Friday, 31 October 2014

Can Mirogabalin Help With Neuropathy Pain?

Today's post from medscape.com (see link below) is an interesting one concerning a new drug - Mirogabalin - to treat neuropathy. It has been tested against pregabalin (Lyrica) which may raise eyebrows considering Lyrica's bad reputation and has shown promise. I can't find out for sure if it's an anticonvulsant but assume that it is, if it's being tested against pregabalin (the name is also similar). Anyway, if you find that your current treatment is not working, it may be worth mentioning it to your doctor. Although the drug is not yet on the market, it's worth getting him or her to note it down. certainly worth doing some more research of your own.
 


Diabetic Neuropathy Pain: Mirogabalin Promising in Pilot StudyMiriam E. TuckerOctober 10, 2014 Medscape Medical News

Mirogabalin (Daiichi Sankyo) has shown promise as a potential treatment for diabetic peripheral neuropathic pain in a dose-ranging, proof-of-concept study that pitted it against both placebo and pregabalin (Lyrica, Pfizer).

Results from a phase 2, randomized, double-blind study were presented September 12 at Neurodiab, the annual meeting of the Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes by Domenico Merante, MD, of Daiichi Sankyo, Buckinghamshire, United Kingdom, and were also published online September 17 in Diabetes Care by Aaron Vinik, MD, of Eastern Virginia Medical School, Norfolk, and colleagues.

In the study of 452 subjects with type 1 or type 2 diabetes who also had painful distal symmetric sensorimotor polyneuropathy for 6 months or longer, mirogabalin doses of 5, 10, 15, 20, and 30 mg produced greater reductions in average daily pain scores at 5 weeks than did either placebo or 300-mg pregabalin, both of which performed similarly.

Both gabapentin and pregabalin are first-line treatments for diabetic peripheral neuropathic pain, but only pregabalin is approved specifically for this indication by the US Food and Drug Administration, Dr. Vinik and colleagues explain. Mirogabalin is being developed worldwide by Daiichi Sankyo for the treatment of neuropathic pain.

Conference session comoderator James W. Russell, MBChB, professor of neurology, anatomy, and neurobiology at the University of Maryland, Baltimore, told Medscape Medical News, "This is a phase 2 study, so it's really the first serious look at this compound. Obviously, one needs more data to be able to say that mirogabalin is superior to pregabalin or is itself efficacious."

He also cited some concerns, including the lack of effect for the established treatment pregabalin compared with placebo, the short duration of the trial, and combining data from patients with type 1 and type 2 diabetes. Nonetheless, he noted that the study was well-conducted and that the investigators are "top-notch."

"I think mirogabalin is definitely a promising medication. It is a potential therapy to be added to our armamentarium for a very serious and disabling complication, painful diabetic sensory polyneuropathy," he told Medscape Medical News.

Mirogabalin More Selective for Pain than Pregabalin?


In the paper, Dr. Vinik and colleagues explain that mirogabalin binds to the same neuropathic pain-associated alpha-2-delta calcium-channel ligand subunits as pregabalin but is preferentially selective for alpha-2-delta-1, which is believed to be associated with analgesic effects, whereas pregabalin nonselectively targets both alpha-2-delta-1 and alpha-2-delta-2, which appears to contribute to central nervous system (CNS) side effects.

Thus, mirogabalin may provide a wider therapeutic index with fewer CNS complications, they suggest.

Of the 452 patients randomized to 1 of the 7 treatment groups in the trial, 383 completed the study, but 433 were included in the analysis using a last-observation-carried-forward design. Discontinuation rates were 13% for placebo, 18% for mirogabalin 30 mg, and 27% for pregabalin.

The subjects were 75% white and 54% male. Most (92%) had type 2 diabetes, with a mean HbA1c of 7.4% at baseline and an average 5.8 years of diabetic peripheral neuropathic pain. About a third had used either pregabalin or gabapentin in the past.

The primary end point was mean change from baseline in the 11-point average daily pain score (with 0 being no pain and 10 being worst possible pain).

At baseline, that score was 7.0 in the placebo arm, 6.7 across mirogabalin groups, and 6.6 for the pregabalin subjects.

Mean Reductions in the Pain Score at Week 5

Treatment Reduction in Pain Score

Placebo 1.9
Mirogabalin, mg
5 2.0
10 2.3
15 2.7
20 2.6
30 2.8
Pregabalin, 1.8 mg 1.8


The drops for the highest 3 mirogabalin doses were statistically significant compared with placebo (P < 0.05), beginning at week 1 and continuing through week 5.

The mean differences for pregabalin vs placebo were significant at weeks 1 and 2 but not weeks 3 through 5. The difference between mirogabalin 15 mg and 30 mg and pregabalin 300 mg were statistically significant, the investigators report.

The proportion of subjects achieving pain-score improvements of 30% or greater were 56% through 67% in the top 3 mirogabalin dose groups, compared with 38% with pregabalin and 42% with placebo.

Improvement of 50% or more points was achieved in 39% to 44% of the 15-, 20- and 30-mg mirogabalin groups, vs 28% with pregabalin and 24% for placebo.

But Lack of Effect of Pregabalin Is Concerning, and Side Effects Seem Similar

Dr. Russell urged caution in interpreting these findings. "The study actually showed a minimal effect on neuropathic pain scores with pregabalin compared with mirogabalin. This to me is a little concerning, since there are at least 3 class I studies showing efficacy of pregabalin and over longer periods of time. When you're doing a comparison of a new drug vs the established approved medication, it raises a little bit of concern when the established proved medication doesn't perform as expected."

He added, "I think most physicians who use pregabalin extensively would agree it clearly has a benefit in the treatment of painful diabetic sensory polyneuropathy."

With regard to safety, adverse events were mostly mild, and included central nervous system events in 2.8% with placebo, 14% in all mirogabalin groups combined, and 12% with pregabalin. Dizziness and somnolence were the most common, and most had resolved by study end.

Edema occurred in 1% of those taking placebo, 5% of the mirogabalin subjects, and in 10% of those on pregabalin. Mildly blurred vision was reported in 2% of both placebo and mirogabalin groups and 4% with pregabalin. No deaths occurred during the study, and only 1 serious medication-related adverse event — a gallstone in a man with comorbidities taking 15 mg mirogabalin — was reported.

Study discontinuations due to adverse events were 2% of the placebo group, 7% of mirogabalin subjects, and 4% with pregabalin.

Dr. Russell told Medscape Medical News that he didn't see much difference between the side-effect profiles of mirogabalin and pregabalin, but that future studies would need to compare whatever the most effective dose of mirogabalin turns out to be with the standard 300-mg dose of pregabalin.

"You compare the optimal dose of each drug, so it's apples to apples."

More Data Needed, and Longer Duration

Dr. Russell added — and the authors acknowledge as well — that 5 weeks is probably not long enough for a study to evaluate the full effects of a neuropathy medication.

"Until we start to see data to at least 12 weeks or even longer showing mirogabalin is efficacious over that period of time, we have to remain open as to its overall efficacy," he commented.

He also said that although mirogabalin's half-life is longer than pregabalin's and therefore could perhaps be dosed less often — once or twice daily vs 2 or 3 times a day — most of the pain effect would likely be related to peak drug levels.

"With a longer study, you'd get more info about when peaks and troughs occur and whether peak levels correspond to changes in average daily pain scores."

Also related to the longer half-life is a potential concern about renal excretion in patients with impaired renal function. The study excluded such patients, but the issue is important because painful diabetic neuropathy and impaired renal function often coexist in patients with long-term diabetes, Dr. Russell noted.

He also said that because neuropathy in type 1 and type 2 diabetes differs, studies shouldn't lump the 2 patient groups together.

"Type 1 diabetes is far more dependent on glycemic control than type 2, whereas other factors are more important in type 2, like lipid metabolism and inflammatory markers. They really are different. I'd like studies to move away from the idea that all diabetic neuropathy is the same."

Dr. Vinik received research funding from Daiichi Sankyo for this study, and Dr. Merante is an employee of the company. Disclosures for the coauthors are listed in the article. Dr. Russell's institution received a grant from Impeto Medical to study a device to measure neuropathy, but he personally received no direct funding.

Diabetes Care. Published online September 17, 2014. Abstract

http://www.medscape.com/viewarticle/833017#vp_2

Thursday, 30 October 2014

Testing Pain: Are You Believed?

Today's excellent post from vox.com (see link below) talks about something that many people living with neuropathy are very much aware of and that is how their doctors perceive their pain experience. The feeling that you're not believed, or taken seriously, is far too common and it comes down to the fact that the methods of testing pain are inherently deficient. The article looks at what it's like to be disbelieved and then goes on to explore new possibilities of more accurate pain testing, with an emphasis on brain imaging, which may be very helpful in the future. Well worth a read.
 

The pain test
Doctors have no idea how much their patients are suffering. That's about to change.
 

by Susannah Locke on October 15, 2014

Ally Niemiec could have lost a kidney because doctors didn't believe she was in pain. It was last fall, and one of at least a dozen times that her rare kidney disease had sent her to the emergency room. She recognized the pain. She knew something was wrong.

