An Honest Reflection Of The Current State Of Neuropathy Treatment

Today's post from medscape.com (see link below) may depress the hell out of you because it's basically an analysis of the failures with neuropathy treatment and diagnostic testing over the last decades. At least Medscape are honest here and don't try to pull the wool over our eyes with promises of exciting new developments in the field of nerve damage control. There are exciting new developments and this blog highlights them when they emerge but as the co-author rightly states: "As a clinician, I'm frustrated that current drugs have no benefit for the underlying nerve damage. We have witnessed failure after failure of clinical trials of disease-modifying drugs, because the end points are not fit for that purpose." Says it all really! That said, as patients, we have to remain optimistic and we have to report individual failures as they happen, so that enough evidence can be built up to confirm or reject any particular drug's effectiveness. We also need to continue to explore options from the alternative circuits. All we're interested in really is reducing our daily discomfort and it has to be said, progress in that area has largely been patient-led during the last decades because standard drug treatments are pretty much the same as they've been for decades and they are largely ineffective. This blog does take issue with the recommendation of Pregabalin as a first-line treatment but apart from that, the article presents a scenario that we can all recognise and reflects our frustrations as patients too.
 

New ADA Guidance Charts Success, Failure in Diabetic Neuropathy
Miriam E Tucker January 09, 2017

Notably missing from the first US guidelines to address diabetic neuropathy in more than a decade is any recommendation for disease-modifying treatments, since none are currently approved by the US Food and Drug Administration (FDA).

Indeed, many candidate drugs for diabetic neuropathy have failed in trials, and one of the new guideline authors believes novel end points — particularly measures of small-nerve fiber damage and repair — that could better assess a potential drug's efficacy need to be employed in clinical studies.

Coauthor Rayaz A Malik, MBChB, FRCP, PhD, of Weill Cornell Medicine-Qatar, Doha and New York, told Medscape Medical News, "As a clinician, I'm frustrated that current drugs have no benefit for the underlying nerve damage. We have witnessed failure after failure of clinical trials of disease-modifying drugs, because the end points are not fit for that purpose."

Such assessments of small-nerve fiber damage should also be used for earlier diagnosis of diabetic neuropathy, says Dr Malik.

"Although about 20% of patients have painful neuropathy and can present to their doctor, the majority have painless neuropathy, which is silent and is diagnosed only when it is too late and the patient has already developed a foot ulcer," he continued.

"Given that the 5-year mortality of a patient with a foot ulcer is worse than most cancers, there is a need to identify early neuropathy. Yet currently advocated tests, like the monofilament, identify only patients with advanced neuropathy. Why do we have robust methods for detecting early retinopathy and nephropathy, but not neuropathy?"

Published in the January issue of Diabetes Care, the new ADA position statement revises ADA's last neuropathy guideline, published in 2004.

The new document covers prevention and management of distal symmetric polyneuropathy (DSPN), diabetic autonomic neuropathies including cardiovascular autonomic neuropathy (CAN), as well as less common forms of neuropathy.

The aim is to provide state-of-the-art information for clinical management of the condition but to also acknowledge the current lack of disease-modifying drugs.

Most Patients Don't Need Sophisticated Testing or Opioids

Lead author of the new guidelines, Rodica Pop-Busui, MD, PhD, of the University of Michigan, Ann Arbor, told Medscape Medical News that there are two key clinical messages in the new document: the first is that electrophysiologic testing or referral to a neurologist is rarely needed for diagnosing neuropathy and the second is that opioids for the pain of diabetic neuropathy should be considered only as a very last resort and not as first- or second-line therapy,

"The purpose of the document is to provide clinicians with evidence-based tools to understand how to diagnose, monitor, and manage some of the aspects related to diabetic neuropathy.…It provides a tool to help them confidently diagnose neuropathy on their own and avoid expensive unnecessary tests or referrals," Dr Pop-Busui said.

The statement also covers neuropathy prevention, including glycemic control and lifestyle modification. Assessment for DSPN, the document advises, should be undertaken at diagnosis of type 2 diabetes, 5 years after diagnosis of type 1 diabetes, in those with prediabetes and symptoms of peripheral neuropathy, and every year thereafter.

