the unimpressive statistical data from the clinical trial, which I accessed by seeking out the journal article in Pain. Medtronic also failed to mention that the study enrolled those suffering from "failed back surgery syndrome." It portrayed its product as "a treatment for chronic, intractable pain of the trunk, limbs or both."
Its web site reiterates the device's usefulness in providing "significant and sustained reduction in chronic pain," using the article above as footnoted documentation of this claim, when in fact the article does not corroborate that claim. The site also says the device is "proven safe and effective when used as directed," which is also contradicted by its own clinical trial.
Medtronic therapy, like other SCS systems, uses a medical device placed under a patient’s skin to deliver mild electrical impulses to the spinal cord to block pain signals from going to the brain.
"Instead of pain, patients feel a tingling sensation from the neurostimulation in areas where they previously experienced pain," Medtronics says. This tingling or prickling sensation is referred to as
paresthesia in the clinical literature. Some patients find it uncomfortable or even intolerable. I think I would like it.
The benefits of Medtronic's system, if the company were accurate, would be substantial:
· Reversible therapy that can be turned off or surgically removed
· Manual adjustability, giving patients the ability to adjust the therapy based on pain level
· AdaptiveStim Diary available with Medtronic’s AdaptiveStim with RestoreSensor, which provides objective data regarding patient activity and enables clinicians to use this data to assess, evaluate, and optimize a patient’s neurostimulation experience.
Medtronic refused to disclose how well the external device works relative to the implanted one, nor would they comment on why a patient who has responded to the external device fails to get relief from the implant. They also would not explain why they don't offer the external neurostimulator for sale.
(The study by Menlo Park-based Nevro, cited above, was for an SCS device that delivers continuous, high-frequency (10,000 Hz) stimulation rather than the "mild electrical impulses" used in its competitors' devices. Its clinical trial data claim far superior relief for back pain, and the new device does not cause the paresthesia that other SCS systems do.
"What's the frequency, Kenneth?" Dan Rather was asked. With Nevro's Senza system, it's high.
In the United States, the SENZA system is for investigational use only. A clinical trial is currently in progress, which is intended compare SENZA's effectiveness with that of SCS devices currently on the market, and to collect data to secure FDA approval. The estimated primary completion date for this trial is March 2014, according to ClinicalTrials.gov. In March of this year, Nevro raised $48 million in a Series C financing round in support of SENZA research and commercialization.
BOSTON SCIENTIFIC PUTS THE 'BS' IN SCS
Another of the Big Three players in the field of neuromodulation, Boston Scientific, announced in May of this year that it had received FDA approval for an even more complex device, the Precision Spectra Spinal Cord Stimulator (SCS) System, and was beginning a limited launch of the "World's First and Only System with Illumina 3D™ Software and 32 Contacts." It had obtained approval in Europe five months earlier.
Pain relief is just 32 electrical jolts away.
Today, more than 60,000 patients worldwide have been treated using Boston Scientific SCS systems, the company says.
The new device uses "a proprietary computer model that takes into account 3D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician simply selects a desired location on the spinal cord and the programming software creates a customized stimulation field to mask the patient’s pain," the company states.
So far, so good.
In a study cited to support the use of the technology, this conclusion was reached: "Precision SCS is a durable therapy and may provide pain relief for more than 50 percent of patients for a year or more."
This kind of cautionary information is not readily available to patients who are considering this major surgical and financial commitment. Would you get this implant if you were informed of the odds?
The study began with 65 patients and ended with four.
That is not a valid study.
In another study, enrolling those who had failed back surgeries, the results were "lower levels of leg pain" and "no difference in back pain."
Thousands of people with back pain have been sold on this device and had it implanted. Too bad for them.
Do our public servants who give the imprimatur of the federal government to these devices even read the journal articles about their performance?
The study cited above is titled: "The Effects of Spinal Cord Stimulation in Neuropathic Pain Are Sustained: A 24-month Follow-up." The implication is clear that the study refers to back pain, even though back pain was not relieved.
As if to add to the "Monty Python" ambiance of this process, the study acknowledged that 45 percent of patients experienced 34 device-related complications, and 31 percent required a device-related surgical revision.
Lacking this information, tens of thousands of patients continue to have SCS devices implanted.