But when she turned up in an Atlanta emergency room that Saturday afternoon, vomiting and doubled over, no one believed her. They looked at her pain medication records and decided she had a drug abuse problem.

"They told my mother that I needed to go to rehab and was a drug addict," she says. The hospital wouldn't give her any narcotic pain medication and refused to do an x-ray, ultrasound, or CT scan.

That time, Niemiec was lucky enough to have other options. She left for another hospital, where they treated her pain and then removed her kidney stone the next morning.

This discouraging experience was nothing new. For many years, she was used to doctors not trusting her. "There's nothing more horrific than a doctor looking you in the eye and saying there's nothing wrong with you when you're in debilitating pain"

One problem has been that her kidney disorder, renal tubular acidosis type 1, is described in medical journals as not painful. But to her, it was. Since she was 13, she's had about 100 kidney stones and 18 surgeries to remove them. At one point, her pain was so bad that she couldn't drive and had to leave her job. She went from doctor to doctor trying to get help. When her pain got really bad, she didn't find adequate treatment for three long years.

"There's nothing more horrific than a doctor looking you in the eye and saying there's nothing wrong with you when you're in debilitating pain," she says. "To me, it's a form of torture."

Eventually, she got a spinal cord implant that uses electrical signals to block her kidney pain. Now she's 24 years old and works at a tech startup. But many others continue to suffer.

Approximately 100 million Americans have chronic pain. That's about a third of the population. Yet the most cutting-edge test for pain is a doctor holding a piece of paper with a bunch of frowny and smiley faces on it or asking you how bad you feel on a scale of 1 to 10, with ten as the worst pain imaginable. It seems a much better test of imagination than of pain.




And as Niemiec can attest, the subjectiveness of the scale causes problems — it only works if the doctor believes you, and relying only on trust can threaten people's lives.

There must be a better way to test if someone is in pain. "That would completely have changed my experience," Niemiec says. "It could have saved me three years of my life."

Right now, such a test doesn't exist. But it's looking likely that it might someday soon. In several key studies, scientists have used brain-scanning machines to accurately predict if someone is in pain.

A more objective pain test could transform pain medicine and lead to new treatments for people who suffer. It could weed out people lying in order to get drugs. And it could prove to doctors that people like Niemiec are really in pain.

But this new technology also raises all kinds of ethical and legal questions. It might also end up as faulty mind-reading that could be used to deny care and insurance coverage to those who are truly in distress.
What is pain?

"Pain is so wonderful because it is so bad," says Sean Mackey, the chief of pain medicine at Stanford's medical school, who was the first to show that pain can be gauged using a brain scan. "It keeps us out of harm and out of danger."

Mackey's right: pain teaches people to stay away from hazards and tells them when they're injured or sick. It trains us to keep our hands away from hot stoves. It lets us know when our appendix has burst. Or when we're having a heart attack. Pain is so important that people who cannot feel pain encounter repeated injuries and have shorter life spans.

Despite pain's importance, it is quite difficult to define. And that difficulty underlies much of the disagreement about whether objective pain testing is even possible.

Today, pain is understood as a type of subjective experience. The International Association for the Study of Pain states that pain is "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."

So although the mechanisms for what usually causes pain — certain receptors on certain neurons — are fairly well known, pain is still not defined as a physical thing that your body does. Your neurons could be firing off pain signals like crazy, but as long as you don't feel pain (like if you've popped an Advil or are under anesthesia), you're not in pain. If you feel pain, you are in pain.


But brain imaging can put an image to the invisible.
It can give them something to see. 


Why the world needs a better pain test

Mackey, the Stanford pain specialist, got his PhD in electrical engineering and also an MD. "Coming out of medical school, you probably couldn't find anyone more mechanistic or linear in their thinking than me," he says. "I ended up going into pain medicine because I was intrigued about the opportunities of really making a difference in people's lives."

Working with pain patients, he often found himself using needles to block pain. (One common treatment for chronic pain is a temporary injection of anesthetic into the body, which stops pain signals from reaching the brain.) But it wasn't working for everyone. "There was large numbers of people that I wasn't helping with that approach," he says. "What really was helping them was listening to them, hearing about their fears, their anxieties, their beliefs about their pain."

Those observations got him interested in the brain side of things, the psychology side, and how things like anxiety, fear, and empathy influence pain. "It was around this time that this field of neuroimaging was being established, which allows us to open up windows into people's brains to see where pain is processed and perceived."

He wanted to use the technology to learn about how people experience pain differently and how thoughts and emotions affect pain, hoping to be able to better tailor therapies to people for better treatment. Along the way, it began to seem possible to create a test that would correlate with someone's pain levels.

A pain test could help all kinds of people. One main group is those who can't speak for themselves. For example, even into the 1980s, some doctors didn't believe that babies felt pain and so routinely did surgery on them using just muscle relaxants to keep them still. And today, some people can't tell others what they're feeling, including small children, some adults with developmental disorders, and people in coma.

And even among people who can communicate fully, not everyone's word is regarded as truth. Researchers have documented discriminatory patterns in how health-care workers treat pain. Women are more likely to have their pain dismissed as not real. And one study found that female emergency room patients with abdominal pain were less likely to be given strong pain meds than men were. Papers have found similar phenomena for racial minorities.

And until the last couple of decades, doctors thought that many people with chronic pain were faking it. Roger Fillingim is a psychologist at the University of Florida who studies pain. He describes patients saying that just the feeling of a long-sleeved shirt on their arm was painful: "We used to call that crazy." Now, doctors know that a lot of chronic pain is actually real. For example, fibromyalgia, which causes pain throughout the body, was in the crazy category, too. Now it's known to affect roughly 15 million people in the United States.
The problems with pain medication

Drug abuse is another reason a better pain test could come in handy. That abuse has led narcotic painkillers to become more tightly controlled in recent years, sometimes so tightly that people with real pain problems have trouble getting their medication.

There's no question that there's a prescription-drug abuse problem in this country. Each year, more people die in the United States from prescription painkillers than from heroin and cocaine combined. And some, but not all, of the people abusing these drugs are people who do not have an actual pain problem.

One recent review on the topic found that about 20 percent of chronic pain patients given opiate drugs long-term had either none of the drug or a non-prescribed opiate in their urine during screening tests, which suggests that they might be selling or giving the drugs away rather than taking them responsibly. (The study also found that very few — 3 percent — of all of the patients personally ended up with an addiction or abuse problem related to these drugs. If patients with a history of drug abuse are excluded, this number drops below one percent. However, screening people out doesn't always happen in today's hectic health-care environment.)

It's difficult to balance what regulations will get pain meds to patients who need them while keeping them from people who don't. You can see where these objectives collide in the recent battle over Zohydro ER. This new drug is an extended-release version of the opiate hydrocodone and the only hydrocodone for sale without another drug in it.

It's also somewhat analogous to OxyContin, which became a preferred drug of abuse in the late 1990s and early 2000s — at least until 2010, when its manufacturers made OxyContin difficult to snort or inject, with pills that were hard to crush and that turn into a gel when wet. "If you could somehow measure pain, would that be helpful? It would be helpful to me because I want to know if my patients are legitimate."

However, Zohydro ER, like every opiate on the market except for OxyContin, has no such anti-abuse features built into its pill. For some with chronic pain, it's their only chance for relief. To others, it's death in a bottle.

In October 2013, the FDA approved Zohydro ER against the recommendation of its independent advisory panel. In the spring of 2014, Massachusetts governor Deval Patrick banned it, but a judge struck the ban down just a month later. And in August, several governors petitioned the US Department of Health and Human Services to undo the decision.

Concerns about abuse have also led to changes in regulation and enforcement that pressure doctors, wholesalers, and pharmacists to give out fewer narcotic painkillers.

For example, in Florida, crackdowns to combat a previously growing problem with pain-medication deaths has made it difficult for legitimate pain patients to actually get their prescribed medication, says Jeffrey Fudin, a pharmacist who specializes in pain treatment and is an adjunct associate professor at Western New England University.

A better pain test is one thing that could help real pain patients prove themselves — and weed out the liars. "If you could somehow measure [pain] would that be helpful? It would be helpful to me because I want to know if my patients are legitimate," Fudin says.
The research on brain imaging

Recent advances in brain-imaging technology have shown that the mind's secrets are sometimes surprisingly readable. For example, some researchers have used brain scanning to guess with some accuracy what shapes people are looking at or what type of object they were dreaming of: a building, a car, a person.

The main technique researchers are using is functional magnetic resonance imaging, or fMRI. An fMRI machine employs a giant magnet that can read where blood is in the brain. And because blood flows more to active brain areas, an fMRI scan can measure brain activity.

In the past few years, researchers have published studies showing that fMRI could determine whether someone is in pain.

In 2011, in a small study of 24 people, Mackey's group used advanced computer algorithms to show whether someone was receiving a painfully hot stimulus to his or her forearm with 81 percent accuracy. The observed differences in brain activity weren’t clustered in only one area, but in many, many places across the entire brain.
A pain test could help all kinds of people. One main group is those who can't speak for themselves.