Modalities for assessment should include careful history and either temperature or pinprick sensation to assess small-fiber function, along with tuning fork for vibration sensation, and 10-g monofilament testing for ulceration risk.

Electrophysiologic testing or referral to a neurologist is rarely necessary, except in atypical situations."There were several neurologists on the writing group, in addition to endocrinologists. We reached the same conclusion — that referral is not needed for typical cases of diabetic neuropathy — and we have provided a stepwise approach to get an idea of whether a patient has typical symptoms and signs," Dr Pop-Busui noted.

For treating neuropathic pain, the document advises the FDA-approved pregabalin or duloxetine as first-line treatment and various nonapproved agents, including gabapentin or tricyclic antidepressants, as second-line. Due to the high risks of addiction and other complications, opioids are advised only for patients with severe pain who don't respond to other medications, and referral to specialized pain clinics is advised in such cases.

Recommendations are also provided for assessment of cardiovascular, gastrointestinal, and urogenital autonomic neuropathies in patients with microvascular and neuropathic complications.

Included are considerations for excluding other conditions or drug effects that could be mimicking the symptoms, use of short-term metoclopramide for treatment of gastroparesis, assessment of patient-specific neuropathy-related end points, such as falls and mobility, and assessment of less common neuropathies.

"Hopefully readers will find this document very useful. We tried to make it very easy to read, with pearls that are all evidence-based.…We want to give them the tools to be able to see a complicated patient with diabetic neuropathy relatively easily in their office," Dr Pop-Busui explained.

Why Aren't There Any Drugs to Treat Neuropathy?

In the document's final section "Neuropathy Clinical End Points for Research and Clinical Trials," the authors point out that "multiple clinical trials for these conditions have failed."

They cite as contributing factors "a lack of agreement and uniformity in the use of the most sensitive DSPN measures that capture the natural history of the disease and detect repair in the specific nerve-fiber populations, as well as the inclusion of appropriate patient populations."

For DSPN drug trials in particular, the statement recommends the use of validated clinical instruments for assessing symptoms and disability, along with advice to "consider" using electrophysiology and measures of small-fiber damage and repair, such as intraepidermal nerve-fiber density or corneal confocal microscopy.

Dr Malik has long maintained that one of the main impediments to better neuropathy treatment in both clinical practice and research has been the focus on measures of symptoms and large-fiber dysfunction, rather than assessment of small-fiber damage and repair that occurs earlier and could therefore serve as a more appropriate target for early intervention and for the development of drugs to treat neuropathy.

"I honestly believe there are many drugs that have failed because of this. If you test small fibers they repair sooner than large fibers. If you do a clinical trial lasting only 1 or 2 years you actually might not see the benefit of that drug because you're not looking at the small fibers….Big Pharma has invested huge amounts of money in disease-modifying drugs, but they've all failed," Dr Malik asserted.

He blames advisors to the FDA for not "moving away from symptoms, signs, and neurophysiology" and for not allowing small-fiber assessment to be at least a secondary end point in drug trials "to give disease-modifying therapies a fighting chance."

He believes that many promising drugs like the aldose reductase inhibitors, nerve growth factor, C-peptide, and the novel investigational peptide ARA 290 (Araim Pharmaceuticals) could well be approved for DSPN if small-fiber evaluation were included as an end point.

However, Dr Pop-Busui pointed out, other candidate drugs have failed due to toxicity — notably the aldose-reductase inhibitors — although one of those (epalrestat) is currently licensed for DSPN in some countries in Asia.

Also, she noted that there has been difficulty in identifying an appropriate animal model for human diabetic neuropathy.

"We are working very hard to try to identify the right targets that can be developed into more successful phase 2 and phase 3 trials....This is a very complex question," she said.

What's the Best Tool for Research and Clinical Practice?

Dr Malik has conducted extensive research demonstrating the utility of corneal confocal microscopy, a tool originating from ophthalmology that has been shown to predict the development of peripheral neuropathy in patients with diabetes and even prediabetes.