In yet another study, less than a third of SCS patients reduced their intake of addictive opiate pain-killers, even though some had the device turned on constantly. Many implant patients have noted that the implant itself has only added to their existing pain, and that such mundane acts as shifting in their chairs or rolling over in bed elicits bursts of discomfort and even electrical shocks.
SCS TECHNOLOGY: THE POSTURE OF DEFEAT
The FDA has permitted the continued marketing, implantation and reimbursement for spinal cord stimulation devices, ignoring the overwhelming lack of evidence that they effectively treat chronic back pain in the vast majority of patients.
Despite the slick, handsomely designed and authoritatively worded promotional materials, the devices remain quite primitive. "The industry is still in its infancy," one researcher admitted.
Why don't they just admit that, instead of luring you into violating your body with a foreign object of dubious value?
Millions of dollars have been paid to install SCS technology in tens of thousands of patients, whose pain has severely diminished their quality of life and ability to work. Many of them have had one or more surgeries prior to the implant, and are still dysfunctional. Clinical depression is a common effect of this condition. Opioid usage of 250 mg. per day is typical among this population.
Back pain is the leading cause of disability for those under 45, according to the National Centers for Health Statistics.
So a lot of both well-established and little upstart medical device firms continue to tweak SCS technology in an attempt to corner the market.
GREATBATCH HATCHES ITS OWN SCS BABY
Greatbatch Inc. is in a different category. It has, up to now, not been a device maker, but rather has been a highly successful and respected supplier of critical components to the largest medical device companies in the world.
It just couldn't resist getting into the SCS game, though.
It announced in March 2013 that Algostim, its "innovative, internally developed SCS system" is nearing completion.
No photos or design illustrations are available. My request to Greatbatch for details about how Algostim differs from products already on the market wase ignored.
Device makers and market analysts were baffled that a firm which had already created a secure niche for itself would do an about-face and engage its customers in direct competition.
"Algostim is a highly differentiated, complete SCS system and platform with extensive offering of innovation, intellectual property, advanced safety features, and future generation capabilities to serve the fast growing $1.4 billion SCS market (which is growing at more than 10 percent a year," commented President Scott Drees.
Highly differentiated, how? One learns to look cynically at every bit of hype these people throw out there as bait to lure venture capital.
The device is nearing completion of development, the firm says, and will be moving into the commercialization phase. The company is looking for a partner to push the product into the end market, after Greatback has completed its design work, obtained FDA approval, and launched the manufacturing phase.
"We have many interested companies who would like to work with us to commercialize this," Hook told the Dallas Business Journal. "We are screening them for their ability to take a product like this and go into a market to paying physicians and sell it."
Was this a slip of the tongue, or a naive bit of honesty? Paying physicians to implant your device is not a new phenomenon, of course, but I have never seen a company admit it. It's illegal and unethical. There have been prosecutions and penalties.
CAN PERIPHERAL NERVES PUT SOME SPINE INTO SCS?
The failure of SCS technology to relieve chronic back pain is addressed forcefully in the September 2012 issue of Neuromodulation by three physician/researchers in Italy. They address what American clinical trials have already discovered (but hidden from public view): SCS has been highly unsatisfactory in relieving the most problematic back pain, which is in the lower, lumbar and sacral, regions.
In a study comparing the effectiveness of SCS to a combination of SCS and peripheral nerve field stimulation (PNfS), the combination therapy was so superior that those on SCS were switched over, to put them out of their misery.
PNfs involves an implant of electrical leads that are connected to a stimulator just under the skin (subcutaneous) of the lower back, rather than into the spine.
"Even with recent improvements (in American SCS devices) such as a self-regulating current, we found recruitment of the (difficult to reach) lumbar fibers still to be problematic," the authors found. "PNfS is an effective, simple way to recruit lumbar and sacral fibers directly from the painful region, by placing electrodes in the superficial subcutaneous layer to stimulate the nerve endings and dermal receptors."
"In the patients we treated with the combined SCS + PNfS system, there has been a drastic reduction in the lumbar pain compared with those treated with SCS only; this has led to a significant improvement in the quality of life, especially in the social activities (work, physical activity, and health), and to a reduction in drugs intake," the doctors reported.
Many patients discontinued their use of opioids altogether. Average use dropped by more than 90 percent.