In 2013, a paper led by Tor Wager, a neuroscientist at the University of Colorado Boulder, confirmed those findings in a bigger study published in a very prestigious journal: The New England Journal of Medicine. It involved 114 participants and correctly guessed whether someone was in pain about 95 percent of the time. Even more impressive was that the brain patterns seemed somewhat universal — that is, the algorithms were developed on one set of volunteers and then worked on another set that had never been scanned before.

Then in 2014, Mackey published another paper that looked at patients with chronic back pain, using still MRI images to examine brain structures rather than brain activity. He was able to produce an algorithm that guessed with 76 percent accuracy whether or not a brain was from a chronic back pain patient. A similar study published the same year identified people who had chronic pelvic pain with 73 percent accuracy.

Still images of brain structure like these could someday help chronic pain patients justify their condition, even though they don't show brain activity itself.

All of these new studies are still firmly in the realm of science, not medicine. These tools are not ready for use on patients to determine a course of treatment. Mackey estimates that that might be 10 years away.

The tests can't yet accurately predict someone's exact level of pain. And they've only been demonstrated within the confines of well-controlled laboratory studies.

In addition, most researchers don't believe that there's just one pain brain-activity pattern, but that different kinds of pain will end up producing different patterns. So, touching something hot might look different than the muscle pain of fibromyalgia, which might look different than chronic back pain. And that means that a lot more research will be needed before such technology could be used on the wide variety of painful health issues that exist.
The problems with an 'objective' pain test

Both Mackey and Wager see a lot of potential in using brain imaging as a research tool to better understand the various causes and types of pain — and to develop new ways to treat it. They think that such scans should only be used to confirm someone's pain, but never to go against their word and deny that they're in pain when they say that they are. That's because pain is defined as a subjective experience. And the brain scan is objective. So, to them, the brain scan is merely an objective marker of possible pain.

Another reason for that stance is that a person could be feeling a kind of pain that they haven't found the brain signature for yet. "It might not look like other people's pain, but it might be their pain," says Wager.

And, says Mackey, "There is the potential for abuse. There's always the potential for people misusing this technology for insurance purposes to deny care."

However, both researchers do support using the technology someday on people who can't say if they're in pain or not, like babies or some people with developmental disabilities. Because any evidence is better than nothing at all.

Another problem is that pain might be something that cannot be reduced to a bunch of neurons firing. "Some people believe that pain isn't simply some sum or algorithm of brain activity, it's an emergent property of brain activity," says Fillingim. "And maybe we won't figure out how the experience of pain emerges from some pattern of brain activity. And maybe the formula is different for different people."

"Could we similarly look at someone's brain and tell you how happy they are, how satisfied with life?" he asks. "These are all pretty high level experiences."

Another problem could come from brain-scan pain tests getting used in court. Some people approximate that awards for pain and suffering make up about half of personal injury damage awards. So there's big money on the line. "The legal system has a tremendous need for more objective ways of measuring pain," says Adam Kolber, a professor at Brooklyn Law School who has written extensively about the future ethical and legal implications of pain testing. "There is the potential for abuse. There's always the potential for people misusing this technology for insurance purposes to deny care."

He's not that concerned about how pain tests will be used in the long run. He notes that there are standards in place to stop new technology from becoming admissible evidence until it's fully developed. And he focuses on the positive side of what the technology could do: "This is a possibility of better compensating people who are in pain. I think that's promising."

But not everyone agrees. And Mark Sullivan is one of them. He's a psychiatrist and bioethicist at the University of Washington who specializes in treating patients with chronic pain. He's been one of the most vocal opponents of the drive to find objective measures of pain.

He's debated both Mackey and Wager in person at pain research meetings and debated on paper in the Journal of Pain in 2013. And he says he's concerned about people who are truly ill being denied workers' compensation and social security because nothing can be found on a brain scan: "You could easily see a situation where someone says, ‘Well, I can't work because I have terrible back pain.' And you stick them in an MRI scanner and it's ‘I don't see any evidence that you're in pain. So we're not going to give you disability payments anymore.'"

Whether it leads to good or bad outcomes, computing power, fMRI resolution, and data from patients will keep increasing. Technology will march on, and someday, someone is going to start selling something called an objective pain test, whether or not that's actually what it's capable of.

And no matter how accurate the test is or isn't, the images it produces could help pain become a more visible problem in health care. Pain isn't something that someone can see, like a physical wound. It can take numerous forms, making it easier for medical practitioners to ignore.

44-year-old Californian Elizabeth Schenk is one of the many patients who've had doctors ignore her agony. She used to be a pilates instructor, but her chronic pain has brought her into a new career counseling people with pain problems. At its worst, her pain has been excruciating: "like someone was dragging a knife down my thigh," and "like someone taking a hammer to my thumb," and "a chisel to my spine."

"What I've experienced in the medical world is that if they don't see anything, they won't do anything," she says. But brain imaging can put an image to the invisible. It can give them something to see.

http://www.vox.com/2014/10/15/6895171/how-doctors-measure-pain-brain-scan-fmri

Wednesday, 29 October 2014

The Pain Of Neuropathy

Today's short post from neuropathyresources.com (see link below) is one that many people living with severe neuropathy will recognise. It concerns how you, the pain sufferer, appear to others and although there's little you can do about it, it's good that someone puts this into words. Useful for friends and family to read and hopefully they will understand what you're going through a little better.


Never-Ending Pain 
David Dakroub 6th october 2014 


I want to explain what it is like to live with the type of nerve pain so common among individuals suffering from a neurological disorder. It is a hard to describe accurately without experiencing it yourself. This is because it is not just about the pain. It is also because the pain is relentless. It does not to ever seem to take a break, thereby leaving the sufferer bug-eyed and weary. This is horrible mental distress as much as physical.

The trickle down effect from the nonstop pain also spiders out into every facet of your life. Every relationship is different because of the difficulty it takes to communicate. It is like trying to carry on a conversation in a loud crowded subway. You must strain to hear what is being said to you with the screeching sound of pain trying to constantly interfere with the conversation. You will often be misunderstood by others as being uncaring and rude because of this.

The work you are trying to accomplish, at home or on the job, is disorganized and incomplete. Whatever you seem to do lacks any joy or sense of accomplishment. People misjudge you as being a poor or sloppy coworker. They wonder why you always look tired; they fail to realize the toll that pain is taking on your sleep.

The individual with this kind of pain has cluttered thoughts; he or she seems to live in a fog that will not clear. This person is tired of explaining himself because he knows it will do no good. After a repeated number of occurrences with people minimizing his attempts to explain his pain, he just keeps it all in. There is nobody in his life--coworkers, doctors, spouses, family, or friends--realizes he thinks of ending the pain everyday. There is not one person who would even understand this; nobody would understand why he feels like he is all alone in this world.

http://www.neuropathyresources.com/

Tuesday, 28 October 2014

Levaquin: A Danger For Neuropathy

Today's post from thomaslawoffices.com (see link below) is another warning post regarding one of the fluoroquinolones type of antibiotics - in this case, Levaquin. it is clearly written and leaves little room for doubt. If you're doctor is prescribing levaquin for you and you already have neuropathy or are in a risk group for getting neuropathy, you really should discuss it with him or her carefully. There are always alternatives and mounting evidence suggests that fluoroquinolones are best avoided due to their potential for causing nerve damage.


Levaquin Use Linked To Nerve Damage
 By Tad Thomas on October 22, 2014 -

 
A new study has shown that users of the antibiotic Levaquin and other drugs in its class can cause permanent nerve damage. Levaquin is manufactured by the Johnson and Johnson subsidiary Ortho-McNeil Pharmaceutical, Inc.

Levaquin is the brand name for the antibiotic levofloxacin. It is commonly used to treat infections in the prostate, urinary tract, and diabetic foot infections. It is part of a class of powerful antibiotics called fluoroquinolones. Other fluoroquinolone drugs include Cipro, Avelox, Noroxin, Floxin, and Factive.

While all antibiotics can present a risk of side effects, the fluoroquinolones are unique in their potential to penetrate the blood-brain barrier. This allows the drug to enter the brain and possibly damage the central nervous system.
FDA Upgrades Warnings

The U.S. Food and Drug Administration (FDA) first approved the drug in 1996. In 2003, generic brands of Cipro became available and then Levaquin became the most popular prescribed fluoroquinolone drug in the US.

In 2008, the FDA issued its first warning about the drug. It required makers of fluoroquinolones to put a warning on the label of a risk of tendon damage and rupture. A warning was added to Levaquin, but it stated that the risk was rare, and suggested it could be alleviated by stopping use of the drug. By 2011, J&J stopped marketing Levaquin because of its generic competition.

Then, in 2013, the FDA upgraded its warning. A number of adverse events had been reported that linked use of fluoroquinolones and nerve damage called peripheral neuropathy. A number of patients had suffered long-lasting nerve damage and disability. The FDA told the manufacturers they could no longer call the risks “rare” and had to state that the damage might be irreversible and can occur soon after the drugs are first taken. These dangers are believed to be present only with versions of the drug taken by mouth or by injection.
Peripheral Neuropathy

In its safety announcement, the FDA described peripheral neuropathy this way:


“Peripheral neuropathy is a nerve disorder occurring in the arms or legs. Symptoms include pain, burning, tingling, numbness, weakness, or a change in sensation to light touch, pain or temperature, or the sense of body position. It can occur at any time during treatment with fluoroquinolones and can last for months to years after the drug is stopped or be permanent.”