Corneal confocal microscopy could serve both clinically and as a surrogate end point in clinical trials as a noninvasive alternative to skin biopsy for the assessment of early small-fiber damage and repair. This is the type of tool needed for drug development, he believes.

"No drug company is going to invest in a 5-year clinical trial. What you need is something that will give you a signal that nerves are beginning to repair within 12 months, which then allows you to continue and show that other tests like [quantitative sensory testing] and neurophysiology also improve," he explained.

"The monofilament and neurological examination are very good at picking up advanced neuropathy and identifying the high-risk foot but are terrible at detecting early neuropathy and indeed nerve repair," he added.

But such tools still play an important role in clinical practice, Dr Pop-Busui stressed.

"Some tools may be ancient but in fact provide extremely important information. These tools can be carried in a physician's pocket and used in a few minutes. Yes, we are using technology in many aspects of diabetes management, but in diabetic neuropathy, the clinical exam is very important."

And she pointed out that use of tools such as corneal confocal microscopy at this point is unlikely to change clinical practice.

"We don't have preventive treatments, so we wouldn't do anything different. We would still treat their glucose and other risk factors. We don't have other pathogenic treatments as we talk right now."

For the current document, she said, "The task given to us was to help physicians and patients to have the best effective care of the complication with all the information critically evaluated. In medicine things change all the time. If the evidence changes, we will update the document."

FDA Still Working on Development Programs for Agents for DSPN

Both Drs Pop-Busui and Malik participated in a February 2013 FDA public workshop, "Clinical Development Programs for Disease-Modifying Agents for Peripheral Neuropathy."

In response to a Medscape Medical News query about the outcome of that meeting and the status of the end-points issue, an FDA spokeswoman responded: "The FDA has taken into account the information discussed at the 2013 public workshop and the comments received as we continue to work with industry on clinical development programs for disease-modifying products for the management of peripheral neuropathy. We will provide updates on this topic as appropriate."

The guidelines authors have no relevant financial relationships.

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.

Diabetes Care. 2017;40:136-154. Article

http://www.medscape.com/viewarticle/874162

The Drawbacks Of Current Neuropathy Treatment

Today's post from hospitalnews.com (see link below) takes a look at the current hit and miss state of neuropathic pain treatment from a Canadian point of view and looks more closely at Gabapentin as one of the options. Conclusions are that the jury's out on gabapentin and other medications prescribed to reduce neuropathic symptoms have limited success and also bring the danger of side effects with them. Nothing new here then but it is interesting to have our suspicions confirmed regarding the effectiveness of current neuropathy treatment.

Neuropathy: What a pain
Dr. Janice Mann September 1, 2015

No one wishes to experience pain. But fortunately when those everyday aches and pains arise, we have over-the-counter medications readily available to help us out. (For a recent review on what the evidence has to say about over-the-counter pain medications, check out the Ask Julie column at Vox with Canada’s own Julia Belluz: http://www.vox.com/2015/8/17/9165189/best-painkiller-tylenol-aspirin-advil).

But what if you are experiencing pain that isn’t likely to get better with these over-the-counter medications? Patients with neuropathic pain find themselves in this category. Neuropathic pain — or as it is sometimes called, neuropathy — is a type of chronic pain that results from damage to the nervous system. Neuropathic pain can be peripheral, resulting from damage to the peripheral nerves (nerves in your arms, legs, hands, and feet for example) or central, resulting from damage to the brain or spinal cord. Common causes of peripheral neuropathy include diabetes and postherpetic neuralgia (nerve pain following shingles). Causes of central neuropathy can include spinal cord injury and multiple sclerosis.

Neuropathic pain is notoriously difficult to treat and may involve both pharmacological and physical therapies. Although painkillers — both over-the-counter and prescription — may be tried, they are not always successful in treating the pain, and in the case of opioids can lead to abuse and addiction. Other classes of medication, not typically used for pain, can be helpful in the treatment of neuropathic pain. These include antidepressant medications and medications normally used to prevent seizures, called anticonvulsant drugs.