Even with this combined therapy, patients cannot resume strenuous physical exertion, the doctors acknowledged. In some patients, the effect recedes over time, and medication use may need to be increased. Others can find continued relief if their devices are recalibrated.
Ever-ready to run after a more promising revenue source, Medtronic announced in April 2013 the first patient enrollments in a "pivotal" clinical trial to pursue FDA approval of a PNfS system for back pain. Christened SubQStim II, it involves an implant of electrical leads that are connected to a stimulator just under the skin of the lower back, as in the Italian study.
Industry media were skeptical. "Medical device company Medtronic continues to battle for its position in the market for neurostimulation systems by launching yet another study," Mass Device reported, a bit irritably. "The new study is the latest in a handful of neurostimulation trials launched by the medical device giant as it faces intense rivalry in the marketplace."
Medtronic posted a request at ClinicalTrials.gov for back patients just last month to enable additional study of its SubQStim II system.
OFF LABEL BUT ON TARGET
Dr. Eugene Lipov, a Chicago pain specialist and Director of Research, Alexian Brothers Hospital Network Pain Program, claims to have invented a hybrid neurostimulator -- SCS plus PNfS -- to treat back, leg and neck pain many years before the Italian study was conducted.
"This is an exciting evolution of (conventional SCS), which has been in clinical use for the last 20 years," he says. "Where the previous stimulator was placed in the spinal canal right behind the spinal chord, this is placed at the site of pain, making it very effective for lower back pain and rendering it essentially free of complications."
Despite the assertion that this approach has been successfully used for many years, it is classified as "investigational," not FDA approved, "and as such use in this context is 'off label'." The procedure costs $60,000.
He declined to answer questions about success rates, the number of patients treated, and complications.
Two eight-polar leads are implanted bilaterally above the gluteal region, over the painful site
EVERYTHING IN MODERATION -- EXCEPT FOR THE EXCESSES
The gross and ongoing flaws in the neuromodulation industry's products have cost Medicare, Medicaid and private insurers hundreds of millions of dollars. Just as they have done with pacemakers and defibrillators, the companies emerge into the media spotlight time after time to announce extraordinary technological breakthroughs. Before long, all hell breaks loose as these "exhaustively tested and proven devices" fail.
And then there are the lawsuits:
The Meyerson law firm in San Antonio, Texas, is representing clients who have been harmed by SCS implants. Currently, the major players in the market include Medtronic, with a market share of 61 percent, followed by St. Jude Medical and Boston Scientific, with market shares of 15.1 percent and 23.8 percent respectively, according to the firm.
Because of the doctrine of pre-emption (discussed earlier), which protects device makers from liability, the only active suit at this time is against St. Jude, because its products have been recalled.
Nevertheless, the law firm is compiling a database of SCS patients who have been harmed by the devices for possible action in the future.
"The failure of a stimulator to operate correctly has had many effects on our clients." attorney Jeff Meyerson says.. "At a minimum, defective devices expose clients to the very pain the devices are supposed to relieve."
In addition to increased pain, other symptoms clients have reported include:
- Severe irritation and burning at the battery site
- An inability to control the stimulator (resulting in unwelcome jolts, pain, or temporary paralysis)
- Severe burns while recharging the battery
- Premature battery depletion
- Bladder problems
- Increased numbness
- Lead migration and broken anchors
- Partial paralysis
"In the push to develop attractive products, these companies have produced stimulators that may not only fail to operate as promised, but can put patients in physical danger," the law firm's web site says. "In a letter dated July 17, 2012, the FDA issued a warning letter related to Medtronic's process for handling complaints and stated that regulatory action might ensue should the manufacturer fail to address the agency's request to take action. The FDA also issued a warning letter to St. Jude Medical, resulting in the company's announcement that there were were failures present within the internal batteries of their units. Patients who may have been implanted with defective stimulators are being notified individually by St. Jude Medical. Since the problem surfaced in 2011, over 300 heat-related complaints have been filed on behalf of carriers of defective units, and several lawsuits have been filed."
GOING DEEP -- A THERAPEUTIC PLUNGE INTO THE BRAIN
In my research on Alzheimer's disease, I have come across extraordinary accounts of deep brain stimulation (DBS) having the effect of uncovering long-lost memories. Electrodes placed in various spots on the brain elicit different memories. Variations in the intensity of the current can cause vivid details to be recalled by test subjects.