A 2014 study in Neurology, the journal of the American Academy of Neurology, provided more evidence of the link to nerve damage. The study found that current users of fluoroquinolones, especially new users, are at a higher risk of developing peripheral neuropathy. The authors advised doctors to weigh the benefits against the risk of adverse events before prescribing these drugs.

http://www.thomaslawoffices.com/blog/dangerous-drugs/levaquin-use-linked-nerve-damage/

Monday, 27 October 2014

Neuropathy Induced By Chemotherapy

Today's post from ncbi.nlm.nih.gov (all references can be seen on the original page by following the link below), is very long, very technical and probably only suitable for those who really want to go to the root of their problem but for those suffering from neuropathy as a result of chemotherapy, the information here is very useful. With the growth of cancers across the world, the incidence of neuropathy as a result of cancer treatment is also growing - it's very unfair but unfortunately something that many people have to face as being the lesser of two evils. 
 

Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature
Cancer Manag Res. 2014; 6: 135–147.
Published online Mar 19, 2014. doi: 10.2147/CMAR.S44261
PMCID: PMC3964029

Andreas A Argyriou,1,3 Athanasios P Kyritsis,2 Thomas Makatsoris,3 and Haralabos P Kalofonos3
Author information ► Copyright and License information ►
This article has been cited by other articles in PMC.

Abstract
Commonly used chemotherapeutic agents in oncology/hematology practice, causing toxic peripheral neuropathy, include taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. This review paper intends to put together and discuss the spectrum of chemotherapy-induced peripheral neuropathy (CIPN) characteristics so as to highlight areas of future research to pursue on the topic. Current knowledge shows that the pathogenesis of CIPN still remains elusive, mostly because there are several sites of involvement in the peripheral nervous system. In any case, it is acknowledged that the dorsal root ganglia of the primary sensory neurons are the most common neural targets of CIPN. Both the incidence and severity of CIPN are clinically under- and misreported, and it has been demonstrated that scoring CIPN with common toxicity scales is associated with significant inter-observer variability. Only a proportion of chemotherapy-treated patients develop treatment-emergent and persistent CIPN, and to date it has been impossible to predict high-and low-risk subjects even within groups who receive the same drug regimen. This issue has recently been investigated in the context of pharmacogenetic analyses, but these studies have not implemented a proper methodological approach and their results are inconsistent and not really clinically relevant. As such, a stringent approach has to be implemented to validate that information. Another open issue is that, at present, there is insufficient evidence to support the use of any of the already tested chemoprotective agents to prevent or limit CIPN. The results of comprehensive interventions, including clinical, neurophysiological, and pharmacogenetic approaches, are expected to produce a consistent advantage for both doctors and patients and thus allow the registration and analysis of reliable data on the true characteristics of CIPN, eventually leading to potential preventive and therapeutic interventions.
Keywords: neurotoxicity, incidence, diagnosis, treatment

Introduction

Chemotherapy drugs used to treat cancer can be neurotoxic by either exerting a direct noxious effect on the brain or the peripheral nerves.1,2 Nonetheless, chemotherapy-induced peripheral neurotoxicity (CIPN) is considered to be among the most common non-hematological adverse effects of a number of effective chemotherapeutic agents. Depending on its severity, CIPN can be dose limiting and may also significantly diminish the quality of life (QOL) of patients, because it can persist or even intensify long after the completion of chemotherapy.2 Moreover, the economic cost of neurotoxicity secondary to antineoplastic agents on health systems is significant, as cancer patients with CIPN have significant excess health care costs and resource use.3

CIPN can usually affect the dorsal root ganglia (DRG) of the primary sensory neurons, but other sites, ie, the nerve terminals (distal terminations of the branches of an axon), may also be involved. Its clinical features vary depending on the type of the offending agent involved and the site of action, ranging from pure sensory or sensory–motor peripheral nerve damage of large myelinated or small unmyelinated fibers. Damage to peripheral nerve systems from chemotherapy can present with or without autonomic impairment. Rarely, cranial nerve involvement occurs.4

The diagnosis of CIPN usually relies on traditional clinical grading scales, such as the World Health Organization (WHO), Ajani, and Eastern Cooperative Oncology Group (ECOG) scales.2,4 Nevertheless, the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) for sensory and motor neuropathy are considered to be the standard method for assessing CIPN. NCI-CTCAE version 3 grades its severity from 1) loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function/subjective weakness with no objective findings, to 4) permanent sensory loss that interferes with function/paralysis. Grade 5 is assigned to death from neurotoxicity. In summary, NCI-CTCAEv3 has been constructed to grade the severity of neurosensory and neuromotor symptoms with particular relevance to their interference with function. However, clinical experience shows that the use of NCI-CTCAEv3 is associated with underestimation of CIPN prevalence and severity.5 The newer NCI-CTCAEv4 was released in May 2009, and its most important difference when compared with version 3 is that NCI-CTCAEv4 harmonizes with the lowest level terms from the Medical Dictionary for Regulatory Activities (MedDRA), which are listed based on their MedDRA primary system organ class, eg, immune system disorders or nervous system disorders.6 One would expect that the changes in NCI-CTCAEv4 would impact the prevalence estimates of CIPN. However, this does not seem to be the case, because again, no formal neurological examination is required and grading of CIPN severity remains subjective, solely relying on patients’ reported symptoms. Moreover, the use of the same tool of peripheral sensory neuropathy as a separate item and addition of definitions, ie, dysesthesia, paresthesia, or neuralgia as distinct items seems to confuse rather than offer clarity.7

Alternatively to NCI-CTCAE, the 11-item neurotoxicity subscale (FACT/GOG-Ntx [Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity]) developed by the Gynecologic Oncology Group has also been used.8 However, significant inter-observer disagreement occurs in scoring CIPN with these scales and as such, initiatives have been launched to define the optimal outcome measures of CIPN assessment.9,10

Recently, the CI-PeriNoms (chemotherapy-induced peripheral neuropathy) study group reported initial validity and reliability findings for grading scales, such as the NCI-CTCAE, the Total Neuropathy Score clinical version (TNSc©), the modified Inflammatory Neuropathy Cause and Treatment (INCAT) scale, and the group sensory sum score (mISS).11 The TNSc, a shorter and more easily applied clinical version of the formal TNS, is a composite measure that includes symptoms, signs, and ability aspects, and its use is proposed because it appears superior to NCI-CTCAE in terms of responsiveness.1115

Furthermore, patients have reported a validated scale that has been used to assess CIPN in a more comprehensive and accurate manner: the Rasch-built Overall Disability Scale (CIPN-R-ODS), consisting of 28 items, was able to detect disability in CIPN patients with proper validity and reliability, and to bypass the difficulties with ordinal-based measures.16 In any case, it seems that clinical and patients’ reported outcome measures should always be combined to achieve a comprehensive knowledge of CIPN, including a reliable assessment of both the severity and the quality of CIPN-related sensory impairment.17

Commonly used chemotherapeutic agents in oncology/hematology practice causing peripheral neuropathy are taxanes, platinum compounds, vinca alkaloids, proteasome inhibitors, and antiangiogenic/immunomodulatory agents. We will herein review and discuss the spectrum of CIPN characteristics resulting from the administration of chemotherapeutic agents. Tables summarizing the common sites of involvement (Table 1), risk factors of CIPN (Table 2), as well as the type of neuropathy and clinical pattern of CIPN (Table 3) by neurotoxic drug classification are also presented. Additionally, we will highlight areas for future research to pursue.

Table 1
Common sites of involvement by neurotoxic drug classification

Table 2
Risk factors of CIPN by neurotoxic drug classification

Table 3
Type of neuropathy and clinical pattern of CIPN by neurotoxic drug classification

Taxanes (paclitaxel/docetaxel)

Pathogenesis


Conventionally, the mechanisms underlying the pathogenesis of taxane-induced peripheral neuropathy (TIPN) include interference with microtubule-based axonal transport, macrophage activation in both the DRG and peripheral nerve, as well as microglial activation within the spinal cord.18 As a result of the problematic signal transduction, there is evidence of a “dying back” process starting from the distal nerve endings followed by effects on Schwann cells and neuronal bodies, or disturbed axonal transport changes in the affected neurons.19,20


Recent evidence shows that the activation of spinal astrocytes and the inhibition of microtubule-based fast axonal transport may al so be significant contributors to TIPN.21 The structure of internodal myelin in peripheral nerves remains unaffected in TIPN.22

Incidence, severity, and risk factors

Paclitaxel appears to be more neurotoxic than docetaxel with an overall incidence of about 60% and 15% for each agent, respectively.23,24 Current evidence shows that the most important triggering factor of TIPN is the accumulation of doses over the course of chemotherapy with a neurotoxic threshold of 1,000 mg/m2 for paclitaxel and 400 mg/m2 for docetaxel.25 Grade 3–4 sensory neuropathy is much more common with paclitaxel than with docetaxel.2,26 The nanoparticle albumin-bound (Nab) form of paclitaxel was formulated to enable lower doses and reduce toxicity, but clinical experience shows that grade ≥2 peripheral neuropathy still remains a significant treatment-limiting toxicity.27,28