Gabapentin, an anticonvulsant originally developed for the treatment of epilepsy, is sometimes used off label to treat neuropathic pain. It is thought to work by inhibiting the transmission of nerve signals in the brain. While gabapentin has been viewed by some health care professionals as a promising option for the treatment of neuropathic pain, others are concerned about the potential for abuse (at high doses it may be associated with sedative and dissociative or psychedelic effects).

Because of the uncertainty of the role of gabapentin in the treatment of neuropathic pain, decision-makers in the Canadian health care system turned to the Rapid Response service at CADTH — an independent, evidence-based agency that finds, assesses, and summarizes the research on drugs, medical devices, and procedures — to find out what the evidence says.

When CADTH searched for the evidence on gabapentin and neuropathic pain, they found 19 relevant publications — nine systematic reviews, two randomized controlled trials, six non-randomized studies, and two guidelines. Overall, the evidence suggests that gabapentin is effective in the treatment of neuropathic pain. A greater reduction in neuropathic pain was found with gabapentin compared with placebo (no active drug) in adults who have a variety of conditions, including diabetic peripheral neuropathy and postherpetic pain. For short-term treatment of painful diabetic neuropathy and postherpetic neuralgia, gabapentin may be as effective as two classes of antidepressants known as tricyclic antidepressants and serotonin norepinephrine reuptake inhibitors, and another drug for seizures called pregabalin — but these findings are based on indirect evidence (evidence on each drug individually rather than evidence that directly compares the drugs with one another). The evidence for gabapentin for other types of neuropathic pain is limited.

The number of adverse events was higher in patients taking gabapentin compared with patients taking placebo (side effects reported include somnolence, dizziness, peripheral edema, and gait disturbances); but, overall, serious adverse events were few and comparable between the two groups. Gabapentin may be used as a recreational drug, but there is an absence of high-quality evidence on the prevalence and risk of misuse among patients prescribed the drug to manage neuropathic pain.

No Canadian evidence-based clinical practice guidelines were identified, but UK guidelines support the use of gabapentin as one of the first-line treatment options for the management of neuropathic pain. US guidelines recommend gabapentin as an option for diabetic neuropathy.

Knowing the evidence on gabapentin for the treatment of neuropathic pain can help to guide decisions about its use — as well as identify areas where more research is needed. As more evidence on gabapentin and neuropathic pain becomes available, further reviews may be necessary to ensure policy and clinical practice is in keeping with the latest evidence.

If you’d like more information about the CADTH Rapid Response service, please visit www.cadth.ca/RapidResponse. If you’d like to see what other drugs, devices, or procedures have been covered by the Rapid Response service at CADTH, visit www.cadth.ca/RapidResponseReports. Here you’ll find all of the freely available reports listed chronologically as they are completed. To learn more about CADTH, visit www.cadth.ca , follow us on Twitter: @CADTH_ACMTS, or talk to our Liaison Officer in your region: https://www.cadth.ca/contact-us/liaison-officers.

Dr. Janice Mann is a Knowledge Mobilization Officer at The Canadian Agency for Drugs and Technologies in Health.

http://hospitalnews.com/neuropathy-what-a-pain/

ELECTRIC CURRENT TO BRAIN BOOSTS MEMORY

Stimulating a particular region in the brain via non-invasive delivery of electrical current using magnetic pulses, called Transcranial Magnetic Stimulation, improves memory, reports a new Northwestern Medicine® study

The discovery opens a new field of possibilities for treating memory impairments caused by conditions such as stroke, early-stage Alzheimer's disease, traumatic brain injury, cardiac arrest and the memory problems that occur in healthy aging.

"We show for the first time that you can specifically change memory functions of the brain in adults without surgery or drugs, which have not proven effective," said senior author Joel Voss, assistant professor of medical social sciences at Northwestern University Feinberg School of Medicine. "This noninvasive stimulation improves the ability to learn new things. It has tremendous potential for treating memory disorders."

The study will be published August 29 in Science.