"Scientists in Canada have raised a tantalising prospect - reversing Alzheimer's disease, using DBS," according to the BBC. Brain shrinkage, declining function and memory loss had been thought to be irreversible. In two patients, the brain's memory hub reversed its expected decline and actually grew by 8 percent.
"How big a deal is 8 percent? It is huge. We’ve never seen the hippocampus grow in Alzheimer’s under any circumstance. It was an amazing finding for us," lead researcher Andres Lozano told the BBC.
THE BANE OF PAIN IS MAINLY IN YOUR BRAIN
Medtronic has developed a deep brain stimulation (DBS) system that "outsmarts your pain" and "embeds the capability of measuring brain disturbances into an implantable device," according to an August 28, 2013, article in Forbes magazine. Over 100,000 patients have been implanted with the Medronic DBS system, the company notes.
Who are these 100,000 people? What is their ailment? How satisfied are they? What complications have they experienced from the electrodes that are permanently implanted in their brains? Medtronic has no comment.
"Medtronic developed and leads the field of neuromodulation, the targeted and regulated delivery of electrical pulses and pharmaceuticals to specific sites in the nervous system," the firm's web site states. "Our neuromodulation business includes implantable neurostimulation and targeted drug delivery systems for the management of chronic pain, common movement disorders, spasticity and urologic and gastrointestinal disorders."
Who would have thought that such a fabulous system would be the subject of an "urgent" Class 1 recall by the FDA due to "potential lead damage"? According to Bloomberg News, this 2013 regulatory action means "there is a reasonable probability that the defect could cause serious health consequences or death."
In an article regarding the recall in the Minneapolis Star-Tribune, Justin Ihle, a Medtronic spokesman, "would not say how many patients have been implanted with Medtronic deep brain stimulation devices. Nor would he provide sales figures."
This kind of secrecy can only lead to more questions about Medtronic's integrity.
And since DBS has been marketed to so many patients for so many years, who would have thought that "the effect of the device on cognitive functions and its psychiatric side-effects are still controversial"? That is the characterization of a study funded by the German Federal Ministry of Education and Research.
An article in the Journal of the American Medical Association (JAMA) substantiates this observation. But how much is disclosed to patients who are considering this therapy for Parkinson's disease?
"Neurocognitive testing revealed decrements in some areas of information processing for patients receiving deep brain stimulation," the 2009 JAMA article reported. "(Moreover), at least one serious adverse event occurred in each of 49 deep brain stimulation patients, including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage."
The most common neurobehavioral adverse events included depression, confusional state, and anxiety, the researchers found. Some 41 percent of patients experienced cognitive problems and 8 percent experienced depression. There also were more falls in the deep brain stimulation group, often resulting in injuries (eg, fractures, dislocations, head trauma) requiring surgery or another intervention, the authors added.
It remains to be explored, they said, "whether patients who undergo deep brain stimulation view (their substantial) improvement in motor function and quality of life as outweighing adverse events."
Why does it remain to be explored? These devices have been implanted in tens of thousands of people with Parkinson's disease and other motor disorders, reaping huge profits. But the profiteers haven't seen fit to launch and publicize the results of studies about patient outcomes.
A 2006 study, funded in part by Medtronic and published in Neuropsychopharmacology concluded that DBS has
"encouraging" therapeutic effects in treating obsessive-compulsive disorder (OCD), but "a more definitive test of the efficacy and tolerability of DBS will require a larger controlled trial."
It seems that "definitive" testing should be performed before such a product is widely marketed, or even approved.
A planned study earlier this year -- to determine whether DBS can safely reduce symptoms of post-traumatic stress disorder (PTSD) in combat veterans was withdrawn after funding was denied by the Veterans Administration.
Recently, Medtronic announced the first human implants of a new DBS system, Activa PC+S.
"This system is the first to enable the sensing and recording of brain signals in some of the deepest areas in the brain while simultaneously providing targeted DBS therapy," according to Forbes contributing writer John Nosta.
"This experimental 'closed loop' system has the potential to enhance the current ability of DBS to treat various physiological and psychological conditions," Nosta writes.
Medtronics' system is FDA approved for movement disorders, such as Parkinson's disease. A Humanitarian Device Exemption been authorized for the treatment dystonia and severe, treatment-resistant obsessive-compulsive disorder, although DBS "has not been shown to be effective in the treatment of these disorders," the company's web site acknowledges.