Other risk factors include prior or concomitant administration of platinum compounds, pre-existing peripheral neuropathy due to various medical conditions, and duration of infusion (1- to 3-hour infusion vs 24-hour infusion).29 The issue relating to the risk of neurotoxicity after the administration of weekly versus every 3 weeks paclitaxel treatment schedules has been conflictingly addressed. There was evidence to suggest that the risk is lower with the weekly paclitaxel schedule, while the opposite was demonstrated in other studies.30,31 The risk appears to be unrelated to advanced age.32

Clinical and electrophysiological characteristics


Usually, patients affected by TIPN complain of paresthesia, numbness, and/or neuropathic pain in a stocking-and-glove distribution. Clinical examination documents loss of proprioception and suppression or loss of deep tendon reflexes (DTRs).23 Nerve conduction studies reveal the decrease or abolishment of sensory responses in keeping with an axonal sensory neuropathy as a result of axonal loss from sensory nerves.33 The sural nerve is particularly affected.34 Motor involvement with reduction of compound muscle action potential responses and myopathy with proximal weakness is less frequently seen.35 The significance of sympathetic skin response to provide electrophysiological evidence of small fiber neuropathy in taxane-treated patients merits further study.36

Course of neurotoxicity

Symptoms usually improve or resolve within 3 months after the discontinuation of treatment, whereas severe symptoms may persist for a longer period.23,33

Options for treatment or prevention

Previous evidence in relation to the symptomatic management of painful TIPN shows that amitriptyline, glutamine, low-dose of oral prednisone, and gabapentin may alleviate the patients’ pain.4 Newer drugs, such as duloxetine alone or in combination with pregabalin have provided additional measures of success in reducing pain, myalgia, and arthralgia.37,38

Although several neuroprotective agents, including amifostine, glutamine, acetyl-l-carnitine, and vitamin E hold promise as possible neuroprotective factors, clinical data are still controversial and their routine use is currently not recommended in everyday clinical practice.3944
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Epothilones (ixabepilone/sagopilone)

Pathogenesis

Epothilones are able to evoke peripheral neuropathy by inducing tubulin polymerization into microtubules, by interfering with the normal process of anterograde and retrograde axonal transport.45,46 Additionally, it seems that epothilones are able to induce damage to the ganglion soma cells and peripheral neuroaxons through the disruption of microtubules of the mitotic spindle and by interfering with axonal transport and cytoplasmic flow in the affected neurons.47 Besides axonopathy, DRG changes have been demonstrated in epothilone-treated animal models.48

Incidence, severity, and risk factors

The neurotoxicity threshold for ixabepilone is reached at a dose of 40 mg/m2.49 Above that dose, a significant percentage of patients exposed to ixabepilone treatment, varying from 40%–88%, exhibit sensory peripheral neuropathy.50,51 The incidence of treatment-related advanced sensory or motor neurotoxicity can affect up to 24% and 5% of patients, respectively.5052

ZK-EPO (sagopilone), a third-generation epothilone B derivative, has been clinically tested in metastatic breast or platinum-resistant ovarian cancer patients, and safety data show that the incidence and severity of neurotoxicity was comparable to that of taxanes and ixabepilone.53 Sagopilone-induced peripheral neuropathy occurs in up to 81.5% of patients, usually in the form of a dose-related sensory neuropathy.54,55 The rates of treatment-emergent neurotoxicity are significant, as up to 16% of patients can experience grade 3 peripheral neuropathy.55

Clinical and electrophysiological characteristics

Both ixabepilone and sagopilone have been reported to produce a clinical and electrophysiological spectrum of neurotoxicity, similar to taxanes.49

Course of neurotoxicity

Current knowledge shows that recovery from neurotoxicity symptoms is relatively faster than the period required for the recovery from symptoms of taxane-related neuropathy; it usually takes only 4–6 weeks for grade 3–4 symptoms to improve by at least one NCI-CTCAE grade after the finalization of treatment with either ixabepilone or sagopilone.54,56

Options for treatment or prevention

To date, the literature has provided only weak evidence to support the use of any prophylactic treatment against ixabepilone-induced neurotoxicity.49 A quite recent Phase II European multicenter clinical trial failed to support the efficacy of acetyl-L-carnitine against the neurotoxicity induced by sagopilone, an analog of ixabepilone.57 Therefore, adherence to dose modification guidelines is clearly warranted.54,58
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Platinum compounds (cisplatin/carboplatin/oxaliplatin)

Pathogenesis

DRG represent the main structure that is affected by the deposition of platinum compounds, thereby generating neurotoxicity.59 Two putative mechanisms are primarily involved in platinum-induced neurotoxicity, and DRG neuron apoptosis is the common cornerstone.60,61

Firstly, they are able to alter the tertiary structure of DNA by forming intrastrand adducts and interstrand crosslinks.62 Moreover, it has been documented that the neuronal apoptosis on DRG could be triggered by oxidative stress, mitochondrial dysfunction with a release of the cytochrome-c pathway, independence of Fas receptor activation, or by increased activity of p53, p38, and ERK1/2.6366

The pathogenesis of oxaliplatin-induced neurotoxicity does not share the same characteristics, as this platinum compound induces two clinically distinct forms of neurotoxicity, namely acute and chronic. The chronic, sensory form is considered to be induced by the morphologic and functional changes in the DRG cells, resulting from the local deposition and accumulation of oxaliplatin. On the other hand, the acute form is thought to be caused by a dysfunction of nodal axonal voltage-gated Na+ channels, likely resulting from the oxalate chelating effect on both Ca2+ and Mg2+.67

Incidence, severity, and risk factors

For cisplatin, evidence of peripheral nerve damage of any grade has been reported in about 60% of patients receiving a total cumulative drug dose ranging from 225–500 mg/m2.2 However, only 10% of them experience treatment-emergent grade 3–4 neurotoxicity.68,69 The combination of cisplatin/paclitaxel exerts additive effects in producing neuropathy at higher rates than cisplatin monotherapy.33,70

Available data show that carboplatin is almost unrelated to peripheral neuropathy when given as monotherapy at an area under the curve of 6 (AUC6), while its administration at an AUC12 is not associated with the occurrence of grade 3–4 neurotoxicity.71,72 As such, carboplatin is definitely much less neurotoxic than cisplatin or oxaliplatin.2

As to the acute form of neurotoxicity induced by oxaliplatin, it is generally acknowledged that the vast majority of patients treated with various oxaliplatin-based regimens at a dose ranging from 85–130 mg/m2 experience some grade of neurotoxicity.4,73,74 Severe acute OXLIPN (oxaliplatin-induced peripheral neuropathy) that requires prolongation of oxaliplatin infusion or treatment discontinuation may occur in up to 22% of treated patients.75 Cold temperatures and the time of oxaliplatin infusion are the main risk factors of acute OXLIPN.76

On the other hand, the overall rate of neurosensory symptoms in the context of chronic oxaliplatin-induced neurotoxicity (OXAIPN) can range from 60%–75% in patients assigned to be treated with oxaliplatin-based regiments, including FOLFOX4, FOLFOX6, or XELOX.77,78 Data from large studies show that treatment-emergent grade 3–4 neurotoxicity can occur in up to 20% of oxaliplatin-treated patients, but it can be predicted by clinical and neurophysiological information obtained at mid-treatment.77,79

The cumulative oxaliplatin dose, time of infusion, and the existence of peripheral neuropathy prior to the initiation of chemotherapy rank among the most important triggers of chronic OXAIPN genesis.80 In addition to these well-known risk factors, recent evidence from a large homogeneous series of colorectal cancer patients showed that patients who have a more complex combination of acute phenomena related to axonal hyperexcitability are those who eventually develop more severe chronic neurotoxicity.75 Furthermore, it seems that the chemotherapy regimen may also represent a risk factor of OXAIPN. This view was supported by a recently published study, which documented that XELOX may be the preferable regimen to avoid the more severe neurotoxicity associated with FOLFOX, despite comparable oxaliplatin cumulative dose.81 Advanced age does not seem to represent a significant risk factor of OXAIPN in patients without any other significant comorbidity.82

Clinical and electrophysiological characteristics

The clinical spectrum of cisplatin-induced peripheral neuropathy is comprised of sensory symptoms in a stocking-and-glove distribution, decreased vibration, and proprioception and suppression or loss of DTRs. Neurophysiology is in keeping with an axonal sensory peripheral neuropathy with a decrease or abolishment of sensory action potentials and normal sensory conduction velocities.4,33

Signs and symptoms of acute OXLIPN may begin during the infusion or within 1–2 days of oxaliplatin administration and mostly include distal and perioral cold-induced paresthesias and dysesthesias. However, other uncommon symptoms, such as shortness of breath, jaw spasm, fasciculations, cramps, and difficulty swallowing may also be present at significant rates. Voice and visual changes, ptosis, and pseudo-laryngospasm rarely occur.83 Recording of repetitive compound action potentials, high-frequency discharges of motor unit multiplets, and bursts of muscle fiber action potentials are evident during nerve conduction study and needle electromyography examination. This pattern is in keeping with neuromyotonia as a result of excessive nerve excitability, distally attenuated.84 The clinical and neurophysiological characteristics of chronic OXLIPN are generally similar to those of cisplatin.2