The study also is the first to demonstrate that remembering events requires a collection of many brain regions to work in concert with a key memory structure called the hippocampus -- similar to a symphony orchestra. The electrical stimulation is like giving the brain regions a more talented conductor so they play in closer synchrony.

"It's like we replaced their normal conductor with Muti," Voss said, referring to Riccardo Muti, the music director of the renowned Chicago Symphony Orchestra. "The brain regions played together better after the stimulation."

The approach also has potential for treating mental disorders such as schizophrenia in which these brain regions and the hippocampus are out of sync with each other, affecting memory and cognition.

TMS Boosts Memory

The Northwestern study is the first to show TMS improves memory long after treatment. In the past, TMS has been used in a limited way to temporarily change brain function to improve performance during a test, for example, making someone push a button slightly faster while the brain is being stimulated. The study shows that TMS can be used to improve memory for events at least 24 hours after the stimulation is given.

Finding the Sweet Spot

It isn't possible to directly stimulate the hippocampus with TMS because it's too deep in the brain for the magnetic fields to penetrate. So, using an MRI scan, Voss and colleagues identified a superficial brain region a mere centimeter from the surface of the skull with high connectivity to the hippocampus. He wanted to see if directing the stimulation to this spot would in turn stimulate the hippocampus. It did.

"I was astonished to see that it worked so specifically," Voss said.

When TMS was used to stimulate this spot, regions in the brain involved with the hippocampus became more synchronized with each other, as indicated by data taken while subjects were inside an MRI machine, which records the blood flow in the brain as an indirect measure of neuronal activity.

The more those regions worked together due to the stimulation, the better people were able to learn new information.

How the Study Worked

Scientists recruited 16 healthy adults ages 21 to 40. Each had a detailed anatomical image taken of his or her brain as well as 10 minutes of recording brain activity while lying quietly inside an MRI scanner. Doing this allowed the researchers to identify each person's network of brain structures that are involved in memory and well connected to the hippocampus. The structures are slightly different in each person and may vary in location by as much as a few centimeters.

"To properly target the stimulation, we had to identify the structures in each person's brain space because everyone's brain is different," Voss said.

Each participant then underwent a memory test, consisting of a set of arbitrary associations between faces and words that they were asked to learn and remember. After establishing their baseline ability to perform on this memory task, participants received brain stimulation 20 minutes a day for five consecutive days.

During the week they also received additional MRI scans and tests of their ability to remember new sets of arbitrary word and face parings to see how their memory changed as a result of the stimulation. Then, at least 24 hours after the final stimulation, they were tested again.

At least one week later, the same experiment was repeated but with a fake placebo stimulation. The order of real stimulation and placebo portions of the study was reversed for half of the participants, and they weren't told which was which.

Both groups performed better on memory tests as a result of the brain stimulation. It took three days of stimulation before they improved.

"They remembered more face-word pairings after the stimulation than before, which means their learning ability improved," Voss said. "That didn't happen for the placebo condition or in another control experiment with additional subjects."

In addition, the MRI showed the stimulation caused the brain regions to become more synchronized with each other and the hippocampus. The greater the improvement in the synchronicity or connectivity between specific parts of the network, the better the performance on the memory test. "The more certain brain regions worked together because of the stimulation, the more people were able to learn face-word pairings, " Voss said.

Using TMS to stimulate memory has multiple advantages, noted first author Jane Wang, a postdoctoral fellow in Voss's lab at Feinberg. "No medication could be as specific as TMS for these memory networks," Wang said. "There are a lot of different targets and it's not easy to come up with any one receptor that's involved in memory."

The Future

"This opens up a whole new area for treatment studies where we will try to see if we can improve function in people who really need it," Voss said.

His current study was with people who had normal memory, in whom he wouldn't expect to see a big improvement because their brains are already working effectively.

"But for a person with brain damage or a memory disorder, those networks are disrupted so even a small change could translate into gains in their function," Voss said.

In an upcoming trial, Voss will study the electrical stimulation's effect on people with early-stage memory loss.

Voss cautioned that years of research are needed to determine whether this approach is safe or effective for patients with Alzheimer's disease or similar disorders of memory.