UNPLANTING THE IMPLANTS
But implantable devices may eventually become obsolete, as tech firms work feverishly on external products that require no surgery or permanent commitment.
Cyberonics, whose invasive, problematic VNS system has undoubtedly deterred many potential customers -- has has seen the light, and has developed an alliance with CerboMed, a private company based in Erlangen, Germany. Its NEMOS t-VNS system, which includes an earplug-like device, is designed to stimulate a branch of the vagus nerve in the outer ear by sending a pulse through the skin.
CerboMed’s device has received clearance for marketing in Europe for patients with epilepsy, depression, and pain, but is not yet approved in the U.S. In September 2013, Cyberonics said it had made an initial investment of about $2.6 million in Cerbomed and gained an exclusive option to market the NEMOS device worldwide as an epilepsy treatment.
In a clinical trial in Germany, "Five of the seven patients who applied t-VNS for nine months showed a reduction in seizure frequency." This information is obviously not adequate to enable a prospective patient to make an informed decision. How much reduction? How severe was the disease in those studied?
The transcutaneous therapy is also being tested in migraine patients.
Cyberonics’ VNS system already dominates the market in devices for epilepsy. Some 100,000 people worldwide have received its relatively primitive and permanent implant. Think how they must feel, knowing that the wire that is gripping a nerve deep in their necks is unnecessary?
ANOTHER NONINVASIVE APPROACH FOR DEPRESSION, EPILEPSY
Another intriguing, nonsurgical option: Los Angeles-based NeuroSigma received EU certification last year for an external trigeminal nerve stimulation (eTNS) system for the adjunctive treatment of epilepsy and major depressive disorder for adults and children aged nine years and older, according to Medscape.
The device has been evaluated in clinical trials conducted at the University of California, Los Angeles (UCLA) and the University of Southern California. It consists of an external pulse generator and disposable electric patches placed on the forehead that are replaced daily and must be worn for 12 hours a day.
But in the clinical trials, the improvement rates "did not achieve significance," according to a 2013 Medscape article. Only 30 percent of patients responded to the treatment.
The study, the first randomized, active controlled trial of external trigeminal nerve stimulation in drug-resistant partial seizures, was published in the February 26 issue of Neurology. The lead investigator was the vice president of NeuroSigma.
Commenting on the results for Medscape Medical News, Gregory Bergey, MD, from Johns Hopkins Epilepsy Center, said, "These things need more study."
An accompaning editorial stated: "The beneficial effect demonstrated by DeGiorgio et al. was modest but is sufficient to encourage design of a more definitive study."
"As a non-invasive neuromodulation therapy, trigeminal nerve stimulation may represent a paradigm shift in the way we treat major depression and offers the potential to significantly improve the lives of millions of people without the side-effects common to medication treatment," said UCLA's Ian A. Cook, MD, who led clinical and human mechanism of action studies of the device in depression.
A TREATMENT WITH REAL MAGNETISM
Yet another contestant in this race to the pot of gold is Neuronetics' Neurostar mechanism, which uses a highly focused pulsed magnetic field, similar in type and strength to those produced by a magnetic resonance imaging (MRI) machine, to stimulate cortical neurons.
It sounds great! But they all do!
The therapy, which won the FDA nod in 2008, according to MassDevice.com, is a rarity in the med-tech world: A device-based approach to a psychiatric disorder.
Treatment is administered five days a week, for approximately four to six weeks, the firm's web site explains. The therapy "stimulates key areas of the brain that are underactive in patients with depression."
"The only other widely used device-based therapy in psychiatry is shock therapy, and that's been around since the 1930s," CEO Bruce Shook told MassDevice in 2011. "While the therapy is not a cure (there is still no known "cure" for depression), clinical tests show that patients treated with NeuroStar experience improvement in anxiety and other symptoms associated with depression, without side effects such as weight gain, sexual dysfunction and nausea often associated with drug therapy."
The key word here is "improvement."