Long-term outcome

Although there are few specifically designed studies to assess the long-term course of platinum-induced neurotoxicity, it is expected to improve or completely resolve within 1 year after the discontinuation of treatment. However, there have been cases in which CIPN remained persistent or at best, partially reversible, because of the “coasting” phenomenon resulting from the capacity of platinum compounds to accumulate in DRG for a long time.25

Options for treatment or prevention

Based on results from randomized controlled trials (RCTs), there are no effective symptomatic treatments, and only duloxetine at a dose of 60 mg per day has been shown in a well-designed RCT to be effective in alleviating oxaliplatin-associated neuropathic pain.37 As to prophylaxis, there have been insufficient data thus far, to support the use of any candidate chemoprotective agents, such as acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, or vitamin E to prevent or limit the neurotoxicity of platinum compounds.85 As such, adherence to the non-pharmacological stop-and-go approach (ie, intermittent oxaliplatin dosing) may be warranted to prevent platinum compound-induced peripheral neuropathy, particularly OXAIPN.86
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Vinca alkaloids (vincristine)

Pathogenesis


Vincristine detrimentally affects both fast- and slow-conducting peripheral nerve fibers by interfering with axonal transport at the level of the cell body and alterations in the cellular microtubuli structure.87

Incidence, severity, and risk factors

Vincristine-induced peripheral neuropathy is dose dependent, as up to 60% of patients may develop a clinically significant (grade 1–2) primarily sensory or sensorimotor neuropathy at vincristine cumulative doses between 30–50 mg.88

Clinical and electrophysiological characteristics


At the initial stage, the clinical manifestations of vincristine-induced peripheral neuropathy include bilateral and symmetrical painful paresthesia and hyperesthesia, distally attenuated. Muscle cramps and mild distal weakness are frequently seen. Neurological examination reveals proprioception and DTR abnormalities. Autonomic dysfunction is frequently seen in vincristine-treated patients, with evidence of orthostatic hypotension, constipation, and erectile impotence. Few cases of cranial nerve palsies have been reported while patients were being treated with chemotherapy using vincristine.89 Nerve conduction abnormalities are in keeping with a length-dependent axonal sensory or sensorimotor peripheral neuropathy.90

Long-term outcome

Neurotoxic symptoms of vincristine are reversible after discontinuation of treatment.88 However, off-therapy worsening of neurotoxic symptoms and signs might unexpectedly occur.91

Options for treatment or prevention

To date, there has been insufficient evidence to recommend the use of any neuroprotectant against vincristine-induced peripheral neuropathy in clinical practice.2
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Binding of growth factor inhibitors (suramin)

Pathogenesis

The cardinal pathogenetic hallmark of suramin neurotoxicity is the axonal degeneration in DRG and the accumulation of glycolipid lysosomal inclusions, probably because of the competition between suramin and nerve growth factor (NGF) at the high-affinity NGF receptor.92

Incidence, severity, and risk factors

Suramin-induced peripheral neuropathy is dose dependent, as up to 60% of patients may develop a clinically significant (grade 1–2) primarily sensory or sensorimotor neuropathy at suramin plasma peak levels higher than 350 μg/mL.93

Clinical and electrophysiological characteristics

At the initial stage, the clinical manifestations of suramin-induced peripheral neuropathy include bilateral and symmetrical painful paresthesia and hyperesthesia, distally attenuated. Neurological examination reveals proprioception and DTR abnormalities. Nerve conduction abnormalities are in keeping with a length-dependent axonal sensory or sensorimotor peripheral neuropathy.93 Single case reports of subacute demyelinating and inflammatory polyneuropathy secondary to suramin therapy have also been occasionally published.94

Long-term outcome

Neurotoxic symptoms of suramin are usually reversible after discontinuation of treatment.93

Options for treatment or prevention

To date, none of the candidate neuroprotective agents have been proven effective to treat suramin-induced peripheral neuropathy.2
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Proteasome inhibitors (bortezomib)

Pathogenesis

The pathogenetic hallmark of bortezomib-induced peripheral neuropathy (BIPN) consists of morphological alterations in the spinal cord, DRG, and peripheral nerves with specific functional alterations in Aδ and C peripheral nerve fibers.95,96 In addition, proteasome inhibition, increased a-tubulin polymerization, mitochondrial and endoplasmic reticulum damage, and dysregulation of neurotrophins through inhibition of NFkB activation may also significantly contribute to BIPN genesis.9799

Incidence, severity, and risk factors

The incidence of clinically significant, ie, grade 1–2 BIPN, can occur in up to 75% patients with multiple myeloma who have relapsed after or were refractory to frontline therapy, while treatment emergent grade 3–4 neurotoxicity may appear in 12% of bortezomib-treated patients.100,101 BIPN is usually exacerbated in patients with pre-existing neuropathy and comorbidities associated with peripheral nerve damage.98,102 However, the cumulative dose effect of bortezomib remains the main triggering factor of BIPN, although the severity of neurotoxicity is escalated until the completion of the first five cycles of bortezomib administration and thereafter remains stable.103

Bortezomib administered subcutaneously rather than intravenously has an improved safety profile and appears to be ideal for patients with pre-existing neuropathy or at a high risk of developing neurotoxicity. In a large randomized, Phase III, non-inferiority study enrolling 222 patients with relapsed multiple myeloma (148 on subcutaneous versus (vs) 74 patients on intravenous bortezomib), it was documented that peripheral neuropathy of any grade (38% vs 53%; P=0.044), grade ≥2 (24% vs 41%; P=0.012), and grade ≥3 (6% vs 16%; P=0.026) was significantly less common with subcutaneous than with intravenous administration.104

Clinical and electrophysiological characteristics


The cardinal symptom of BIPN is neuropathic pain and paresthesias in distal extremities of limbs, in keeping with a painful neuropathy due to dysfunction in all three major fiber (Aβ, Aδ, and C) types of sensory nerves, as demonstrated in both clinical and animal models.95,105 Neurological examination reveals distal sensory loss to all modalities and changes in proprioception, while DTRs are either suppressed or absent. Nerve conduction study usually reveals typical findings of CIPN consistent with a distal, sensory, axonal neuronopathy. Motor involvement is occasionally present. Reversal of BIPN usually occurs after a median interval of 3 months following the discontinuation of bortezomib treatment, but it may persist for up to 2 years or remain indefinitely in some cases.98,103

Options for treatment or prevention

Lafutidine, a H2-blocker with gastroprotective activity, may be able to prevent or improve BIPN, based on the results of a recently published small case series of eight patients.106 However, the protective activity of lafutidine against BIPN needs to be further demonstrated in large RCTs. As such, there is no proven effective prophylactic treatment to prevent the development of BIPN, and medication towards this aspect is merely symptomatic.98 Therefore, likewise to the case of EIPN, adherence to the dose-modification guidelines is advised.
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Antiangiogenic/immunomodulatory agents (thalidomide/lenalidomide/pomalidomide)

Pathogenesis

Neurotoxicity is considered to be generated by both thalidomide and lenalidomide as either the result of their antiangiogenic properties with a reduction of nerve blood supply or because of functional and metabolic changes in the DRG. Dysregulation of neurotrophin activity may also play a significant role in the pathogenesis of neurotoxicity.107

Incidence, severity, and risk factors

Quoting the results of an analysis of clinical trials assessing the efficacy and safety of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma, the overall incidence of PN can range up to 44%, with a rate of early treatment discontinuation of about 15%.108 Moreover, another meta-analysis of safety data after thalidomide monotherapy in multiple myeloma patients revealed that the rate of treatment-emergent neurotoxicity (grade 3–4) was 6%, whereas according to the same report, there is no well-established factor to increase the risk of thalidomide-induced neurotoxicity.109

Lenalidomide appears to be less neurotoxic and better tolerated than thalidomide at a dose of 30 mg/day in relapsed/refractory multiple myeloma patients, with only 3% of significant grade 3 neurotoxicity after the completion of chemotherapy.110,111

Orally administered pomalidomide was recently approved by the US Food and Drug Administration for use in multiple myeloma patients who have received at least two prior therapies, including lenalidomide and bortezomib, and whose disease did not respond to treatment and progressed within 60 days of the last treatment. Grade 1–2 peripheral neurotoxicity can occasionally (up to 9% of patients) be seen but no grade 3–4 peripheral neuropathy was reported in large RCTs testing the efficacy and safety of this agent.112,113

Clinical and electrophysiological characteristics

The clinical and neurophysiological characteristics of neurotoxicity secondary to thalidomide, lenalidomide, and pomalidomide are generally similar to those of bortezomib.107

Options for treatment or prevention

The symptomatic treatment of painful peripheral neuropathy secondary to these agents does not differ from that of BIPN.107
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Other drugs less commonly associated with CIPN

Fluorouracil or 5-FU is a pyrimidine analog, and peripheral neuropathy associated with its administration is unusual. Anyhow, the literature contains a small series of two patients experiencing neurotoxicity while they were receiving chemotherapy with 5-FU.114 Gemcitabine may occasionally evoke peripheral neuropathy with paresthesias and myalgias, whereas neurotoxicity rarely occurs while patients are treated with methotrexate, cytosine arabinoside (Ara-C), or topoisomerase inhibitors, such as irinotecan or topotecan.25
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Rehabilitation and complementary/alternative therapies against CIPN

CIPN can significantly undermine the daily living activities and QOL of patients. Sensory ataxia is a common clinical phenomenon in the context of neuronopathies and it is associated with unsteady gait and impaired balance and coordination, as well as poor mobility. As a consequence, falls may occur in a significant proportion of cancer survivors. An increased risk of falls was associated with the degree of CIPN, particularly with evidence of sensory ataxia and severe muscle weakness.115

A variety of rehabilitative methods, such as balance and gait retraining as well as the use of gait aids and orthotics, have been tested with positive effects to prevent falls in patients with peripheral neuropathies and to assist them in adapting their activities and their environment.116 Both aerobic and resistance exercise, mindfulness, occupational therapy, and environmental planning are also proposed among effective self-management strategies in reducing the impact of CIPN symptoms.117

Acupuncture is the most widely used complementary intervention in CIPN subjects. However, a recently published meta-analysis of clinical studies found that there is no evidence to support the use of acupuncture for treating CIPN, and further studies with robust methodology are needed before one can conclude with confidence about its true usefulness.118 Supplementation with single medical herbs or herbal combinations might hold promise for its ability to exert neuroprotection or neuroregeneration in CIPN. However, it is similar to acupuncture in that the level of evidence is at present too low to establish a standard practice.119
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CIPN in the era of pharmacogenetics

Although candidate gene approaches have been launched during the last decade to extract results from single nuclear polymorphisms (SNPs) in genes involved in the pharmacokinetic and pharmacodynamic properties of neurotoxic drugs, no reliable biomarker has thus far been identified to detect patients at high risk of developing CIPN. In the past, several SNPs have been reported to be associated with CIPN. For instance, SNPs in genes involved in the pharmacokinetic, transport, and pharmacodynamic properties of taxanes have been shown to be relevant for TIPN.120,121 Likewise, increased susceptibility to peripheral neurotoxicity after exposure to oxaliplatin and other platinum compounds has been associated with pharmacogenetic variations in genes encoding for drug transporters, detoxification enzymes, genes involved in DNA repair mechanisms, and integrin B3 Leu33Pro polymorphism.122124

However, the results of most previous pharmacogenetic studies focused on oxaliplatin were limited, and with several methodological flaws, including small sample size, retrospective study design, and the implementation of a post-hoc analysis of oncology-based databases of different, not pre-planned sizes. Other major limitations of these studies include the lack of a pre-study hypothesis based on the known role of the investigated targets in the peripheral nervous system and the inappropriate outcome measures for neurological impairment.122,123,125

A recently published collaborative international study attempted to overcome all of those limitations, thoroughly investigating a series of SNPs in genes coding for neurologically relevant targets in an adequately powered, prospective cohort of well-characterized patients, such as the voltage-gated sodium channels (SCNA). The results of this study provided evidence to support a causal relationship between SCN4A and SCN10A polymorphisms and increased incidence and/or severity of oxaliplatin-induced peripheral neuropathy.78 Further SCNA SNPs, such as the SCN2A R19K polymorphism, have been previously investigated with negative results.126

Other polymorphisms in genes involved with immune function, reflexive coupling within Schwann cells, drug binding, neuron function, and steroid hormone biosynthesis have been associated with BIPN.127,128 Table 4 summarizes genetic biomarkers that have been linked with liability to CIPN, by neurotoxic drug classification.

Table 4
Genetic biomarkers linked to CIPN by neurotoxic drug classification

Conclusion and future perspectives for research

CIPN is one of the most severe adverse effects of treatment, with a significant impact on the QOL of affected patients, mostly because the long-term effects of the persistence of symptoms/signs cannot be estimated. In the framework of promoting cancer therapies with fewer adverse effects, there are several open issues to be addressed in the future.

Important clinically relevant questions include: how to measure the incidence of neurotoxicity; how to grade the severity of the peripheral neuropathy; how to estimate its long-term course after the discontinuation of chemotherapy; and how to utilize this information clinically. An additional important issue is to determine reliable biomarkers to allow prompt identification of patients at high risk to develop CIPN. To address these gaps in knowledge, further large systematic prospective collection of data on CIPN is needed, comprising a comprehensive set of reliable clinical assessments and patient-reported outcomes, with the support of focused neurophysiological examinations, skin biopsies, and DNA analysis. Of note, skin biopsy may be a useful tool to examine the clinical applicability and correlation of intraepidermal nerve fiber density in CIPN with other clinical outcome measures, eventually leading to both possible preventive and therapeutic intervention.129

The results of such interventions would significantly contribute to improved comfort and QOL of cancer survivors. Proper and well-evaluated approaches would also produce a consistent advantage for both doctors and patients to allow the registration and analysis of reliable data on the incidence, prevalence, risk factors, and long-term impact of CIPN, eventually leading to both potential preventive and therapeutic multidimensional interventions.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964029/

Sunday, 26 October 2014

Tips From Neuropathy Sufferers

Today's post from myelomacrowd.org (see link below) is a facebook reaction to someone asking for ideas as to how to best control her neuropathic symptoms. As you can see, there is a huge range of answers and it has to be pointed out that certain things work for certain people but that's no guarantee they'll work for you. It would also be unwise to choose any one for yourself without consulting your doctor first; everybody reacts differently to different drugs and there's no 'one size fits all' solution I'm afraid. What the article does do is give you some ideas of what to look into and discuss with your doctor. Remember also, lyrica is not recommended for people with HIV-related neuropathy and every drug has side effects to be taken into account.

I have neuropathy in my feet, hands, and legs. Is there help?
Lizzy October 2014

Neuropathy is that painful, numb feeling in legs, hands, and feet. Because the extremities are numb, you can also hurt or cut yourself and not even know what. We asked our Facebook friends how they cope with it. Here’s what they said:

Shirley E:
I have neuropathy and vasculitis which I have numbness to my knees. I stopped Lyrica due to blurred vision. I take Tylenol for pain and also potassium gluconate for cramps. I find sleeping on my back and elevating my legs on pillows at a 45-degree angle helps. It relieves numbness and back pain. I pray and read my Bible right before sleeping and find that praising the Lord gets my mind on Him and He helps me get my mind off of my problems.

Sonya L:
Lyrica, Alpha Lipoic Acid, B12, and stronger depending on if I can’t deal with the pain. As for shoes, Crocs have been my go-to of choice.

Victor S: I need to be careful to not let my feet or hands get too cold.

Jeanine M: Alpha lipoic acid, b-12, b-2, b-6. Marinol

Chris P: Lyrica and Crocs

Julie B: Neuropathy was first “symptom” of multiple Myeloma—both in my arms and hands, later legs and feet. Worse after sct and tx. Numbness, burning, shooting pains and sensory loss. Also had extreme swelling. Pain meds help. I have learned to live with it. Massage helps and seems to desensitize feet and hands especially. I take plaquenel (a malaria med) for swelling and inflammation, which has mostly resolved that.

Frances V: My hubby had it bad. He took Lyrica. He would not let me touch his feel to rub them with anything. Pain meds helped some.

Patti S: Howard has it in his hands and feet. He takes tramadol and gabapentin. He wears a fentynal patch and takes oxy for the breakthrough pain. Sounds like a lot, but keeps it down.

Julie W: I’ve had it forever it seems and it’s HORRIBLE!!! Started out on Amitriptyline and Neurontin. When I maxed out on those, they changed me to Lyrica. The Lyrica worked GREAT, but made me a disoriented mess and I couldn’t drive! But I had to go back to original meds, but they didn’t work anymore! I was changed to Nortriptyline and Neurontin and have gotten about 80% relief! I had my first visual of how bad my feet have gotten yesterday. I bumped my foot on a chair. It didn’t hurt at all. I went to the bathroom, came back out and when I reclined in my chair, I noticed that half my nail was gone on that toe! I didn’t feel it at all…still don’t!

Pamela C: My husband Sam has neuropathy in his feet… That’s actually how we found out he had multiple myeloma. Thankfully, it’s been three years and two back-to-back transplants later, but the neuropathy hasn’t worsened. At night he puts Vics Vapor rub on his feet and slips some socks on. I breathe better and he sleeps better. Sounds weird, but it helps the stinging.

Donna D
: Cymbalta 60 mg every other day. Walking and exercise.

Kathy C: I just have smoldering multiple myeloma – MRI’s a few weeks ago show no myeloma and lab work O.K. But I have the peripheral neuralgia and lots of arthritis pain. My doctor put me on cymbalta about 6-8 weeks ago but I hate the dizzy groggy feeling (60 mg).

Sandy W: I got neuropathy in my feet and ankles from taking thalidomide. I take Lyrica for it. I was taking 600 MG a day but I cut back to 150 at night and just live with the discomfort during the day.

Lillie K: I take neurotin 300 mg 3 or 4 times a day. It helps some. I can sure tell when I haven’t taken the neurontin. I have the burning pain yet numbness. It is worse in my feet and hands. My back hurts very badly.