Upon further examination of the data, it was revealed that one half of patients "responded" to TMS. Half, obviously, didn't. But a "response" can mean anything from mild mood improvement to a joyful relief from gloom and anguish. NeuroStar
ELECTROCORE KEEPS YOU OUT OF THE OPERATING ROOM, TOO
Another promising example of external neuromodulation comes from New Jersey-based ElectroCore, maker of the handheld gammaCore device. The firm conducted clinical trials on the use of vagus nerve stimulation to treat migraine headaches. The attractive little invention also holds promise for such disparate conditions as coma, irritable bowel syndrome, asthma and obesity, according to Scientific American.
The results of ElectroCore's trial, which involved only 21 volunteers, were presented in July month at the International Headache Congress in Boston. Eighteen of the test subjects reported a reduction in the severity and frequency of their headaches, rating them, on average, 50 per cent less painful after using the device daily and whenever they felt a headache coming on.
The device also appears to stimulate the release of inhibitory neurotransmitters, which counter the effects of glutamate, Scientific American added. This is a neurotransmitter, which is pertinent to the treatment of depression.
The big question is whether a non-implantable device can really trigger changes in brain chemistry in humans, or whether people are simply experiencing a placebo effect.
"The vagus nerve is buried deep in the neck, and something that's delivering currents through the skin can only go so deep," says Mike Kilgard of the University of Texas at Dallas. As you turn up the voltage, there's a risk of it activating muscle fibers that trigger painful cramps, he adds.
THE ALLURE OF VAGUS: AN INTERESTING NEW GAMBLE
Giant drugmaker GlaxoSmithKline and medical-device powerhouse Boston Scientific, among others, recently invested in $27 million SetPoint, which describes itself as “a biomedical technology company developing neuromodulation therapies for patients with inflammatory autoimmune diseases, such as rheumatoid arthritis and Crohn's Disease.”
The company’s particular spin on bioelectronics medicine uses stimulation of the vagus nerve to activate the inflammatory reflex, which, according to the company, “produces a potent systemic anti-inflammatory effect.” Inflammation is one of the most damaging bodily conditions, and creates or exacerbates numerous major health problems. However, it is also the body's potent response to harm or infection, so it is unclear what unwanted results might occur if it were suppressed effectively.
The collar pictured above also provides wireless communication with an iPad app, which monitors and adjusts the stimulator.
Now, with such high-profile backers lending weight to the technology, the company has reached "an inflection point" in its work to find an alternative to immunosuppressive drugs, CEO Anthony Arnold said.
If its clinical development goes according to plan, neuromodulation could be a breakthrough treatment for inflammatory diseases, Arnold added.
SetPoint Medical announced "positive" results from the first-ever human study using an implanted neuromodulation device to treat rheumatoid arthritis at the American College of Rheumatology Annual Meeting in November 2012.
In this "proof of concept" trial, SetPoint's device reduced the severity of rheumatoid arthritis in six of eight patients who didn't respond to the RA drug methotrexate. In an August 2013 article, the company said its results "validate neuromodulation as a viable option for sufferers of inflammatory diseases including Crohn's, ulcerative colitis and psoriasis."
If you dig up the actual documentation, you find that the study doesn't necessarily even validate the treatment for sufferers of arthritis, much less of the three other diseases. It was not double-blind, and there was no control group.
The unpublished, non peer-reviewed study acknowledges that only two of the eight patients achieved remission, as measured on a self-reporting scale, and six of the eight had results similar to those typically achieved in larger studies with drugs currently used to treat RA.
Many RA drugs are not well-tolerated, and one reason is that they suppress the immune system, just as SetPoint's system does. But drugs don't require a surgical implant, and they can be stopped or changed when they become problematic or ineffective, unlike a permanent appliance.
According to a company press release, SetPoint is developing "a novel platform to treat a variety of inflammation-mediated autoimmune diseases. The company is planning larger clinical studies in several diseases this year."
Autoimmune diseases -- like quite a few others -- have been described as "a new epidemic" in the media over the past few years. The notion of regulating the immune system is intriguing, but one has to wonder what undesirable and unanticipated effects could result. Our immune systems are extremely complex and not well understood. The same can be said for inflammation, which has only in recent years been measured, through the CRP test, and tied to a wide range of chronic health problems.
It is interesting, albeit seemingly fraught with peril, to start messing around with these processes until medicine has a clearer understanding of their dynamics.
A SPUNKY, SAVVY FIRM JUMPS INTO THE FRAY
An overview of the neuromodulation industry that I cited above listed "the usual suspects" as the major players, and then named three up-and-coming young firms. One of them is MicroTransponder, a privately held, Dallas-based, medical device startup, which is a University of Texas at Dallas spin-off. I doubt I would have had the opportunity to learn about this small operation if its president hadn't written to me regarding my VNS article.
Microtransponder is sponsoring research, announced earlier this year, at the University of Glasgow, hoping to help victims of stroke to overcome physical disabilities by nudging their brains to "rewire" themselves. Like most aggressive little tech startups, MicroTransponder hopes to turn itself into a hot property and get gobbled up by one of the Big Guys, making everyone rich. Its current areas of research are stroke rehab, tinnitus and chronic pain.
Would it? Greatly? Having been asked to consider VNS surgery myself, I certainly wouldn't accept the risks involved in order to hold a cup of tea. The benefits would have to be far, far greater than that for me to have a wire permanently wrapped around that big nerve in my neck, and to live forever with the side effects.
Microtransponder is also exploring vagus nerve stimulation as a treatment for tinnitus, which is described by the Mayo Clinic as a common problem perceived as noise or ringing in the ears. "Tinnitus isn't a condition itself — it's a symptom of an underlying condition, such as age-related hearing loss, ear injury or a circulatory system disorder," Mayo explains.
Vagus nerve stimulation is an expensive, invasive procedure that is minimally effective for other conditions and has major risks associated with it. It seems like an extreme solution to pursue for tinnitus.
The Mayo Clinic, and other respected medical resources, list an array of relatively simple and inexpensive ways to treat tinnitus, including changing your medications (which are a common culprit), using white-noise machines (which actually seemed to cure my condition over time), tinnitus retraining, which involves a wearable device that delivers individually programmed tonal music to mask the specific frequencies of the tinnitus you experience. Over time, the patient becomes oblivious to the problem. Medications such as amitryptiline and alprazolam can also help.
But apparently there are people whose tinnitus is much more severe and requires a bolder approach.
Microtransponder's web site refers to a survey, conducted by an unnamed source and consisting of an unspecified number and demographic of people, in which 85 percent said they were willing to have an invasive surgery with a permanent implant if it could reduce their tinnitus by one half.
When I sought documentation for this impressive statistic, I was provided with a study published in Neuromodulation in 2012. It was conducted by MicroTransponder principals and a doctor paid by the company, and it consisted of an Internet survey. Even this extremely suspect "investigational protocol" was inaccurately reported by MicroTransponder on its web site. The online survey indicated that "70 percent of those with very loud tinnitus would be willing to have a temporary implant, and about 60 percent would be willing to have a permanent implant." That's not the 85 percent touted on the web site -- and most of those who said they'd consider an implant were considering a temporary one, which is not what MicroTransponder is developing.
Only about 60 percent of those who had signed up for an email list on tinnitus research responded to the survey. Fewer than 10 percent of veterans who were on a mailing list of the American Tinnitus Association responded. The defects in this sampling were not disclosed when MicroTransponder cited the study. The company's materials infer a very large market for their product, when in fact their corroboration is based upon a small subset of those severely afflicted.
"If the therapy was able to completely eliminate the tinnitus, then a full 83 percent would be WILLING or ABSOLUTELY WILLING to pay $5,000," the company claims.
The likelihood that VNS treatment can "completely eliminate" tinnitus is virtually zero, and in fact other company data suggest that a 50 percent reduction is a reasonable target.
"We did not have the respondents consider potential risks of treatments," the authors added, and, "It might very well be that the respondents did not have a clear picture ...or realistic understanding of (the invasive nature of ) what was involved."
Moreover, although the survey asked those with "very LOUD tinnitus" if they would implant a device, the study's misleading conclusion was: "The results of this survey indicate that VNS would be an acceptable therapeutic solution for individuals with moderate to severe tinnitus and should be developed for the market."
This is not a legitimate study. It is an advertisement -- a self-serving bit of propaganda -- to attract investors, which MicroTransponder is trying aggressively to do. The company's characterization of study results is totally misleading.