Dorothy G: I take 400mg 4x a day of gabepentiin every day, I also take topamax along with that, 200mg every day.

Chris G: I take gabapentin and duloxetine (Cymbalta) and that helps as long as I am not on my feet for too long on hard surfaces. I have not found any shoes that I can tolerate very well. The cushioning always seems to be in the wrong place…the heel, not the ball of the foot.

Joanne V: Yup and nothing works. I will not put anymore toxins in my body.

Julie v: I had neuropathy really bad for months after my auto SCT. It slowly subsided over the years, but never fully disappeared and continues on, as I continue on with Revlimid 10mg. Best advise I have… keep moving as best you can! WALK, walk, walk!! And HYDRATE all the time! Water, water, water and I also mix 100% cranberry/juice blends with water and sparking water.

Lin C:
I did, as I get further out from chemo, it seems to be dissipating. I feel blessed!

Sharon H: gabapinten

Londa L: I take Neurotin 600mg 3 x a day

Ginger F: My hubby has neuropathy really bad from his thighs to his feet. He uses flex aril to help and a heating pad when it get really bad.

Olga G
: I take Gabapentin 300 mg 3 times daily. My symptoms are numbness, burning sensation, and sharp pain.

Patty S: My husband takes neurotin and amitryptaline

Sherrill F: Neurontin

Vicky N
: I am on Tylenol 4 x5 a day minimum

Beverly M: I have it in my toes, I massage them a lot, and love summer when I can wear open shoes, which feels much better.

Frederick D
: For neuropathy make sure that you take ALL B VITAMINS. They are important for nerve function. STANDARD PROCESS is the gold standard for quality vitamins. Their vitamins are 100% all natural and contain B4 which is missing in most all commercial vitamins. Alpha or R-Lipoic Acid, N acetyl cysteine, l carnitine– excellent anti oxidants to prevent free radical damage. Also consider taking serrapeptase or nattokinase for proper blood circulation.

Diana L: gabapentin

Dave F: I take Gebapentin, which takes the edge off of it but I still have numb toes. I was prescribed EMLA cream and it works ok but it’s a bit messy to apply.

Lizzy S: Peppermint essential oils mixed with fractionated coconut oil rubbed on my feet and calves every morning. I never go barefoot. In the summer, I live in flip flops and in the winter, it’s Uggs all the way.

Mike H:
I had neuropathy so horribly by the time I went home after ASCT I couldn’t return to work. Tried gabapentin, lyrica & cymbalta. I finally went to a higher dose of cymbalta to keep it reigned in, but still need oxycodone to be able to have a sort of normalcy.

Angela W:
I take metanx or L-methyl B6-B12. It seems to help some. I still use a pain patch that I hope will come off soon.

Bianca B:
I’m using Bebapentin. It does help but I still feel it, especially at night.

Migdalia B: My husband takes oxyconden and oxycontin for the pain!

Aliece T
: I take the OxyContin and Lyrica when pain is at its worse, which is usually in middle of night. My husband has to massage my hand and I run it under hot water.

Sarah L
: I have neuropathy in my forefoot. Fortunately it’s the numb kind, not the pain kind, but occasionally the nerves get irritated and it itches like crazy. The only thing that helps that is Bert’s Bees hand salve. I think the eucalyptus oil in it is soothing to the nerves.

Kim S:
Vitamin B6 has helped me. I was also told fish oil and amino acid helps.

Kevin G: I have it BAD as well. I went to a pain doctor and I’m doing a thing called NEUROSTIMALTION THERAPY. It basically tricks your brain from feeling the pain. Two small (50 cent piece size) probes in your back. One up by the shoulders and the other by other hips. Sends electric pulses that you can control the speed and strength to your hands and feet. No need for Fentanyl patches or OxyContin anymore. It does wonders for the pain

Mark B:
I have it bad after my recent stem cell transplant. I have tried icy hot patches on my feet, tylenol, and nuerontin. I was also told to try riding an exercise bike to increase blood flow which help a little but that was before my transplant. I haven’t found a solution.

Kevin G
: Exercise helps me (walking and riding a bike), lots of WATER 12oz an hour that is what I try to do. I’m in the restroom a lot.

Lisa K:
I do IVIG and I take 1800 Gabapentin. I also take 15 MG morphine sulfate as needed at bed time 50 Nortriptyline.

Maria P: My husband has it really bad to the point where it’s too painful to walk. Gabapentin did not work. Lyrica was 150.00 on my insurance (couldn’t afford it). Heating pad works temporarily. He takes morphine 25mg in the am and 25mg in the pm, also dilaudid 4mg as needed, b complex and lots of water. He’s up trying to walk a little more than before. We were told not to be inpatient it will get better.

Donna F
: Gabapentin works for me. It was so bad in my feet I couldn’t even walk. If I try to cut back I can tell the difference right away!!

Michael C
: I had neuropathy and they prescribed Gabapentin. Had it for about 3 months then it just went away.

Sonya L
: Lyrica, Alpha lipoic acid, oxy…

Teddy T: I use Gabapentin too and I also wear socks to bed and that helps at night. If your feet are worse when lying down then what’s happening is it’s in your back that’s triggering the neuropathy. Our vertebrae deplete with MM and it might be causing a pinched nerve that’s hitting your feet. I notice if I move around and add more pillows, I can get comfy. If you get up and the pain goes away when you walk around, then it’s in your back so tell the doctor and maybe they can get you some shots of steroid from a pain clinic. It works for me and I also noticed my Neuropathy isn’t as bad.

Donna P: I have had C.I.D.P. (Chronic Inflammatory Demyelinating Polyneuropathy) for 15 years and I was having I.V.I.G every 3 mounts. I had a stem cell transplant because of my Multiple Myeloma and now my C.I.D.P. isn’t as bad, my doctor has me on Neurontin 300mg twice a day. So far it is working.

Joni S: Using Gabapentin 1100mg 3x a day, for bilateral peripheral neuropathy. I take 150mg Elavil at night. Fentanyl 25mg patch change q48hrs. Oxycodone 5mg as needed for breakthrough pain. When I do my Neupogen injection I have increased pain in bilateral femurs & sacral pain (had pathological stress fracture across my sacrum).

Sara G: My mother has reversed her mild neuropathy with toe tapping. She does it twice daily as often as she can.

Liz S: Mine is much better thanks to accupuncture, neurotin, alpha lipoic acid.

Michelle L: They’re starting me on lyrica

Peter W: I am using lyrica, morning and night to mask neuropathic pain in my feet. It works fairly well masking about 75% of the pain.

Cathy S
: I’ve been using gabapentin, three times a day. Doesn’t take it away completely but I’m satisfied.

Karen K: I got severe neuropathy from valcade five years ago. I take neurotic three times a day. It is helpful but I can’t exercise like I want to. Bike riding is the best for me.

Janice R: Mine started with chemo, and got really bad at the sct. Both feet and legs, both hands and fingers. Gabanentin caused hallucinations. Nortriptyline helps a little. Can get insurance company to approve Lyrica. Went to a program with a chiropractor that was 3 months, not covered by insurance was 4k. Had vibration, laser and tens electrical. Had some exercising. It also helped a bit. Now have it in feet, and ankles, and fingers above the last joint. Hard to walk, picking up things is hard, but at least I don’t have the constant pain. I feel lucky with no pain.

Rhonda T: They gave me lyrica but I haven’t started yet. I have it bad in my feet. It caused me to have a bad fall on the sidewalk. I had to use a cane for a month.

Barb M:
After my SCT my legs started to get better – now almost 6 months post – I have very little discomfort. You will get thru it – it sucks right now but try to take as many breaks as possible and don’t put yourself in a situation that you can’t sit down right away. Good Luck.

Susan D:
My husband has peripheral neuropathy in both feet. He is 7 years post auto sct. 10mg maintenance revl. Walking walking walking helps. Recently having a little dizziness on standing but passes. Then out with the dog again.

Silvia O: Oxicodone, massage and walking helps a little but I think there’s no cure for neuropathy.

Kathy A: Neurontin 300mg TID and cutting Velcade to 50% dosage has helped greatly. Just a little annoying numbness in toes now. Tart cherry juice at bedtime and I’m sleeping better than I have for years. Which helps my energy level, too.

Joanne L: I take 300mg of Gabapentin 3 times a day for the neuropathy. I have it mostly in my hands and arms. It’s a real pain. I have to stop every 10 minutes or so and let my arms hang until the numbness goes away. Some days are better than others, but when it’s bad…it’s bad!!! Stay Positive and stay strong!

Susan A:
I got some neuropathy from Velcade, some numbness in my feet. After SCT it was worse. 2+ years later it has gotten much worse with sharp pains and all over aching. Tried neurontin and Lyrica, which did nothing. Now on Cymbalta which may be helping a little. Doctor gave me a compounded cream.


About Lizzy
Lizzy was diagnosed with Multiple Myeloma in January 2012. Upon learning of her illness, she promptly left her husband and moved to Utah with her two children and entered treatment. Following a tandem stem cell transplant regiment, she is doing well and is in maintenance therapy. She chronicles her journey at www.lizzysmilez.blogspot.com. 

 
http://www.myelomacrowd.org/neuropathy-feet-hangs-legs-help/