This is yet another example of so-called peer-reviewed journals permitting articles that will be very influential in various aspects of health care to be ghost written; to be written by physicians and others who have been paid by the party who will benefit from the research; and to present the data in a misleading -- or entirely fabricated -- way. It has recently been reported several times that studies which reach conclusions that don't benefit the device- or drug-maker that sponsored them are withheld from publication, and it has been acknowledged that "peer reviewed" -- which formerly was so valuable in establishing credibility -- means nothing anymore. "Peers" are too busy advancing their own careers to spend time reviewing your article. It's a thankless task, providing nothing to the "peer," except perhaps a sense of integrity and social responsibility. But that's not going to pay for the Escalade.
RINGY-DINGY: IMPLANT THAT THINGY
The American Tinnitus Association, which I don't regard as a particularly credible source either, estimates that as many as two million Americans currently suffer from "severe debilitating tinnitus that prevents them from functioning on a daily basis."
I don't believe that.
Tinnitus has become an especially common problem in soldiers returning from Iraq and Afghanistan with over 850,000 veterans currently having tinnitus, according to the association.
The medical device industry as a whole has been very effective in exploiting sympathy for our veterans to obtain funding from NIH and the VA, not just for tinnitus but for a mind-boggling array of conditions. War is such a windfall for everyone involved. The military-industrial complex has become the military-industrial-tech complex, with a major hunk of "independent contractor" thrown in. And the taxpayers are throwing money at all of them. Neuromodulators want their share!
Last summer Microtransponder officials presented data from the initial 10-patient tinnitus clinical trial at the Tinnitus Research Initiative conference in Belgium, according to a company press release.
Patients with tinnitus were treated using "a novel paired vagus nerve stimulation therapy which pairs listening to tones with small bursts of stimulation to the vagus nerve in the neck." The results for this initial trial were "positive," the company claims, and "many" of the patients "experienced a reduction in the severity and perception of tinnitus." No supportive data were provided.
MicroTransponder recently reached another milestone, raising $2 million in angel funding to continue its development of the Serenity System™, a contraption designed to deliver the tinnitus therapy at the home of the patient, a company press release reported.
The aim of the therapy is to "reverse this maladaptive plasticity by retraining the brain to 'shrink' the abnormal representation of the phantom sound. To do this, the researchers targeted the vagus nerve...(which) stimulates other brain structures to release neuromodulators such as acetylcholine and norepinephrine,," company materials explain.
WHAT A PAIN: FAILURE AND MISUNDERESTIMATION
In 2010, MicroTransponder received nearly $10 million -- $2.6 million of it from a National Institutes of Health grant -- to help it conduct clinical trials to develop a wireless neurotransmitter that would treat chronic pain. The Saint (Subcutaneous Arrangement of Implantable Neural Transponders) MicroStim System had already received about $5 million in funding, private investment and grants, including $1.38 million from Texas’ Emerging Technology Fund.
A patent, obtained the year before by Microtransponder, was characterized as "a major step to ensure that the Company maintains a competitive edge in our newly developed wireless stimulator technology," by Frank McEachern, CEO of the company.
The proposed device would involve having a microchip the size of two grains of rice injected where a patient feels pain, said MicroTransponder board chairman Will Rosellini. With the push of a button, patients could send electrical pulses to the microchip, and block pain in the affected area. The implant would be controlled with an external device that can be worn like an armband, according to an article at OneMedPlace. Patients would be able to hook the controller up to a laptop or PDA to alter the device settings to the patient’s specifications. The SAINT Microstim System concept is based on technology developed in a prosthetics program at the University of Texas in Dallas, OneMedPlace reports.
Currently, the smallest neurotransmitter for pain on the market is 100 times larger, Rosellini said.
“Our solution is smaller and more elegant,” Curnes added. “It gets rid of all of those batteries and wires.”
Rosellini said that for the five million to 10 million people whose chronic pain can’t be helped by pharmaceuticals, the Saint MicroStim System “would be a treatment of last resort.”
The funding was intended to finance clinical trials to test the effectiveness of the system and obtain FDA approval, Curnes said. The firm announced that the device would be on the market by the end of 2011.
And that was the end of that. I could find no further information, anywhere, about what happened to this grand vision.
What happened to this much-ballyhooded and well-funded project? Nothing.
In a September 6, 2013, email to me, Curnes admitted that Microsponder had been "far too optimistic" in its projections about its ability to build and test this product.
How could the company have conducted clinical trials, if it hadn't even created the product? And what happened to the $10 million?
To be fair, this kind of overselling is endemic in this industry, in which everyone is saying whatever is required to make a killing.